Role and clinical significance of TGF‑β1 and TGF‑βR1 in malignant tumors (Review)
- Authors:
- Published online on: February 15, 2021 https://doi.org/10.3892/ijmm.2021.4888
- Article Number: 55
-
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
1. Introduction
Transforming growth factor-β (TGF-β) is a complicated polypeptide that exerts essential effects on cell cycle regulation, growth and development, differentiation, extracellular matrix (ECM) synthesis, hematopoiesis, chemotaxis and the immune response (1-3). TGF-β1 and TGF-β receptor 1 (TGF-βR1) serve important roles in the TGF-β family, and have irreplaceable effects on cell reproductive capacity, growth, wound regeneration and immunological reactions (4,5). Almost all cells in the body, not only the epithelium and lymphocytes, but also the stroma, cellular immunity and endotheliocytes, are associated with tumor occurrence and development (6,7). Furthermore, most tumor cells express TGF-β1 and TGF-βR1 (8-10). Previous studies have found that cancer cells create an environment that hinders the immune response by producing factors, such as TGF-β1, to evade T-cell surveillance (11,12). Other studies have revealed that TGF-β1 can cause epithelial-mesenchymal transformation (EMT), resulting in increased migration of cancer cells (13,14). TGF-βR1 is an irreplaceable downstream molecule of TGF-β1 that participates in the entire life cycle of cells, including cell movement, differentiation, adsorption, fission and death (4,15). Mutant cells that lack TGF-βR1 do not respond to TGF-β1, which further affects the transduction of the TGF-β signaling pathway (16,17). Additionally, the activation or overexpression of TGF-βR1 is observed in different types of tumor and can serve an important role in tumor cell proliferation and migration to other tissues by taking part in EMT (18), such as in colon (19) and gastric cancer (20). Previous studies (20-22) have revealed that TGF-βR1 is observed in different types of tumor and serves an important role in tumor metastasis by participating in cancer development, cell migration and blood vessel regeneration, leading to unsatisfactory responses to treatment.
The present review primarily discusses the impact of TGF-β1 and TGF-βR1 on malignant tumors, to offer different strategies to restrain and cure these tumors.
Methods
Literature searches of PubMed/MEDLINE (https://pubmed.ncbi.nlm.nih.gov/) for relevant articles published between January 1995 and October 2020 were performed using the key term combinations of 'TGF-β1', 'TGF-βR1', 'transforming growth factor-β1', 'transforming growth factor-β receptor1', 'ALK5', 'TGF-β1' with 'tumor', 'TGF-βR1' with 'tumor', 'TGF-β1' with 'cancer', 'TGF-βR1' with 'cancer', 'TGF-β1' with 'inhibitor', 'TGF-βR1' with 'inhibitor' or 'ALK5' with 'inhibitor'. Studies associated with breast cancer, gastric cancer, colon cancer, hepatocellular carcinoma, thyroid cancer, leukemia, cervical cancer, ovarian cancer, lung cancer and inhibitors of TGF-β1 and TGF-βR1 were selected from the search results. Moreover, to identify clinical progress on inhibitor research, the terms 'LY2382770', 'LY2157299', 'TEW-7197' or 'LY3200882' were searched for at https://clinicaltrials.gov/.
2. TGF-β family and its signaling pathway
The TGF-β superfamily is a class of structural and functional polypeptide growth factor subfamilies, including bone morphogenetic protein, growth differentiation factor, anti-Mullerian tube hormone, activin Nodal and TGF-β (4,23). Since TGF-β was first isolated from serum-free culture medium of mouse sarcoma virus-transformed embryonic fibroblasts in 1978, five subtypes of TGF-β have been identified, namely TGF-β1-5. However, only TGF-β1/2/3 exist in mammals (24). These three growth factors have 70-82% homology at the amino acid level, but their functions are distinct, with TGF-β1 being the most important (25). TGF-βR exists on the cell surface and has high affinity for TGF-β (26). According to the features and roles of the receptor, it can be divided into TGF-βR1 (or ALK-5), TGF-βR2 and TGF-βR3 (27,28). At present, seven types of TGF-βR1 and five types of TGF-βR2 have been identified in humans (29). TGF-β signaling positively influences early embryonic growth and tissue and organ formation, immune supervision, tissue repair and adult cell homeostasis (30). Abnormal TGF-β cell signaling transduction pathways are finely regulated at different levels, including ligands, receptors, Smad and nuclear transcription. In the classical Smad signaling pathway (Fig. 1), TGF-β family cytokines first induce serine/threonine kinase receptors on the cell membrane to form functional complexes: two TGF-βR2 and two TGF-βR1 (31,32). Subsequently, TGF-βR2 phosphorylates the domains of glycine and serine in TGF-βR1, activating the kinase activity of TGF-βR1, which then phosphorylates Smad2 and Smad3, binding them to Smad4 and resulting in the synthesis of Smad compounds, nuclear transport and Smad-DNA binding (30). Next, Smad mediates the transcription of target gene DNA to RNA, together with the general transcription factor, other transcription factors or helper proteins (2,33). Additionally, TGF-β can exert signal transduction through non-Smad pathways (Fig. 1). To date, these pathways primarily include the RhoA-Rock1, RAS, ShcA, ERK1/2 and MAPK signaling pathways (34,35).
3. Function and structure of TGF-β1 and TGF-βR1
In mammals, the TGF-β family uses 33 genes to encode a polypeptide, a predomain of 250 residues and a structural domain of growth factors composed of 110 residues (24). TGF-β1 is an important member of the cytokine TGF-β superfamily and is located on chromosome 19q3 (30). Mature TGF-β1 is composed of 112 amino acids and contains nine highly conserved cysteine residues at the C-terminus, which form the rigid structure of cysteine through disulfide linkages (36). TGF-β1 exerts a critical effect on cellular development with respect to cell proliferation, differentiation, adsorption and programmed cell death (37).
The generation and secretion of TGF-β1 is based on latency-associated peptide (LAP), which is a potentially inactive compound with a large predomain and a dimeric non-covalent binding TGF-β1 growth factor domain (36). Latent TGF-β1 is activated through coordination with its binding protein. Latent TGF-β binding proteins (LTBPs) consist of four subtypes (LTBP-1, LTBP-2, LTBP-3 and LTBP-4), which covalently bind to LAP through disulfide bonds to form a potential complex with pre-TGF-β1 (38). Once hydrolyzed by proteases or LAP interactions with integrin αvβ3, αvβ5 or αvβ8, TGF-β1 can combine with downstream receptors (15).
At present, seven types of TGF-β1 receptors and five types of TGF-β2 receptors have been identified in humans (29). The TGF-β1 receptor contains seven protein activin receptor-like kinases (ALK1-ALK7), and ALK5 is also known as TGF-βR1 (39). TGF-βR1, an essential molecule in the TGF-β signaling pathway with a weight of 53 kDa, phosphorylates serine or threonine in downstream signaling proteins; it consists of a signal peptide, a hydrophilic extracellular region, a transmembrane domain and an intracellular region (27,30). The extracellular region contains multiple cysteines and has a glycosyl slip site; the intracellular region near the membrane contains a region rich in glycine and serine that is associated with its autophosphorylation (40). On the other hand, there is a segment rich in serine/threonine in the intracellular region of TGF-βR2 that can phosphorylate TGF-βR1 during signal transduction, activating the TGF-βR1 kinase region, further phosphorylating downstream substrates and transferring the TGF-β signal into cells (2) (Fig. 2).
4. TGF-β, TGF-βR1 and malignant tumors
In vivo, the development of malignant tumors is a complicated process that is regulated by a variety of genes. Numerous tumor suppressor genes serve a role through TGF-β1 signaling (41), while TGF-β1 acts through different pathways, such as ERK1/2, NF-κB, PUMA and p21WAF1 (42-44). TGF-β1 regulates the cell cycle, induces apoptosis and inhibits cell proliferation to inhibit the progression of tumors in healthy and precancerous epithelial cells (3); however, this does not always prevent cancer cells from surviving and successfully spreading to other tissues, since in some cases, when the TGF-β1 signaling pathway is altered, it can affect other signaling pathways or cell signaling molecules (1,45).
Some studies have demonstrated that TGF-β1 expression is increased in prostate cancer (46), ovarian cancer (47), hepatocellular carcinoma (12), bladder cancer (48), breast cancer (49) and cholangiocarcinoma (50), suggesting that abnormal TGF-β1 expression can influence tumor invasiveness and result in a poor prognosis. Regarding TGF-βR1, a previous study has found that it promotes tumor angiogenesis by upregulating matrix metalloproteinase 9 in metastatic human melanoma cells (51) Moreover, changes in TGF-βR have been observed in numerous types of human tumors, such as breast (52,53), colon (54) and gastric cancer (20), and are characterized by gene mutations, decreased levels or inactivation of TGF-βR. TGF-βR1 mutations have been reported in malignant tumors of the ovary, breast and pancreas, as well as in colon cancer (16,52-56). These findings all suggest that TGF-βR mutations serve an important role in the genesis and progression of tumors (57). The functions of TGF-β and TGF-βR1 can be either direct or indirect in the pathogenesis of some tumors (Table I).
Breast cancer (BC)
Worldwide, BC is one of the most common types of cancer in women, with high mortality and recurrence rates (58,59). Although numerous efforts have been made to increase the quality of treatment for BC, the 5-year survival rate of patients after metastasis is 27% (60).
TGF-β1 is well known to regulate the development, differentiation, carcinogenesis and tumor progression of breast epithelial cells. TGF-β1 was first identified as a regulatory factor of BC >20 years ago (49). Previous studies have revealed that TGF-β1 promotes BC metastasis by promoting EMT in tumor cells (61,62). These cells lose epithelial characteristics during EMT, as well as cell polarity and adhesion, developing migratory and invasive capacities (63). It has been demonstrated that microRNAs (miRNAs/miRs) are key factors in the growth and metastasis of numerous invasive tumors (64), and TGF-β1 signaling is associated with miRNAs (65-67). Compared with benign proliferative breast diseases, TGF-β1 upregulates miR-21 expression, but it downregulates miR-196A-3p expression (66,68). miR-21 expression is significantly upregulated in BC (66). A series of steps to promote tumor development through miR-21 occur via mutual interaction with tumor suppressor genes, such as PTEN (66). Thus, the process of TGF-β1 upregulating miR-21 expression and miR-21 interacting with tumor suppressor genes promotes the progression and therapy resistance of BC (66). The downregulation of miR-196A-3p by TGF-β1 is associated with the progression of BC and is a biomarker for predicting BC metastasis and patient survival (68). However, Wang et al (63) revealed that overexpression of miR-133b markedly restrained the function of TGF-βR1 in TGF-β1/Smad signal transduction and inhibited TGF-β induced endometrial stromal transformation and BC cell invasion in vitro.
In addition, a previous study has demonstrated that TGF-β1 can regulate the expression of C-X-C motif chemokine receptor 4 (CXCR4) in MCF-7 BC cells, which has a critical effect on the metastasis of BC (69). Moreover, the upstream regulator of the TGF-β1/Smad3 signaling pathway in BC is hypoxia-inducible factor-1 (HIF-1), which regulates the proliferation and apoptosis of BC cells (70). Furthermore, another study has revealed that leptin mediates the metastatic invasiveness and cancer stem cell behavior of BC cells via binding TGF-β1 and its receptor (71), which may explain why women with BC who are obese or overweight have a poor prognosis according to epidemiological studies (72,73).
Catteau et al (74) performed CD34, smooth muscle actin (SMA), TGF-β1 and TGF-β1 immunohistochemical experiments on 155 cases of invasive BC and 10 cases of normal breast tissue, and treated breast fibroblast cell lines with TGF-β1. The results showed that TGF-β1 was highly expressed in tumor cells and that TGF-βR1 was highly expressed in tumor stroma compared with in normal breast tissue (74). TGF-β1 can induce the transformation of breast fibroblasts to SMA-positive fibroblasts, and this transformation process is associated with the invasion of BC cells (74). From a genetic point of view, Moore-Smith and Pasche (52) have demonstrated that TGF-βR1*6A is a common low-deformation variant of TGF-βR1, which is associated with the risk of numerous types of cancer, especially BC. Patients with the TGF-βR1*6A allele have a higher risk of BC; in addition, functional analysis revealed that the aforementioned mutation changes the TGF-β signaling pathway and promotes tumorigenesis (52,53,75). Rosman et al (53) demonstrated that TGF-βR1*6A enhanced MCF-7 cell migration and invasion by activating the RhoA and ERK signaling pathways.
Colon cancer (CC)
CC is a common type of cancer of the digestive system (76). Colorectal cancer is the third most common cause of cancer-associated death in both men and women in the United States according to the American Cancer Society, with ~147,950 individuals diagnosed with CRC and 53,200 who died from the disease in 2020 (77). In previous years, some studies have revealed that TGF-β1 and TGF-βR1 are significantly associated with the risk of developing human colorectal cancer and may have great importance in tumor metastasis (19,78,79). It is generally believed that TGF-β1 can restrain the proliferation of tumor cells since it suppresses the proliferation of epithelial cells in vitro; additionally, TGF-β1 promotes ECM remodeling, which may regulate the mutual effect between tumor cells and the matrix/epithelial cell differentiation (80). Furthermore, TGF-β1 is an effective regulator of immune and inflammatory cells (81). By regulating the function of immune cells, TGF-β1 is thought to decrease the production of local growth factors and relieve tissue damage caused by free radicals (82,83). Therefore, controlling the proliferation and differentiation of epithelial cells and cell-matrix mutual effects, and keeping organisms away from genetic damage caused by inflammatory cells may serve a large role in the occurrence, acceleration or formation of CC (80-83). The long non-coding (lnc)RNA mortal obligate RNA transcript (MORT) is inhibited in numerous types of human cancer (84), such as ovarian, gastric and colon cancer, indicating its role as a tumor suppressor. Zhou et al (85) has revealed that TGF-β1 increases the invasiveness and mobility of CC cells, while lncRNA MORT stops CC cells from invading and migrating by inactivating TGF-β1.
BAG-1 is a multifunctional protein associated with the heat shock response, cell signal transduction, cell survival and apoptosis (86). A previous study has found that BAG-1 expression is upregulated during the relatively early stages of colorectal tumorigenesis (87). Notably, BAG-1 is thought to promote the progression of colorectal tumors by inhibiting TGF-β1 to allow more tumor cells to avoid death (87). Neuropilins were originally thought to be neuron receptors and were later found to be co-receptors for cancer-associated growth factors. The neuropilin family consists of two genes, neuropilin-1 and neuropilin-2 (88). Grandclement et al (19) revealed that neuropilin-2 was the receptor of TGF-β1 through surface isomer resonance experiments. It was demonstrated that the synergistic action of neuropilin-2 and TGF-βR1 facilitated EMT in colorectal cancer cells (19). However, Huang et al (89) revealed that TGF-β1 induced glutathione peroxidase-1 (GPx-1), which is an antioxidant enzyme (90), expression and enzyme activity by activating TGF-βR1/Smad2/ERK1/2/HIF-1α signaling cascades, and this GPx-1 upregulation protects human colon adenocarcinoma DLD-1 cells or colorectal cancer cells from oxidative damage. TGF-β1 and TNF-α also induce EMT in CC cells through the NF-κB signaling pathway (91).
Slattery et al (54) identified several high-risk alleles in the TGF-β signaling family, including in TGF-β1 and TGF-βR1, in 1,553 patients with CC and 754 patients with rectal cancer, demonstrating that these high-risk alleles increase the possibility of death after a definite diagnosis of CC or rectal cancer. Moreover, a slight decrease in the expression of one allele (the TGF-βRA IVS7G+24A minor allele) of the TGF-βR1 gene is a risk factor for CC (92). Another study has shown that TGFBR1*6A, a subtype of TGF-βR1, enhances the propensity of SW48 cells for metastasis through the MAPK signaling pathway, which may participate in the development of colorectal cancer independently of TGF-β/Smad signaling (93). This indicates that TGF-βR1*6A exerts a carcinogenic function and has an important impact on the migration and invasion of CC cells (93).
Gastric cancer (GC)
GC is a malignant neoplasm of the alimentary canal that derives from the gastric mucosal epithelium (94). GC accounted for 5.7% of global cancer cases, and its death rate (8.2%) ranked second among all cancer cases according to the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer (IARC) (95). At present, the pathogenesis of GC has not been entirely elucidated, and previous studies have demonstrated that multiple genes and regulatory factors are associated with the occurrence and progression of solid tumors, such as GC (96,97). Abnormalities in any part of the TGF-β/Smad signaling pathway may lead to signal transduction disorders, which lead to the development and progression of GC (98). Some studies have shown that TGF-β1 and TGF-βR1 are highly expressed in GC and are associated with the initiation, development and metastasis of GC (20,99,100). Yanagihara and Tsumuraya (101) have demonstrated that TGF-β1 restrains proliferation and leads to apoptosis of the GC cell lines HSC-39 and HSC-43 in vitro. It has been speculated that TGF-β1 may regulate the metastatic ability of GC cells by facilitating the destruction and penetration of the basement membrane barrier, and the adhesion and activity of GC cells (102). Therefore, blocking the TGF-β1 signaling pathway may inhibit the invasion and migration of GC cells. Furthermore, immunosuppression mediated by regulatory T cells (Tregs) is an important mechanism of tumor immune escape, as well as the primary obstacle to the success of tumor immunotherapy (103). A previous study has suggested that GC may gain strength by inducing Tregs under hypoxic conditions through the TGF-β signaling pathway, allowing tumor cells to escape immunosurveillance (104). In addition, increased Tregs in the tumor are critically associated with a poor prognosis in patients with GC (105). A previous study has demonstrated that TGF-β1 can downregulate miR-193b expression in GC cell lines, and that miR-193b can downregulate urokinase-type plasminogen activator protein expression in GC cells to promote the invasion and peritoneal metastasis of GC cells (106). In addition, some studies have revealed that the enhanced motility of tumor cells, tumor development and metastasis are associated with the ERK signaling pathway (107-109). TGF-β1 mediates the ERK signaling pathway in GC with the participation of CD133 (107).
He et al (20) conducted a retrospective study of TGF-βR1 genotyping polymorphisms in 479 patients with GC and 483 healthy individuals. The results revealed that two polymorphisms (rs334348 and rs10512263) in TGF-βR1 were associated with a high risk of GC, while rs1927911 and rs10512263 were associated with decreased survival of patients with GC (20). Zhang et al (22) performed circular RNA expression profiling and cell culture experiments on GC tissue samples, revealing that TGF-βR1 was overexpressed in GC tissues and that circular RNAs promoted the proliferation, invasion, migration and EMT of GC cells through the regulation by miR-331-3p of TGF-βR1 mRNA and protein expression.
In addition to the aforementioned studies, an increasing number of studies have confirmed a significant impact of TGF-β1 and TGF-βR1 expression on the biological behavior of malignant tumors, which is closely associated with prognosis (56,75,78).
Hepatocellular carcinoma (HCC)
HCC is associated with more than half of the cases of primary liver cancer, ranking sixth among the most frequent types of cancer worldwide and third in cancer-associated deaths according to the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the IARC (95). The occurrence of liver cancer, like other malignant tumors, is a complex process of multistep, multifactorial and multilink interactions. In recent years, some studies have begun to focus their attention on the TGF-β signaling pathway in HCC (110-112). Numerous studies have demonstrated that TGF-β1 and TGF-βR1 expression has critical impacts on the growth, metastasis, invasion and prognosis of liver cancer (32,111-114). Peng et al (12) analyzed the association between TGF-β1 expression and clinicopathological characteristics in patients with HCC using The Cancer Genome Atlas, and assessed the impact of TGF-β1 expression on the ability to recover after treatment. The results demonstrated that increased expression levels of TGF-β1 promoted a poor prognosis in patients with HCC (12). TGF-β1 expression is significantly upregulated in HCC tissues and regulates the tumor microenvironment by stimulating angiogenesis, increasing tumor cell adhesion and immunosuppression, or inducing Treg production to promote tumor invasion and metastasis (115). EMT has a critical effect on the development and metastasis of human cancer. TGF-β1 induces EMT and promotes HepG2 cells to metastasize and invade other tissues through JAK/STAT3/Twist signal transduction (111). Moreover, the TGF-β1/miR-140-5p axis promotes EMT in liver cell carcinoma by regulating the Flap endonuclease 1 (67). In addition, TGF-β1 affects the interaction between HCC-derived stromal cells and liver-derived microvascular endothelial cells by downregulating the expression levels of neural cell adhesion molecule, in this way promoting vascular changes induced by HCC (116). Another study has reported that TGF-β1 activates miR-135a-5p to downregulate Krüppel-like factor 4 (KLF4) to promote proliferation and metastasis of HCC cells (117). KLF4, a zinc finger transcription factor, can regulate the cell cycle, proliferation and apoptosis (118), and inhibit tumor growth in HCC (119). In addition, Zhang et al (120) have demonstrated that TGF-β1 targets the Hippo signaling pathway by regulating a series of key proteins, such as large tumor suppressor 1 and Yes-association protein 1; this process inhibits the proliferation of hepatoma cells.
Zhang et al (121) confirmed TGF-βR1 as a new target gene of miR-4458 through dual-luciferase reporter gene analysis and revealed that miR-4458 inhibited EMT in liver cancer cells by targeting TGF-βR1 to inhibit the TGF-β signaling pathway.
Thyroid cancer (TC)
TC represents a group of malignant tumors that primarily originate from follicular cells, which are the main components of the thyroid unicellular epithelium. Anaplastic TC (ATC) is the main cause of death among all malignant thyroid tumors, and the median survival time of patients is ~6 months (122). The tolerance of ATC to routine treatment of TC, including surgery and radioiodine and thyrotropin inhibition, results in a very unsatisfactory therapeutic effect (123). At present, effective means to treat ATC have not been identified, and therefore the survival rate of patients has not improved for >60 years (124). In TC, it has been demonstrated that high expression levels of TGF-β1 closely affect TC development (125,126). TGF-β1 promotes apoptosis of ATC cells via TGF-β/ERK1/2/NF-κB/PUMA signaling (127). Additionally, TGF-β1 upregulates the expression levels of high mobility group A1 (128), which belongs to the superfamily of non-histone chromatin-binding proteins, serves an important role in multiple cellular biology processes through the PI3K/Akt signaling pathway and upregulates lncRNA-ATB expression to promote TC cell proliferation, migration and invasion (129). miRNAs are also critical factors in the occurrence and growth of numerous tumors. For example, Zhang et al (126) found that miR-483-3p targeting par-3 family cell polarity regulator induced TGF-β1 to promote ATC cell migration, invasion and EMT. Notably, Li et al (130) found that epigallocatechin-3-gallate significantly inhibited the invasion and migration of ATC8505C cells in vitro by mediating EMT and the TGF-β/Smad signaling pathway.
For TGF-βR1, it has been found that solute carrier family 35 member F2 activates the MAPK signaling pathway by targeting the phosphorylation of TGF-βR1 and apoptosis signal-regulating kinase 1, accelerating the proliferation and migration of thyroid papillary carcinoma cells (131).
Leukemia
Leukemia is a type of malignant clonal disease of hematopoietic stem cells (132). Due to uncontrolled proliferation, impaired differentiation and inhibition of apoptosis, clonal leukemia cells proliferate and accumulate in the bone marrow and other hematopoietic tissues, leading to infiltration of other non-hematopoietic tissues and organs, and inhibition of normal hematopoietic functions (133). According to the degree of differentiation of leukemia, the natural course of disease can be divided into acute and chronic leukemia (134). Although the cure rate of acute lymphoblastic leukemia (ALL) in children is ~90%, the outcome and rescue rate of high-risk subgroups remain poor (135). TGF-β1 protein has multiple effects on the entire process of hematopoiesis; it can have proliferative or anti-proliferative effects in different types of cells over time (136,137). Therefore, TGF-β1 and its downstream molecules have long provided new orientation for the treatment of blood cancers. TGF-β1 is expressed in numerous human acute myeloid leukemia (AML) cell lines, such as OCI-AML-1, AML-193 and THP-1 cells, and TGF-β1 affects their proliferation and differentiation through both autocrine and paracrine pathways (138). Natural killer (NK) cells serve a critical role in the inborn immunoreaction of malignant tumors, including leukemia (139). Tumor cells can destroy NK cells by regulating their surface receptors and releasing soluble immunosuppressive substances, including IL-10 and TGF-β (140). Rouce et al (141) found that ALL fibroblasts caused NK changes to help them escape innate immune system surveillance by mediating the TGF-β/Smad signaling pathway.
In the early stage of leukemia, megakaryocytes can produce excessive TGF-β1 and directly upregulate early growth response 3 expression to interfere with the development of normal hematopoietic stem cells in patients with AML (142). This process may provide an effective therapeutic target for improving normal hematopoiesis in AML (142). Ma et al (5) found that leucine-rich repeat containing protein 33, a cell membrane-associated protein, formed complexes with pro-TGF-β1 and regulated the function of TGF-β1 in AML cells and other myeloid malignancies. However, to the best of our knowledge, no studies have investigated the mechanism of TGF-βR1 in leukemia.
Lung cancer
Lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer, is the dominant cause of cancer-associated death worldwide according to the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the IARC (95). Modern treatment primarily depends on radiotherapy and chemotherapy (143). NSCLC is the major type of lung cancer and is a severe public health issue in China and in numerous developing countries (144). More than half of patients with NSCLC experience tumor recurrence after surgical resection, and the survival rate of these patients is low (145). TGF-β1 is closely associated with EMT in epithelial cancers, including NSCLC. Li et al (146) found that the interaction between heterogeneous ribonucleoprotein K (HnRNP K) and microtubule-associated protein 1B-light chain 1 promoted the transformation of lung cancer cells from epithelial to mesenchymal cells mediated by TGF-β1. Shi et al (147) investigated the function of hematopoietic pre-B-cell leukemia transcription factor-interacting protein (HPIP) in the transformation of A549 lung cancer cells induced by TGF-β1 in vitro, revealing that HPIP silencing significantly decreased the transformation, migration or invasion of A549 cells mediated by TGF-β1, which makes HPIP a new potential target for lung cancer treatment.
Previous studies have demonstrated that miRNAs have critical effects on the early diagnosis and treatment of NSCLC. It has been demonstrated that overexpression of miR-29c inhibits the Sp1/TGF-β axis, which induces lung cancer endothelial cells to metastasize (148). miR-144-3p suppresses the metastasis and adhesion of lung carcinoma cells induced by TGF-β1 by meditating the Src-Akt-Erk signaling pathway (149). AWPPH is a recently discovered lncRNA with carcinogenic effects in HCC and bladder cancer (150,151). Tang et al (152) revealed that AWPPH upregulated TGF-β1 expression, promoting long-term recurrence after NSCLC.
Kim et al (21) found that transcription factor activation enhancer binding protein 2c, which is part of the transcription factor AP-2 family, induced TGF-βR1 upregulation, promoted cell migration and led to malignant development of lung cancer. Jiang et al (18) recently discovered that a member of the let-7 miRNA family, miR-98-5p, decreased tumor development and transformation by inhibiting TGF-βR1 and EMT in NSCLC. Notably, SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) regulates the degradation of TGF-βR1, so that it can be used as a negative adjustment factor in TGF-β signaling (153). Chae et al (153) revealed that miR-195 and miR-497 inhibited tumor development by suppressing ubiquitination-mediated degradation of TGF-βR1 through SMURF2, and suggested that they may be used as latent effective targets for the treatment of lung cancer.
Cervical cancer
In recent years, with the improvements in screening and diagnostic techniques and the development of new vaccines, both the prevalence and mortality rates of cervical cancer have decreased; however, cervical cancer ranked fourth in morbidity (6.6%) and mortality (7.5%) rates among all female cancer cases according to the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the IARC (95). The pathogenesis of cervical cancer is complex and human papilloma virus (HPV) is considered one of the main risk factors (154). Development of EMT is a critical reason for the progression of primary cervical cancer, increased invasiveness and insensitivity to chemotherapy (155). TGF-β1 can regulate the development of EMT and is considered to be the driving force of EMT in cervical cancer (156). Yang et al (157) reported that semaphorin 4C (Sema4C) downregulation inhibited cervical cancer cell EMT, invasion and metastasis, possibly by inhibiting TGF-β1-induced activation of p38 MAPK in HeLa cells. However, Li et al (156) found that p68 promoted EMT in cervical cancer cells through transcriptional activation of the TGF-β1 signaling pathway. Cheng et al (158) revealed that miR-106b was highly expressed in human cervical cancer tissues, and miR-106b targeting disabled-2 (DAB2) genes enhanced TGF-β1-induced HeLa cell migration and promoted cervical cancer progression. DAB2 is a multimodular scaffold protein with signaling roles in cell proliferation and differentiation (159). Some studies have shown that TGF-β1 promotes the development and metastasis of cervical cancer by regulating its role in the tumor microenvironment (160-162). Moreover, TGF-β1 facilitates maspin expression in cervical cancer cells through Smad and non-Smad signaling pathways (163). Recently, miRNAs involved in cancer progression have come into focus. Studies have demonstrated that carcinogenic HPV infection influences the levels of multiple miRNAs in cervical cancer and cervical intraepithelial neoplasia (154,164,165). Cheng et al (158) demonstrated that high levels of miR-106b promoted cervical carcinoma cell metastasis by inducing TGF-β1. Notably, it has been demonstrated that interference with the lncRNA CDKN2B-AS1 upregulates the miR-181a-5p/TGF-β1 axis, inhibiting metastasis of cervical carcinoma cells and accelerating apoptosis and senescence (166). Additionally, let-7a restrains cell proliferation in cervical carcinoma through the TGF-β/Smad signaling pathway (167).
Fang et al (168) indicated that miR-27a served an anti-cancer role in cervical carcinoma, especially adenocarcinoma, by suppressing the TGF-βR1 signaling pathway. Therefore, enhancement of miR-27a expression and function may be considered as a new therapeutic modality for cervical carcinoma.
Ovarian cancer (OC)
OC ranked 8th in mortality (4.4%) among all female cancer cases in 2018 (95). At the time of diagnosis, 75-80% of patients with OC are at stage III/IV disease, since early disease is often asymptomatic (169). Studies have demonstrated that TGF-β1 has carcinogenic activity in different types of cancer, including OC (48,128,169,170). It has been reported that ubiquitin-specific protease 22 (USP22) facilitates tumor cell proliferation and development of epithelial OC (EOC) by cooperating with TGF-β1 (171). USP22 serves the role of an oncogene in EOC and may therefore represent a new treatment strategy for individualized EOC therapy. Additionally, it has been reported that ID-1, a member of the inhibitor of differentiation protein family, promotes the development of OC cells by promoting TGF-β1-induced EMT in human OC cells (172). Notably, TGF-β1 induces CD8+ Tregs in the OC microenvironment through the p38 MAPK signaling pathway; Tregs are highly enriched in the tumor microenvironment and contribute to cancer progression and immune escape (173). The increased CD8+ Tregs may help OC cells escape immune surveillance (169). Moreover, TGF-β1 stimulation increases the expression levels of miR-520h in EOC cells by upregulating its transcription factor c-Myb (a DNA-binding transcription factor), and miR-520h promotes the progression of EOC by downregulating Smad7 and then activating the TGF-β signaling pathway (174).
For TGF-βR1, Baxter et al (16) found that carrying TGF-βR1*6A alleles increased the risk of OC in women in case-control studies, but the mechanism of this process remains unclear (16,175).
5. TGF-β1 and TGF-βR1 inhibitors as treatment
TGF-β1 and TGF-βR1 in the TGF-β signaling pathway exert multiple functions in regulating tumorigenesis, tumor growth and metastasis. Different inhibitors have been developed for potential anticancer treatments. Numerous inhibitors have been developed against TGF-βR1 or TGF-β1 (Table II), such as LY2382770 (176), LY2157299 (galunisertib) (177-182), TEW-7197 (183,184) and LY3200882 (185), which have entered experimental clinical research.
LY2382770 is a TGF-β1 inhibitor for the treatment of diabetic nephropathy and diabetic glomerulosclerosis currently in phase II clinical research (176). LY2157299 is a TGF-βR1 inhibitor currently in development as a drug for the treatment of myelodysplastic syndromes (MDS) in phase II/III (NCT0008318), HCC in phase II (NCT012246986), pancreatic cancer in phase I (NCT02154646) and NSCLC in phase I/II clinical studies (NCT02423343). LY2157299 is the only small molecule inhibitor of TGF-βR currently in a phase III clinical trial (177-182). TEW-7197 (vactosertib), an ALK5 kinase inhibitor developed by MedPacto, is currently undergoing phase II clinical trials for MDS and phase I clinical trials for advanced solid tumors, such as melanoma, BC, HCC and prostate cancer (183,184). LY3200882 is another highly selective small molecule ALK5 inhibitor developed by Eli Lilly and Company that competitively binds to the ATP-binding site of the ALK5 kinase domain; a phase I clinical trial for healthy participants has been completed in 2019 (NCT03792139) and participants for a phase I clinical trial for solid tumors are currently being recruited (185).
However, some inhibitors are in the preclinical phase of experimental research, such as SB-431542 (186-188), LY2109761 (189,190), SD208 (191), SB505154 (192), GW6604 (193), EW-7203 (194), Ki26894 (195) and SM16 (196) (Table II). LY2109761 completely inhibits the phosphorylation of Smad2 mediated by TGF-β and has indicated antitumor effects in pancreatic cancer models (189,190). SM16 is a new oral bioavailable kinase inhibitor that combines with the ATP-binding pocket of ALK5, inhibiting its activation (196). SD-208 suppresses the proliferation and migration of mouse and human glioma cells, and enhances their immunogenicity by suppressing ALK-5 autophosphorylation (191). EW-7203 inhibits TGF-βR1 kinase activity, efficiently inhibiting TGF-β1-induced Smad signaling, EMT and BC metastasis to the lung in vivo (194). Further inhibitors should be developed for the clinical treatment of malignant tumors in the future.
6. Conclusion and perspectives
The TGF-β signaling pathway serves an important role in cell cycle regulation, growth and development, differentiation, ECM synthesis, hematopoiesis, chemotaxis and immune response (1-3). In recent years, studies on malignant tumors have revealed that TGF-β1 and TGF-βR1 may serve important roles in tumor occurrence and development, including in promoting tumor angiogenesis, invasion, EMT and immune escape (4,5,197). Increased expression levels of miR-331-3p (22), HnRNP K (146), Sema4C (157) and p68 (156), and the activation of the JAK/STAT3/Twist (111), NF-κB (127) and TGF-β signaling pathways in tumor cells can promote proliferation, migration and EMT through the action of TGF-β1 or TGF-βR1. Increased levels of some molecules, such as miR-133b (63), miR-4458 and miR-27a (168), inhibit the progression of tumors by acting on TGF-β1 or TGF-βR1. The increased levels of TGF-β1 in the tumor itself lead to increases in miR-21, CXCR4, SMA and ECM remodeling, activation of ERK, TGF-β/Smad and NF-κB signaling pathways, and a decrease of growth factors, miR-196A-3p, miR-193b and KLF4 expression, which promote tumor progression (66,68,69,117,198). On the other hand, self-mutation of TGF-βR1 is considered to promote tumor development through the MAPK signaling pathway (93). Some inhibitors have been developed for both TGF-β1 and TGF-βR1, including LY2157299, TEW-7197 and LY3200882 (177-185). LY2157299 specifically downregulates phosphorylation of Smad2 protein induced by TGF-β1, and significantly inhibits the proliferation and migration of cancer cells (177-182). TEW-7197 (183,184) and LY3200882 (185) competitively bind to the ATP-binding site of the intracellular kinase domain of ALK5 to produce kinase inhibitory activity. These inhibitors are currently in clinical trials. Additionally, there are some inhibitors that can block the activity of ALK5, which are currently in preclinical research, such as SB-431542, LY2109761 and SD208 (186-191).
Therefore, TGF-β1 and TGF-βR1 seem to have dual effects on tumors. With the development of molecular biology, the dual mechanism of TGF-β1 inhibition and promotion in tumors is becoming increasingly clear, but the mechanism of TGF-βR1 in tumors remains unclear. At the same time, it has been difficult to clarify the mechanism of TGF-β1 from tumor suppressor to tumor promoter. However, most studies have indicated that malignant tumors proliferate, metastasize, invade, undergo EMT and escape immune surveillance by acting on TGF-β1 or TGF-βR1. With the development of clinical trials in the future, the understanding of TGF-β1 and TGF-βR1 will become more comprehensive. Further exploration of the association between TGF-β1 and TGF-βR1, and the mechanism of the occurrence and development of malignant tumors will provide useful information for the discovery of new therapeutic targets.
Availability of data and materials
Not applicable.
Authors' contributions
JW wrote the manuscript. JW, YL, HX and TW investigated the roles of TGF-β1 and TGF-βR1 in tumors. JW and TW are responsible for confirming the authenticity of the data. TW supervised and revised the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Acknowledgments
Not applicable.
References
|
Massagué J: TGF-β signaling in development and disease. FEBS Lett. 586:18332012. View Article : Google Scholar | |
|
Hata A and Chen YG: TGF-beta signaling from receptors to smads. Cold Spring Harb Perspect Biol. 8:a0220612016. View Article : Google Scholar | |
|
Zhang Y, Alexander PB and Wang XF: TGF-beta family signaling in the control of cell proliferation and survival. Cold Spring Harb Perspect Biol. 9:a0221452017. View Article : Google Scholar | |
|
Wu MY and Hill CS: Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell. 16:329–343. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Ma W, Qin Y, Chapuy B and Lu C: LRRC33 is a novel binding and potential regulating protein of TGF-β1 function in human acute myeloid leukemia cells. PLoS One. 14:e02134822019. View Article : Google Scholar | |
|
Maishi N and Hida K: Tumor endothelial cells accelerate tumor metastasis. Cancer Sci. 108:1921–1926. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Selleri S, Rumio C, Sabatino M, Marincola FM and Wang E: Tumor microenvironment and the immune response. Surg Oncol Clin N Am. 16:737–753. vii–viii. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Yamamoto T, Akisue T, Marui T, Fujita I, Matsumoto K, Hitora T, Kawamoto T, Nagira K, Nakatani T and Kurosaka M: Expression of transforming growth factor beta isoforms and their receptors in malignant fibrous histiocytoma of soft tissues. Clin Cancer Res. 10:5804–5807. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Dropmann A, Dediulia T, Breitkopf-Heinlein K, Korhonen H, Janicot M, Weber SN, Thomas M, Piiper A, Bertran E, Fabregat I, et al: TGF-β1 and TGF-β2 abundance in liver diseases of mice and men. Oncotarget. 7:19499–19518. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Ebert MP, Yu J, Miehlke S, Fei G, Lendeckel U, Ridwelski K, Stolte M, Bayerdörffer E and Malfertheiner P: Expression of transforming growth factor beta-1 in gastric cancer and in the gastric mucosa of first-degree relatives of patients with gastric cancer. Br J Cancer. 82:1795–1800. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O'Shea JJ and Shevach EM: CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med. 205:1975–1981. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Peng L, Yuan XQ, Zhang CY, Ye F, Zhou HF, Li WL, Liu ZY, Zhang YQ, Pan X and Li GC: High TGF-beta1 expression predicts poor disease prognosis in hepatocellular carcinoma patients. Oncotarget. 8:34387–34397. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Neuzillet C, de Gramont A, Tijeras-Raballand A, de Mestier L, Cros J, Faivre S and Raymond E: Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas. Oncotarget. 5:78–94. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Papageorgis P: TGFbeta signaling in tumor initiation, epithelial-to-mesenchymal transition, and metastasis. J Oncol. 2015:5871932015. View Article : Google Scholar | |
|
Vander Ark A, Cao J and Li X: TGF-β receptors: In and beyond TGF-β signaling. Cell Signal. 52:112–120. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Baxter SW, Choong DY, Eccles DM and Campbell IG: Transforming growth factor beta receptor 1 polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev. 11:211–214. 2002.PubMed/NCBI | |
|
Liu J, Johnson K, Li J, Piamonte V, Steffy BM, Hsieh MH, Ng N, Zhang J, Walker JR, Ding S, et al: Regenerative phenotype in mice with a point mutation in transforming growth factor beta type I receptor (TGFBR1). Proc Natl Acad Sci USA. 108:14560–14565. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang F, Yu Q, Chu Y, Zhu X, Lu W, Liu Q and Wang Q: MicroRNA-98-5p inhibits proliferation and metastasis in non-small cell lung cancer by targeting TGFBR1. Int J Oncol. 54:128–138. 2019. | |
|
Grandclement C, Pallandre JR, Valmary Degano S, Viel E, Bouard A, Balland J, Rémy-Martin JP, Simon B, Rouleau A, Boireau W, et al: Neuropilin-2 expression promotes TGF-β1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS One. 6:e204442011. View Article : Google Scholar | |
|
He B, Xu T, Pan B, Pan Y, Wang X, Dong J, Sun H, Xu X, Liu X and Wang S: Polymorphisms of TGFBR1, TLR4 are associated with prognosis of gastric cancer in a Chinese population. Cancer Cell Int. 18:1912018. View Article : Google Scholar : | |
|
Kim W, Kim E, Lee S, Kim D, Chun J, Park KH, Youn H and Youn B: TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial-mesenchymal transition. Exp Mol Med. 48:e2732016. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang L, Song X, Chen X, Wang Q, Zheng X, Wu C and Jiang J: Circular RNA CircCACTIN promotes gastric cancer progression by sponging MiR-331-3p and regulating TGFBR1 expression. Int J Biol Sci. 15:1091–1103. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Knight PG and Glister C: TGF-beta superfamily members and ovarian follicle development. Reproduction. 132:191–206. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Hinck AP, Mueller TD and Springer TA: Structural biology and evolution of the TGF-β family. Cold Spring Harb Perspect Biol. 8. pp. a0221032016, View Article : Google Scholar | |
|
Meng XM, Nikolic-Paterson DJ and Lan HY: TGF-β: The master regulator of fibrosis. Nat Rev Nephrol. 12:325–338. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Huang T, David L, Mendoza V, Yang Y, Villarreal M, De K, Sun L, Fang X, López-Casillas F, Wrana JL and Hinck AP: TGF-β signalling is mediated by two autonomously functioning TβRI:TβRII pairs. EMBO J. 30:1263–1276. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Feng XH and Derynck R: A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity. EMBO J. 16:3912–3923. 1997. View Article : Google Scholar : PubMed/NCBI | |
|
Lo RS, Chen YG, Shi Y, Pavletich NP and Massagué J: The L3 loop: A structural motif determining specific interactions between SMAD proteins and TGF-beta receptors. EMBO J. 17:996–1005. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Itman C, Mendis S, Barakat B and Loveland KL: All in the family: TGF-beta family action in testis development. Reproduction. 132:233–246. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Attisano L and Wrana JL: Signal transduction by the TGF-beta superfamily. Science. 296:1646–1647. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Huynh LK, Hipolito CJ and Ten Dijke P: A perspective on the development of TGF-beta inhibitors for cancer treatment. Biomolecules. 9:7432019. View Article : Google Scholar | |
|
Wu Y, Tran T, Dwabe S, Sarkissyan M, Kim J, Nava M, Clayton S, Pietras R, Farias-Eisner R and Vadgama JV: A83-01 inhibits TGF-β-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells. Breast Cancer Res Treat. 163:449–460. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Katagiri T and Watabe T: Bone morphogenetic proteins. Cold Spring Harb Perspect Biol. 8:a0218992016. View Article : Google Scholar : PubMed/NCBI | |
|
Katz LH, Li Y, Chen JS, Muñoz NM, Majumdar A, Chen J and Mishra L: Targeting TGF-β signaling in cancer. Expert Opin Ther Targets. 17:743–760. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Krenning G, Barauna VG, Krieger JE, Harmsen MC and Moonen JR: Endothelial plasticity: Shifting phenotypes through force feedback. Stem Cells Int. 2016:97629592016. View Article : Google Scholar : PubMed/NCBI | |
|
Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T and Springer TA: Latent TGF-β structure and activation. Nature. 474:343–349. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang J, Li H, Yi D, Lai C, Wang H, Zou W and Cao B: Knockdown of vascular cell adhesion molecule 1 impedes transforming growth factor beta 1-mediated proliferation, migration, and invasion of endometriotic cyst stromal cells. Reprod Biol Endocrinol. 17:692019. View Article : Google Scholar : PubMed/NCBI | |
|
Robertson IB, Horiguchi M, Zilberberg L, Dabovic B, Hadjiolova K and Rifkin DB: Latent TGF-β-binding proteins. Matrix Biol. 47:44–53. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Ehrlich M, Horbelt D, Marom B, Knaus P and Henis YI: Homomeric and heteromeric complexes among TGF-beta and BMP receptors and their roles in signaling. Cell Signal. 23:1424–1432. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
ten Dijke P, Miyazono K and Heldin CH: Signaling via hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors. Curr Opin Cell Biol. 8:139–145. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Sun D, Han S, Liu C, Zhou R, Sun W, Zhang Z and Qu J: Microrna-199a-5p functions as a tumor suppressor via suppressing connective tissue growth factor (CTGF) in follicular thyroid carcinoma. Med Sci Monit. 22:1210–1217. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Das R, Xu S, Nguyen TT, Quan X, Choi SK, Kim SJ, Lee EY, Cha SK and Park KS: Transforming growth factor β1-induced apoptosis in podocytes via the extracellular signal-regulated kinase-mammalian target of rapamycin complex 1-NADPH Oxidase 4 axis. J Biol Chem. 290:30830–30842. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Mihaly SR, Ninomiya-Tsuji J and Morioka S: TAK1 control of cell death. Cell Death Differ. 21:1667–1676. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Tvrdík D, Dundr P, Povýsil C, Pytlík R and Planková M: Up-regulation of p21WAF1 expression is mediated by Sp1/Sp3 transcription factors in TGFbeta1-arrested malignant B cells. Med Sci Monit. 12:BR227–BR234. 2006.PubMed/NCBI | |
|
Stanilova S, Stanilov N, Julianov A, Manolova I and Miteva L: Transforming growth factor-β1 gene promoter -509C/T polymorphism in association with expression affects colorectal cancer development and depends on gender. PLoS One. 13:e02017752018. View Article : Google Scholar | |
|
Al Shareef Z, Kardooni H, Murillo-Garzó V, Domenici G, Stylianakis E, Steel JH, Rabano M, Gorroño-Etxebarria I, Zabalza I, Vivanco MD, et al: Protective effect of stromal Dickkopf-3 in prostate cancer: Opposing roles for TGFBI and ECM-1. Oncogene. 37:5305–5324. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Wang ST, Liu JJ, Wang CZ, Lin B, Hao YY, Wang YF, Gao S, Qi Y, Zhang SL and Iwamori M: Expression and correlation of Lewis y antigen and TGF-beta1 in ovarian epithelial carcinoma. Oncol Rep. 27:1065–1071. 2012. View Article : Google Scholar | |
|
Zhang N, Bi X, Zeng Y, Zhu Y, Zhang Z, Liu Y, Wang J, Li X, Bi J and Kong C: TGF-β1 promotes the migration and invasion of bladder carcinoma cells by increasing fascin1 expression. Oncol Rep. 36:977–983. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Wakefield LM, Letterio JJ, Chen T, Danielpour D, Allison RS, Pai LH, Denicoff AM, Noone MH, Cowan KH, O'Shaughnessy JA, et al: Transforming growth factor-beta1 circulates in normal human plasma and is unchanged in advanced metastatic breast cancer. Clin Cancer Res. 1:129–136. 1995.PubMed/NCBI | |
|
Shuang ZY, Wu WC, Xu J, Lin G, Liu YC, Lao XM, Zheng L and Li S: Transforming growth factor-β1-induced epithelial-mesenchymal transition generates ALDH-positive cells with stem cell properties in cholangiocarcinoma. Cancer Lett. 354:320–328. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Safina A, Vandette E and Bakin AV: ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene. 26:2407–2422. 2007. View Article : Google Scholar | |
|
Moore-Smith L and Pasche B: TGFBR1 signaling and breast cancer. J Mammary Gland Biol Neoplasia. 16:89–95. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Rosman DS, Phukan S, Huang CC and Pasche B: TGFBR1*6A enhances the migration and invasion of MCF-7 breast cancer cells through RhoA activation. Cancer Res. 68:1319–1328. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Slattery ML, Lundgreen A, Herrick JS, Wolff RK and Caan BJ: Genetic variation in the transforming growth factor-β signaling pathway and survival after diagnosis with colon and rectal cancer. Cancer. 117:4175–4183. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Javle M, Li Y, Tan D, Dong X, Chang P, Kar S and Li D: Biomarkers of TGF-β signaling pathway and prognosis of pancreatic cancer. PLoS One. 9:e859422014. View Article : Google Scholar | |
|
Bian Y, Knobloch TJ, Sadim M, Kaklamani V, Raji A, Yang GY, Weghorst CM and Pasche B: Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development. Hum Mol Genet. 16:3128–3135. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Pasche B, Pennison MJ, Jimenez H and Wang M: TGFBR1 and cancer susceptibility. Trans Am Clin Climatol Assoc. 125:300–312. 2014.PubMed/NCBI | |
|
Myers ER, Moorman P, Gierisch JM, Havrilesky LJ, Grimm LJ, Ghate S, Davidson B, Mongtomery RC, Crowley MJ, McCrory DC, et al: Benefits and harms of breast cancer screening: A systematic review. JAMA. 314:1615–1634. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Oeffinger KC, Fontham ET, Etzioni R, Herzig A, Michaelson JS, Shih YC, Walter LC, Church TR, Flowers CR, LaMonte SJ, et al: Breast cancer screening for women at average risk: 2015 guide-line update from the American cancer society. JAMA. 314:1599–1614. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
DeSantis CE, Ma J, Goding Sauer A, Newman LA and Jemal A: Breast cancer statistics, 2017 racial disparity in mortality by state. CA Cancer J Clin. 67:439–448. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Park SJ, Kim JG, Kim ND, Yang K, Shim JW and Heo K: Estradiol, TGF-β1 and hypoxia promote breast cancer stemness and EMT-mediated breast cancer migration. Oncol Lett. 11:1895–1902. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Menezes ME, Shen XN, Das SK, Emdad L, Sarkar D and Fisher PB: MDA-9/Syntenin (SDCBP) modulates small GTPases RhoA and Cdc42 via transforming growth factor β1 to enhance epithelial-mesenchymal transition in breast cancer. Oncotarget. 7:80175–80189. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Wang S, Huang M, Wang Z, Wang W, Zhang Z, Qu S and Liu C: MicroRNA-133b targets TGFβ receptor I to inhibit TGF-β-induced epithelial-to-mesenchymal transition and metastasis by suppressing the TGF-β/SMAD pathway in breast cancer. Int J Oncol. 55:1097–1109. 2019.PubMed/NCBI | |
|
Lee YS and Dutta A: MicroRNAs in cancer. Annu Rev Pathol. 4:199–227. 2009. View Article : Google Scholar : | |
|
Ye Z, Zhao L, Li J, Chen W and Li X: MiR-30d blocked transforming growth Factor beta1-induced epithelial-mesenchymal transition by targeting snail in ovarian cancer cells. Int J Gynecol Cancer. 25:1574–1581. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Dai X, Fang M, Li S, Yan Y, Zhong Y and Du B: MiR-21 is involved in transforming growth factor β1-induced chemoresistance and invasion by targeting PTEN in breast cancer. Oncol Lett. 14:6929–6936. 2017.PubMed/NCBI | |
|
Li C, Zhou D, Hong H, Yang S, Zhang L, Li S, Hu P, Ren H, Mei Z and Tang H: TGFβ1-miR-140-5p axis mediated up-regulation of Flap Endonuclease 1 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Aging (Albany NY). 11:5593–5612. 2019. View Article : Google Scholar | |
|
Chen Y, Huang S, Wu B, Fang J, Zhu M, Sun L, Zhang L, Zhang Y, Sun M, Guo L and Wang S: Transforming growth factor-β1 promotes breast cancer metastasis by downregulating miR-196a-3p expression. Oncotarget. 8:49110–49122. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao XP, Huang YY, Huang Y, Lei P, Peng JL, Wu S, Wang M, Li WH, Zhu HF and Shen GX: Transforming growth factor-beta1 upregulates the expression of CXC chemokine receptor 4 (CXCR4) in human breast cancer MCF-7 cells. Acta Pharmacol Sin. 31:347–354. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Chen HS, Bai MH, Zhang T, Li GD and Liu M: Ellagic acid induces cell cycle arrest and apoptosis through TGF-β/Smad3 signaling pathway in human breast cancer MCF-7 cells. Int J Oncol. 46:1730–1738. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Mishra AK, Parish CR, Wong ML, Licinio J and Blackburn AC: Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer. PLoS One. 12:e01784542017. View Article : Google Scholar : PubMed/NCBI | |
|
Fallone F, Deudon R, Muller C and Vaysse C: Breast cancer, obesity and adipose tissue: A high-risk combination. Med Sci (Paris). 34:1079–1086. 2018.In French. View Article : Google Scholar | |
|
Lee K, Kruper L, Dieli-Conwright CM and Mortimer JE: The impact of obesity on breast cancer diagnosis and treatment. Curr Oncol Rep. 21:412019. View Article : Google Scholar : PubMed/NCBI | |
|
Catteau X, Simon P and Noël JC: Myofibroblastic stromal reaction and lymph node status in invasive breast carcinoma: Possible role of the TGF-β1/TGF-βR1 pathway. BMC Cancer. 14:4992014. View Article : Google Scholar | |
|
Cox DG, Penney K, Guo Q, Hankinson SE and Hunter DJ: TGFB1 and TGFBR1 polymorphisms and breast cancer risk in the Nurses' Health Study. BMC Cancer. 7:1752007. View Article : Google Scholar : PubMed/NCBI | |
|
Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Engstrom PF, et al: NCCN guidelines insights: Colon cancer, version 2. 2018.J Natl Compr Canc Netw. 16:359–369. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, Cercek A, Smith RA and Jemal A: Colorectal cancer statistics, 2020. CA Cancer J Clin. 70:145–164. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Xu Y and Pasche B: TGF-beta signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet. 16(Spec 1 SPEC): R14–R20. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Kong J, Du J, Wang Y, Yang M, Gao J, Wei X, Fang W, Zhan J and Zhang H: Focal adhesion molecule Kindlin-1 mediates activation of TGF-β signaling by interacting with TGF-βRI, SARA and Smad3 in colorectal cancer cells. Oncotarget. 7:76224–76237. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Chen K, Wei H, Ling S and Yi C: Expression and significance of transforming growth factor-beta1 in epithelial ovarian cancer and its extracellular matrix. Oncol Lett. 8:2171–2174. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS and Doetschman T: Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res. 59:3379–3386. 1999.PubMed/NCBI | |
|
Schmidt-Weber CB and Blaser K: Regulation and role of transforming growth factor-beta in immune tolerance induction and inflammation. Curr Opin Immunol. 16:709–716. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Bierie B and Moses HL: Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev. 21:49–59. 2010. View Article : Google Scholar | |
|
Vrba L and Futscher BW: Epigenetic silencing of lncRNA MORT in 16 TCGA cancer types. F1000Res. 7:2112018. View Article : Google Scholar : | |
|
Zhou T, Wu L, Zong Z, Ma N, Li Y, Jiang Z, Wang Q and Chen S: Long non-coding RNA mortal obligate RNA transcript inhibits the migration and invasion of colon cancer cells by inactivating transforming growth factor β1. Oncol Lett. 19:1131–1136. 2020.PubMed/NCBI | |
|
Townsend PA, Cutress RI, Sharp A, Brimmell M and Packham G: BAG-1: A multifunctional regulator of cell growth and survival. Biochim Biophys Acta. 1603:83–98. 2003.PubMed/NCBI | |
|
Skeen VR, Collard TJ, Southern SL, Greenhough A, Hague A, Townsend PA, Paraskeva C and Williams AC: BAG-1 suppresses expression of the key regulatory cytokine transforming growth factor β (TGF-β1) in colorectal tumour cells. Oncogene. 32:4490–4499. 2013. View Article : Google Scholar | |
|
Dumond A, Demange L and Pagès G: Neuropilins: Relevant therapeutic targets to improve the treatment of cancers. Med Sci (Paris). 36:487–496. 2020.In French. View Article : Google Scholar | |
|
Huang Y, Fang W, Wang Y, Yang W and Xiong B: Transforming growth factor-β1 induces glutathione peroxidase-1 and protects from H2O2-induced cell death in colon cancer cells via the Smad2/ERK1/2/HIF-1α pathway. Int J Mol Med. 29:906–912. 2012.PubMed/NCBI | |
|
Lei XG, Cheng WH and McClung JP: Metabolic regulation and function of glutathione peroxidase-1. Annu Rev Nutr. 27:41–61. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Li Y, Zhu G, Zhai H, Jia J, Yang W, Li X and Liu L: Simultaneous stimulation with tumor necrosis factor-α and transforming growth factor-β1 induces epithelial-mesenchymal transition in colon cancer cells via the NF-κB pathway. Oncol Lett. 15:6873–6880. 2018.PubMed/NCBI | |
|
Tomsic J, Guda K, Liyanarachchi S, Hampel H, Natale L, Markowitz SD, Tanner SM and de la Chapelle A: Allele-specific expression of TGFBR1 in colon cancer patients. Carcinogenesis. 31:1800–1804. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou R, Huang Y, Cheng B, Wang Y and Xiong B: TGFBR1*6A is a potential modifier of migration and invasion in colorectal cancer cells. Oncol Lett. 15:3971–3976. 2018.PubMed/NCBI | |
|
Luyimbazi D, Nelson RA, Choi AH, Li L, Chao J, Sun V, Hamner JB and Kim J: Estimates of conditional survival in gastric cancer reveal a reduction of racial disparities with long-term follow-up. J Gastrointest Surg. 19:251–257. 2015. View Article : Google Scholar | |
|
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Pennison M and Pasche B: Targeting transforming growth factor-beta signaling. Curr Opin Oncol. 19:579–585. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Derynck R and Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 425:577–584. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Ijichi H, Ikenoue T, Kato N, Mitsuno Y, Togo G, Kato J, Kanai F, Shiratori Y and Omata M: Systematic analysis of the TGF-beta-Smad signaling pathway in gastrointestinal cancer cells. Biochem Biophys Res Commun. 289:350–357. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Ma GF, Miao Q, Zeng XQ, Luo TC, Ma LL, Liu YM, Lian JJ, Gao H and Chen SY: Transforming growth factor-β1 and -β2 in gastric precancer and cancer and roles in tumor-cell interactions with peripheral blood mononuclear cells in vitro. PLoS One. 8:e542492013. View Article : Google Scholar | |
|
Zhou Y, Jin GF, Jiang GJ, Wang HM, Tan YF, Ding WL, Wang LN, Chen WS, Ke Q, Shen J, et al: Correlations of polymorphisms of TGFB1 and TGFBR2 genes to genetic susceptibility to gastric cancer. Ai Zheng. 26:581–585. 2007.In Chinese. PubMed/NCBI | |
|
Yanagihara K and Tsumuraya M: Transforming growth factor beta 1 induces apoptotic cell death in cultured human gastric carcinoma cells. Cancer Res. 52:4042–4045. 1992.PubMed/NCBI | |
|
Wang KS, Hu ZL, Li JH, Xiao DS and Wen JF: Enhancement of metastatic and invasive capacity of gastric cancer cells by transforming growth factor-beta1. Acta Biochim Biophys Sin (Shanghai). 38:179–186. 2006. View Article : Google Scholar | |
|
Takeuchi Y and Nishikawa H: Roles of regulatory T cells in cancer immunity. Int Immunol. 28:401–409. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Deng B, Zhu JM, Wang Y, Liu TT, Ding YB, Xiao WM, Lu GT, Bo P and Shen XZ: Intratumor hypoxia promotes immune tolerance by inducing regulatory T cells via TGF-β1 in gastric cancer. PLoS One. 8:e637772013. View Article : Google Scholar | |
|
Lee MS, Kim TY, Kim YB, Lee SY, Ko SG, Jong HS, Kim TY, Bang YJ and Lee JW: The signaling network of transforming growth factor beta1, protein kinase Cdelta, and integrin underlies the spreading and invasiveness of gastric carcinoma cells. Mol Cell Biol. 25:6921–6936. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou H, Wang K, Hu Z and Wen J: TGF-β1 alters microRNA profile in human gastric cancer cells. Chin J Cancer Res. 25:102–111. 2013.PubMed/NCBI | |
|
Zhu Y, Kong F, Zhang C, Ma C, Xia H, Quan B and Cui H: CD133 mediates the TGF-β1-induced activation of the PI3K/ERK/P70S6K signaling pathway in gastric cancer cells. Oncol Lett. 14:7211–7216. 2017. | |
|
Zhao Y, Xia S, Cao C and Du X: Effect of TGF-β1 on apoptosis of colon cancer cells via the ERK signaling pathway. J BUON. 24:449–455. 2019.PubMed/NCBI | |
|
Jin S, Gao J, Qi Y, Hao Y, Li X, Liu Q, Liu J, Liu D, Zhu L and Lin B: TGF-β1 fucosylation enhances the autophagy and mitophagy via PI3K/Akt and Ras-Raf-MEK-ERK in ovarian carcinoma. Biochem Biophys Res Commun. 524:970–976. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Cascione M, Leporatti S, Dituri F and Giannelli G: Transforming growth factor-β promotes morphomechanical effects involved in epithelial to mesenchymal transition in living hepatocellular carcinoma. Int J Mol Sci. 20:1082018. View Article : Google Scholar | |
|
Sun SL and Wang XY: TGF-β1 promotes proliferation and invasion of hepatocellular carcinoma cell line HepG2 by activating GLI-1 signaling. Eur Rev Med Pharmacol Sci. 22:7688–7695. 2018.PubMed/NCBI | |
|
Qu Z, Feng J, Pan H, Jiang Y, Duan Y and Fa Z: Exosomes derived from HCC cells with different invasion characteristics mediated EMT through TGF-β/Smad signaling pathway. Onco Targets Ther. 12:6897–6905. 2019. View Article : Google Scholar : | |
|
Zhang C, Chen B, Jiao A, Li F, Sun N, Zhang G and Zhang J: MiR-663a inhibits tumor growth and invasion by regulating TGF-β1 in hepatocellular carcinoma. BMC Cancer. 18:11792018. View Article : Google Scholar | |
|
Tang YH, He GL, Huang SZ, Zhong KB, Liao H, Cai L, Gao Y, Peng ZW and Fu SJ: The long noncoding RNA AK002107 negatively modulates miR-140-5p and targets TGFBR1 to induce epithelial-mesenchymal transition in hepatocellular carcinoma. Mol Oncol. 13:1296–1310. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Y, Li B, Li X, Tan H, Cheng D and Shi H: An imaging target TGF-β1 for hepatocellular carcinoma in mice. Hell J Nucl Med. 20:76–78. 2017.PubMed/NCBI | |
|
Balzarini P, Benetti A, Invernici G, Cristini S, Zicari S, Caruso A, Gatta LB, Berenzi A, Imberti L, Zanotti C, et al: Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma. Lab Invest. 92:1297–1309. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Yao S, Tian C, Ding Y, Ye Q, Gao Y, Yang N and Li Q: Down-regulation of Krüppel-like factor-4 by microRNA-135a-5p promotes proliferation and metastasis in hepatocellular carcinoma by transforming growth factor-β1. Oncotarget. 7:42566–42578. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Li W, Liu M, Su Y, Zhou X, Liu Y and Zhang X: The Janus-faced roles of Krüppel-like factor 4 in oral squamous cell carcinoma cells. Oncotarget. 6:44480–44494. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Tian C, Yao S, Liu L, Ding Y, Ye Q, Dong X, Gao Y, Yang N and Li Q: Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma. Int J Mol Med. 39:47–56. 2017. View Article : Google Scholar | |
|
Zhang X, Fan Q, Li Y, Yang Z, Yang L, Zong Z, Wang B, Meng X, Li Q, Liu J and Li H: Transforming growth factor-beta1 suppresses hepatocellular carcinoma proliferation via activation of Hippo signaling. Oncotarget. 8:29785–29794. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Y, Shi K, Liu H, Chen W, Luo Y, Wei X and Wu Z: MiR-4458 inhibits the epithelial-mesenchymal transition of hepatocellular carcinoma cells by suppressing the TGF-β signaling pathway via targeting TGFBR1. Acta Biochim Biophys Sin (Shanghai). 52:554–562. 2020. View Article : Google Scholar | |
|
Perrier ND, Brierley JD and Tuttle RM: Differentiated and anaplastic thyroid carcinoma: Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 68:55–63. 2018. View Article : Google Scholar | |
|
Saini S, Tulla K, Maker AV, Burman KD and Prabhakar BS: Therapeutic advances in anaplastic thyroid cancer: A current perspective. Mol Cancer. 17:1542018. View Article : Google Scholar : PubMed/NCBI | |
|
Kebebew E: Anaplastic thyroid cancer: Rare, fatal, and neglected. Surgery. 152:1088–1089. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Li Y, Chen D, Hao FY and Zhang KJ: Targeting TGF-β1 and AKT signal on growth and metastasis of anaplastic thyroid cancer cell in vivo. Eur Rev Med Pharmacol Sci. 20:2581–2587. 2016.PubMed/NCBI | |
|
Zhang X, Liu L, Deng X, Li D, Cai H, Ma Y, Jia C, Wu B, Fan Y and Lv Z: MicroRNA 483-3p targets Pard3 to potentiate TGF-β1-induced cell migration, invasion, and epithelial-mesenchymal transition in anaplastic thyroid cancer cells. Oncogene. 38:699–715. 2019. View Article : Google Scholar | |
|
Yin Q, Liu S, Dong A, Mi X, Hao F and Zhang K: Targeting transforming growth factor-Beta1 (TGF-β1) inhibits tumorigenesis of anaplastic thyroid carcinoma cells through ERK1/2-NFκB-PUMA signaling. Med Sci Monit. 22:2267–2277. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Zhong J, Liu C, Zhang QH, Chen L, Shen YY, Chen YJ, Zeng X, Zu XY and Cao RX: TGF-β1 induces HMGA1 expression: The role of HMGA1 in thyroid cancer proliferation and invasion. Int J Oncol. 50:1567–1578. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Cui M, Chang Y, Du W, Liu S, Qi J, Luo R and Luo S: Upregulation of lncRNA-ATB by transforming growth factor-β1 (TGF-β1) promotes migration and invasion of papillary thyroid carcinoma cells. Med Sci Monit. 24:5152–5158. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Li T, Zhao N, Lu J, Zhu Q, Liu X, Hao F and Jiao X: Epigallocatechin gallate (EGCG) suppresses epithelial-mesenchymal transition (EMT) and invasion in anaplastic thyroid carcinoma cells through blocking of TGF-β1/Smad signaling pathways. Bioengineered. 10:282–291. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
He J, Jin Y, Zhou M, Li X, Chen W, Wang Y, Gu S, Cao Y, Chu C, Liu X and Zou Q: Solute carrier family 35 member F2 is indispensable for papillary thyroid carcinoma progression through activation of transforming growth factor-β type I receptor/apoptosis signal-regulating kinase 1/mitogen-activated protein kinase signaling axis. Cancer Sci. 109:642–655. 2018. View Article : Google Scholar : | |
|
Bonnet D: Cancer stem cells: Lessons from leukaemia. Cell Prolif. 38:357–361. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Xie W, Wang X, Du W, Liu W, Qin X and Huang S: Detection of molecular targets on the surface of CD34+CD38-bone marrow cells in myelodysplastic syndromes. Cytometry A. 77:840–848. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Lyengar V and Shimanovsky A: Leukemia. StatPearls Publishing, StatPearls Publishing LLC; Treasure Island, FL: 2020 | |
|
Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, Reaman GH and Carroll WL: Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: A report from the children's oncology group. J Clin Oncol. 30:1663–1669. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Huang F, Wan J, Hu W and Hao S: Enhancement of anti-leukemia immunity by leukemia-derived exosomes via downregulation of TGF-β1 expression. Cell Physiol Biochem. 44:240–254. 2017. View Article : Google Scholar | |
|
Geyh S, Rodríguez-Paredes M, Jäger P, Koch A, Bormann F, Gutekunst J, Zilkens C, Germing U, Kobbe G, Lyko F, et al: Transforming growth factor β1-mediated functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 103:1462–1471. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Taetle R, Payne C, Dos Santos B, Russell M and Segarini P: Effects of transforming growth factor beta 1 on growth and apoptosis of human acute myelogenous leukemia cells. Cancer Res. 53:3386–3393. 1993.PubMed/NCBI | |
|
Verheyden S and Demanet C: NK cell receptors and their ligands in leukemia. Leukemia. 22:249–257. 2008. View Article : Google Scholar | |
|
Nursal AF, Pehlivan M, Sahin HH and Pehlivan S: The Associations of IL-6, IFN-γ, TNF-α, IL-10, and TGF-β1 functional variants with acute myeloid leukemia in turkish patients. Genet Test Mol Biomarkers. 20:544–551. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Rouce RH, Shaim H, Sekine T, Weber G, Ballard B, Ku S, Barese C, Murali V, Wu MF, Liu H, et al: The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia. Leukemia. 30:800–811. 2016. View Article : Google Scholar | |
|
Gong Y, Zhao M, Yang W, Gao A, Yin X, Hu L, Wang X, Xu J, Hao S, Cheng T and Cheng H: Megakaryocyte-derived excessive transforming growth factor β1 inhibits proliferation of normal hematopoietic stem cells in acute myeloid leukemia. Exp Hematol. 60:40–46.e2. 2018. View Article : Google Scholar | |
|
Wang H, Wu Q, Zhang Y, Zhang HN, Wang YB and Wang W: TGF-β1-induced epithelial-mesenchymal transition in lung cancer cells involves upregulation of miR-9 and downregulation of its target, E-cadherin. Cell Mol Biol Lett. 22:222017. View Article : Google Scholar | |
|
Xue C, Hu Z, Jiang W, Zhao Y, Xu F, Huang Y, Zhao H, Wu J, Zhang Y, Zhao L, et al: National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China. Lung Cancer. 77:371–375. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Yano T, Okamoto T, Fukuyama S and Maehara Y: Therapeutic strategy for postoperative recurrence in patients with non-small cell lung cancer. World J Clin Oncol. 5:1048–1054. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Li L, Yan S, Zhang H, Zhang M, Huang G and Chen M: Interaction of hnRNP K with MAP 1B-LC1 promotes TGF-β1-mediated epithelial to mesenchymal transition in lung cancer cells. BMC Cancer. 19:8942019. View Article : Google Scholar | |
|
Shi S, Zhao J, Wang J, Mi D and Ma Z: HPIP silencing inhibits TGF-β1-induced EMT in lung cancer cells. Int J Mol Med. 39:479–483. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang HW, Wang EW, Li LX, Yi SH, Li LC, Xu FL, Wang DL, Wu YZ and Nian WQ: A regulatory loop involving miR-29c and Sp1 elevates the TGF-β1 mediated epithelial-to-mesenchymal transition in lung cancer. Oncotarget. 7:85905–85916. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang W, Xu Z, Yu L, Che J, Zhang J and Yang J: MicroRNA-144-3p suppressed TGF-β1-induced lung cancer cell invasion and adhesion by regulating the Src-Akt-Erk pathway. Cell Biol Int. 2019.Epub ahead of print. | |
|
Zhao X, Liu Y and Yu S: Long noncoding RNA AWPPH promotes hepatocellular carcinoma progression through YBX1 and serves as a prognostic biomarker. Biochim Biophys Acta Mol Basis Dis. 1863:1805–1816. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zhu F, Zhang X, Yu Q, Han G, Diao F, Wu C and Zhang Y: LncRNA AWPPH inhibits SMAD4 via EZH2 to regulate bladder cancer progression. J Cell Biochem. 119:4496–4505. 2018. View Article : Google Scholar | |
|
Tang L, Wang T, Zhang Y, Zhang J, Zhao H, Wang H, Wu Y and Liu K: Long non-coding RNA AWPPH promotes postoperative distant recurrence in resected non-small cell lung cancer by upregulating transforming growth factor beta 1 (TGF-β1). Med Sci Monit. 25:2535–2541. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Chae DK, Park J, Cho M, Ban E, Jang M, Yoo YS, Kim EE, Baik JH and Song EJ: MiR-195 and miR-497 suppress tumorigenesis in lung cancer by inhibiting SMURF2-induced TGF-β receptor I ubiquitination. Mol Oncol. 13:2663–2678. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Hypes MK, Pirisi L and Creek KE: Mechanisms of decreased expression of transforming growth factor-beta receptor type I at late stages of HPV16-mediated transformation. Cancer Lett. 282:177–186. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Xu F, Zhang J, Hu G, Liu L and Liang W: Hypoxia and TGF-β1 induced PLOD2 expression improve the migration and invasion of cervical cancer cells by promoting epithelial-to-mesenchymal transition (EMT) and focal adhesion formation. Cancer Cell Int. 17:542017. View Article : Google Scholar | |
|
Li MY, Liu JQ, Chen DP, Li ZY, Qi B, Yin WJ and He L: p68 prompts the epithelial-mesenchymal transition in cervical cancer cells by transcriptionally activating the TGF-β1 signaling pathway. Oncol Lett. 15:2111–2116. 2018.PubMed/NCBI | |
|
Yang L, Yu Y, Xiong Z, Chen H, Tan B and Hu H: Downregulation of SEMA4C inhibit epithelial-mesenchymal transition (EMT) and the invasion and metastasis of cervical cancer cells via inhibiting transforming growth factor-beta 1 (TGF-β1)-induced Hela cells p38 mitogen-activated protein kinase (MAPK) activation. Med Sci Monit. 26:e9181232020. View Article : Google Scholar | |
|
Cheng Y, Guo Y, Zhang Y, You K, Li Z and Geng L: MicroRNA-106b is involved in transforming growth factor β1-induced cell migration by targeting disabled homolog 2 in cervical carcinoma. J Exp Clin Cancer Res. 35:112016. View Article : Google Scholar | |
|
Finkielstein CV and Capelluto DG: Disabled-2: A modular scaffold protein with multifaceted functions in signaling. Bioessays. 38(Suppl 1): S45–S55. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Tao MZ, Gao X, Zhou TJ, Guo QX, Zhang Q and Yang CW: Effects of TGF-beta1 on the proliferation and apoptosis of human cervical cancer Hela cells in vitro. Cell Biochem Biophys. 73:737–741. 2015. View Article : Google Scholar | |
|
Wang H, Wang J, Liu H and Wang X: TGF-β1 activates NOX4/ROS pathway to promote the invasion and migration of cervical cancer cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 35:121–127. 2019.In Chinese. PubMed/NCBI | |
|
Deng M, Cai X, Long L, Xie L, Ma H, Zhou Y, Liu S and Zeng C: CD36 promotes the epithelial-mesenchymal transition and metastasis in cervical cancer by interacting with TGF-β. J Transl Med. 17:3522019. View Article : Google Scholar | |
|
Wongnoppavich A, Dukaew N, Choonate S and Chairatvit K: Upregulation of maspin expression in human cervical carcinoma cells by transforming growth factor β1 through the convergence of Smad and non-Smad signaling pathways. Oncol Lett. 13:3646–3652. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Ju W, Luo X and Zhang N: LncRNA NEF inhibits migration and invasion of HPV-negative cervical squamous cell carcinoma by inhibiting TGF-β pathway. Biosci Rep. Apr 26–2019.Epub ahead of print. View Article : Google Scholar | |
|
Levovitz C, Chen D, Ivansson E, Gyllensten U, Finnigan JP, Alshawish S, Zhang W, Schadt EE, Posner MR, Genden EM, et al: TGFβ receptor 1: An immune susceptibility gene in HPV-associated cancer. Cancer Res. 74:6833–6844. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Zhu L, Zhang Q, Li S, Jiang S, Cui J and Dang G: Interference of the long noncoding RNA CDKN2B-AS1 upregulates miR-181a-5p/TGFβI axis to restrain the metastasis and promote apoptosis and senescence of cervical cancer cells. Cancer Med. 8:1721–1730. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Wu T, Chen X, Peng R, Liu H, Yin P, Peng H, Zhou Y, Sun Y, Wen L, Yi H, et al: Let-7a suppresses cell proliferation via the TGF-β/SMAD signaling pathway in cervical cancer. Oncol Rep. 36:3275–3282. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Fang F, Huang B, Sun S, Xiao M, Guo J, Yi X, Cai J and Wang Z: MiR-27a inhibits cervical adenocarcinoma progression by downregulating the TGF-βRI signaling pathway. Cell Death Dis. 9:3952018. View Article : Google Scholar | |
|
Wu M, Chen X, Lou J, Zhang S, Zhang X, Huang L, Sun R, Huang P, Wang F and Pan S: TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment. Oncotarget. 7:44534–44544. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Wang YQ, Li YM, Li X, Liu T, Liu XK, Zhang JQ, Guo JW, Guo LY and Qiao L: Hypermethylation of TGF-β1 gene promoter in gastric cancer. World J Gastroenterol. 19:5557–5564. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Ji M, Shi H, Xie Y, Zhao Z, Li S, Chang C, Cheng X and Li Y: Ubiquitin specific protease 22 promotes cell proliferation and tumor growth of epithelial ovarian cancer through synergy with transforming growth factor β1. Oncol Rep. 33:133–140. 2015. View Article : Google Scholar | |
|
Teng Y, Zhao L, Zhang Y, Chen W and Li X: Id-1, a protein repressed by miR-29b, facilitates the TGFβ1-induced epithelial-mesenchymal transition in human ovarian cancer cells. Cell Physiol Biochem. 33:717–730. 2014. View Article : Google Scholar | |
|
Facciabene A, Motz GT and Coukos G: T-regulatory cells: Key players in tumor immune escape and angiogenesis. Cancer Res. 72:2162–2171. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang J, Liu W, Shen F, Ma X, Liu X, Tian F, Zeng W, Xi X and Lin Y: The activation of microRNA-520h-associated TGF-β1/c-Myb/Smad7 axis promotes epithelial ovarian cancer progression. Cell Death Dis. 9:8842018. View Article : Google Scholar | |
|
Wang YQ, Qi XW, Wang F, Jiang J and Guo QN: Association between TGFBR1 polymorphisms and cancer risk: A meta-analysis of 35 case-control studies. PLoS One. 7:e428992012. View Article : Google Scholar : PubMed/NCBI | |
|
Eli Lilly: Company: A study in participants with diabetic kidney disease. ClinicalTrials.gov. 2010, https://clinicaltrials.gov/ct2/show/NCT01113801. Accessed Sep 17, 2019. | |
|
Zhang Q, Hou X, Evans BJ, VanBlaricom JL, Weroha SJ and Cliby WA: LY2157299 monohydrate, a TGF-βR1 inhibitor, suppresses tumor growth and ascites development in ovarian cancer. Cancers (Basel). 10. pp. 2602018, View Article : Google Scholar | |
|
Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, et al: Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther. 9:4479–4499. 2015.PubMed/NCBI | |
|
Fujiwara Y, Nokihara H, Yamada Y, Yamamoto N, Sunami K, Utsumi H, Asou H, TakahashI O, Ogasawara K, Gueorguieva I and Tamura T: Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 76:1143–1152. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Brandes AA, Carpentier AF, Kesari S, Sepulveda-Sanchez JM, Wheeler HR, Chinot O, Cher L, Steinbach JP, Capper D, Specenier P, et al: A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol. 18:1146–1156. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Ikeda M, Takahashi H, Kondo S, Lahn MMF, Ogasawara K, Benhadji KA, Fujii H and Ueno H: Phase 1b study of galunisertib in combination with gemcitabine in Japanese patients with metastatic or locally advanced pancreatic cancer. Cancer Chemother Pharmacol. 79:1169–1177. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Rodón J, Carducci M, Sepulveda-Sánchez JM, Azaro A, Calvo E, Seoane J, Braña I, Sicart E, Gueorguieva I, Cleverly A, et al: Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest New Drugs. 33:357–370. 2015. View Article : Google Scholar | |
|
MedPacto: Dose escalation and proof-of-concept studies of vactosertib (TEW-7197) monotherapy in patients with MDS. ClinicalTrials.gov. 2017, https://clinicaltrials.gov/ct2/show/NCT03074006. Accessed Mar 24, 2020. | |
|
MedPacto: First in human dose escalation study of vactosertib (TEW-7197) in subjects with advanced stage solid tumors. ClinicalTrials.gov. 2014, https://clinicaltrials.gov/ct2/show/NCT02160106 Accessed Sep 5, 2019. | |
|
Eli Lilly: Company: A study of LY3200882 in participants with solid tumors. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/results/NCT02937272. Accessed Aug 19, 2020. | |
|
Callahan JF, Burgess JL, Fornwald JA, Gaster LM, Harling JD, Harrington FP, Heer J, Kwon C, Lehr R, Mathur A, et al: Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J Med Chem. 45:999–1001. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ and Hill CS: SB-431542 is a potent and specific inhibitor of transforming growth factor-beta super-family type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 62:65–74. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Tanaka H, Shinto O, Yashiro M, Yamazoe S, Iwauchi T, Muguruma K, Kubo N, Ohira M and Hirakawa K: Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol Rep. 24:1637–1643. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL and Chiao PJ: LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther. 7:829–840. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang ZH, Miao YY, Ke BL, Liu K and Xu X: LY2109761, transforming growth factor β receptor type I and type II dual inhibitor, is a novel approach to suppress endothelial mesenchymal transformation in human corneal endothelial cells. Cell Physiol Biochem. 50:963–972. 2018. View Article : Google Scholar | |
|
Tandon M, Salamoun JM, Carder EJ, Farber E, Xu S, Deng F, Tang H, Wipf P and Wang QJ: SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor growth in vivo by inducing G2/M cell cycle arrest. PLoS One. 10:e01193462015. View Article : Google Scholar : PubMed/NCBI | |
|
Araujo SC, Maltarollo VG, Almeida MO, Ferreira LL, Andricopulo AD and Honorio KM: Structure-based virtual screening, molecular dynamics and binding free energy calculations of Hit candidates as ALK-5 inhibitors. Molecules. 25:2642020. View Article : Google Scholar : | |
|
de Gouville AC, Boullay V, Krysa G, Pilot J, Brusq JM, Loriolle F, Gauthier JM, Papworth SA, Laroze A, Gellibert F and Huet S: Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis. Br J Pharmacol. 145:166–177. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Park CY, Kim DK and Sheen YY: EW-7203, a novel small molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor/activin receptor-like kinase-5, blocks TGF-β1-mediated epithelial-to-mesenchymal transition in mammary epithelial cells. Cancer Sci. 102:1889–1896. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Ehata S, Hanyu A, Fujime M, Katsuno Y, Fukunaga E, Goto K, Ishikawa Y, Nomura K, Yokoo H, Shimizu T, et al: Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci. 98:127–133. 2007. View Article : Google Scholar | |
|
Suzuki E, Kim S, Cheung HK, Corbley MJ, Zhang X, Sun L, Shan F, Singh J, Lee WC, Albelda SM and Ling LE: A novel small-molecule inhibitor of transforming growth factor beta type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Cancer Res. 67:2351–2359. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Moore-Smith LD, Isayeva T, Lee JH, Frost A and Ponnazhagan S: Silencing of TGF-β1 in tumor cells impacts MMP-9 in tumor microenvironment. Sci Rep. 7:86782017. View Article : Google Scholar | |
|
Li XF, Yan PJ and Shao ZM: Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer. Oncogene. 28:3937–3948. 2009. View Article : Google Scholar : PubMed/NCBI |
