Cancer remains a principal cause of human mortalities worldwide. The incidence of cancer and the consequent mortalities are a principal cause for concern. It is estimated that by 2030, there may be 22 million novel cases of cancer and 13 million mortalities worldwide each year due to different types of cancer (1). In China, the incidence of cancer has increased between 215.8 cases per 100,000 people in 2003 and 250.3 cases per 100,000 people in 2011 (2). The onset of gastrointestinal malignancy is frequently clinically silent (3), with the early occurrence of tumor invasion and metastasis leading to high mortality rates (4). For example, at present, the 5-year survival rate for pancreatic cancer is 8%, whereas, the 5-year survival rate for patients with distant metastases is 3% (5). Due to early vessel metastasis of pancreatic cancer, it may be difficult to conduct radical surgical resections for advanced gastrointestinal malignancies in certain situations (6). Therefore, effective targeted therapy may be indispensable in reducing the severity of gastrointestinal malignancies and the degree of radical surgery required.

F-box/WD-40 repeat-containing protein 7 (Fbw7) is a member of the F-box protein family. Fbw7 is an essential component of the E3 ubiquitin ligase, S-phase kinase-associated protein 1 (Skp1)-cullin-1 (Cul1)-F-box (SCF)^Fbw7, which serves as a binding site for substrates, and mediates their ubiquitination and degradation (7). The majority of Fbw7 substrates regulate a number of cell behaviors, including progression through the cell cycle, differentiation and apoptosis (7). In solid tumors, Fbw7 substrates are typically identified to be oncoproteins. Therefore, FBW7, which encodes Fbw7, is frequently considered a tumor suppressor gene (7). In tumor cells, FBW7 has been demonstrated to possess mutations and deletions, to be methylated or post-transcriptionally modified (8). Fbw7 expression is additionally regulated by numerous proteins, resulting in its dysfunctional expression and subsequent tumor progression (8). The present review aimed to provide a comprehensive overview of the mechanisms involved in dysfunctional Fbw7 expression caused by mutations in the FBW7 gene. Additionally, it may provide information on the shared molecular regulatory mechanisms involved in the progression of gastrointestinal malignancies, including colorectal, liver, gastric and pancreatic cancer, in addition to oral and esophageal squamous cell carcinomas.

Fbw7 (additionally termed Fbxw7, hAgo, hCdc4 and SEL-10) is a protein encoded by the FBW7 gene and is located on the chromosomal band 4q32 (9). Fbw7 is present as one of three subtypes: Fbw7α exists in the nucleoplasm; Fbw7β exists in the cytoplasm; and Fbw7γ exists in the nucleoli (9). Each of the three subtypes are transcribed by a different promoter, and thus, are considered as three different proteins (9). At present, the regulatory mechanisms of the three proteins remain largely unknown. Of the three subtypes, Fbw7α serves a leading ubiquitylation role (9). All of the three isoforms contain a dimerization-domain that mediates protein dimerization and regulates substrate binding and ubiquitination, an F-box connecting Skp1 and a WD40 repeat region that forms a β propeller, binding to phosphorylated substrates (9). Fbw7 binds to Skp1, Cul1 and E3 ubiquitin-protein ligase RBX1 to form an SCF E3 ubiquitin ligase, which allows the ubiquitination of substrates, together with E1 ubiquitin-activating and E2 ubiquitin-conjugating enzymes (Fig. 1). The cell division control protein 4 phosphorylation domain (CPD) of substrates is recognized by Fbw7 and leads to their ubiquitylation subsequent to being phosphorylated by glycogen synthase kinase 3 (GSK3). The majority of substrates that are recognized for degradation by Fbw7 contain at least one CPD (10). Numerous substrates of Fbw7, including Myc proto-oncogene protein (c-Myc), Neurogenic locus notch homolog protein (Notch), cyclin E and c-Jun, are vital due to their important regulatory role in tumor progression; Fbw7 serves as a scavenger by degrading such substrates (9). Additionally, previous studies demonstrated that substrates of Fbw7, including myeloid cell leukemia 1, mediator complex subunit 13/13 ligand, Krüppel-like factor 5, thymine guanine-interacting factor and numerous other proteins, may additionally exert their influence on tumor progression (Fig. 2) (11–14).

In normal tissues, Fbw7 is stably expressed, maintaining a balance between tumor suppressor proteins and proto-oncoproteins in vivo, thus inhibiting tumor progression (15). In tumor tissues, FBW7 is typically mutated, resulting in the downregulation or dysfunction of Fbw7 (15). During transcription, multiple transcriptional factors bind to Fbw7 mRNA to decrease the expression level of Fbw7, including a number of miRNAs (16,17) and p53 (18). Proteins may bind to the functional region of Fbw7, resulting in an incomplete or non-functional E3 ubiquitin ligase and other proteins may promote the self-ubiquitination of Fbw7, targeting itself for degradation, including the role of Parkin (19). Upregulation of proteins that result in the downregulation, dysfunction or degradation of Fbw7 expression serve key roles in tumorigenesis (Fig. 3).

Missense point mutations on three arginine residues (R465, R479 and R505) occurring at the β propeller phosphorylation-binding site, impair the substrate recognition function of Fbw7 (9). Additionally, monoallelic or biallelic knockouts or the hypermethylation of the promoter of FBW7 may occur in tumors, in humans and in mice (20–22). Numerous previous studies demonstrated that microRNAs (miRs), including miR-223 and miR-27a, bind to Fbw7 mRNA in tumors, leading to the inhibition of Fbw7 expression (23,24). Dimerization and post-transcriptional modifications stabilize the structure of Fbw7. Specifically, dimerization of Fbw7 improves its affinity for substrates, whereas, post-transcriptional modifications allow Fbw7 to alter between an autocatalytic mode and a substrate degradation mode (7). A mutation of the CPD at the binding site of Fbw7 decreases the affinity of Fbw7 for a substrate, resulting in downstream substrate accumulation (25). In addition to mutations of FBW7 and modifications of product structure subsequent to transcription and translation, the expression of Fbw7 is regulated by a variety of other factors. Ubiquitin specific peptidase (Usp) 28 regulates the stability of Fbw7 and the degradation of substrates through a series of complex mechanisms (26). Loss of the deubiquitinase Usp28 monoallele stabilizes and facilitates Fbw7-mediated substrate degradation, whereas, complete knockout of Usp28 promotes the degradation of Fbw7, leading to the accumulation of Fbw7 substrates (26). Cellular tumor antigen p53 (p53) directly binds to the first exon of FBW7 and promotes Fbw7 expression. Therefore, targeted activation of the p53 signaling pathway exerts antitumor effects by restoring Fbw7 expression (18). In addition, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), CCAAT/enhancer-binding protein-δ (C/EBP-δ), hairy and enhancer of split (Hes)-5 and Numb additionally regulate the expression of Fbw7 (17). Of the aforementioned proteins, C/EBP-δ and Hes-5 are additionally substrates of Fbw7 (13,27).

Fbw7 serves a crucial role in chemoresistance. Chemotherapy is an effective adjuvant therapy to radical surgery. However, the chemoresistance that cancer cells develop to various chemotherapy drugs is one of the principal obstacles of successfully treating cancer. The mutation in FBW7, including FBW7 missense mutation in three arginine residues (R465, R479 and R505), which leads to dysfunctional Fbw7, can cause the accumulation of numerous substrates, which may be important in chemoresistance (28). Gong et al (29) conducted a comprehensive review of the role of F-box proteins in chemoresistance, including Fbw7. Numerous previous studies investigated the involvement of Fbw7 in the chemoresistance of numerous types of cancer (11,30–32). A number of downstream targets of Fbw7, including c-Myc, nuclear factor erythroid 2-related factor 2, myeloid leukemia cell differentiation protein Mcl-1 (Mcl-1) and transcription factor SOX-9, are involved in chemoresistance of various types of cancer, including colorectal cancer, gastric cancer and pancreatic cancer (11,30–32). In comparison, a number of upstream proteins, including Epstein-Barr virus nuclear antigen-binding protein 2 (33), C/EBP-δ (13) and miR-27a (34), may regulate FBW7 to increase drug sensitivity. Therefore, the downregulation of such proteins may lead to chemoresistance, and increasing the expression of these proteins may be a novel method for overcoming chemoresistance. Additionally, the miR-223/Fbw7 signaling pathway has been demonstrated to serve an important role in chemoresistance of numerous gastrointestinal malignancies, including oral and esophageal squamous (35), gastric (36), pancreatic (37) cancer. Therefore, targeting the miR-223/Fbw7 pathway may be an effective way to overcome chemoresistance in gastrointestinal cancer.

Fbw7 is able to promote ubiquitination and degrade a number of key proteins that regulate the cell cycle, proliferation and apoptosis and thus, serves as a tumor suppressor. In mitosis, the deletion of Fbw7 causes hyperphosphorylation of a serine residue at position 18 of the centromere recognition protein, histone H3-like centromeric protein-A, by cyclin E1/cyclin-dependent kinase 2 (CDK2) resulting in the inability of the centromere to become localized, in addition to increased chromosomal instability and the promotion of tumorigenesis (38). Fbw7 additionally mediates γ-catenin ubiquitination, resulting in an inhibition of the G2/M cell cycle transition and cell proliferation (39). Furthermore, Fbw7 is closely associated with epithelial to mesenchymal transition (EMT), invasion and metastasis (40). Numerous previous studies investigated the association between FBW7 mutations and clinicopathological features of gastrointestinal malignancies (Table I). A number of the previous studies in Table I suggested that a poor prognosis was closely associated with FBW7 mutations. In a number of previous studies, it was demonstrated that aberrant Fbw7 expression additionally serves a pivotal role in the resistance of numerous gastrointestinal tumors to chemotherapeutic drugs (Table II). Therefore, examining novel methods to restore the physiological expression levels of Fbw7 may increase the sensitivity of tumors to chemotherapy and thus facilitate the treatment of cancer.

Additionally, Fbw7 is involved in the progression of other tumors. In a previous study by Yu et al (54), transfection of Fbw7 into a non-small cell lung cancer cell line, NCI-H1299, which exhibits low endogenous expression levels of Fbw7, significantly increased its chemosensitivity to cisplatin, which was closely associated with the effect of Fbw7 on EMT. Therefore, Fbw7 may be regarded as a potential target for lung cancer resistance (75). An additional previous study on drug resistance in non-small cell lung cancer demonstrated that ERK, combined with GSK3β, phosphorylated the serine 159 residue of Mcl-1, which promoted the degradation of Mcl-1 in the nucleus by binding to Fbw7. In tumor tissues, the lack of Fbw7 disrupted this process and induced drug resistance in non-small cell lung cancer (76). Lin et al (77) demonstrated that Fbw7 overexpression inhibited proliferation, invasion and metastasis of the glioma cell lines, U251 and U373, by downregulating Aurora B, Mcl-1 and Notch-1 expression levels, and enhanced the cytotoxicity of temozolomide. Fbw7 additionally serves a role in the development of triple-negative breast cancer. Takada et al (78) demonstrated that EgIN2 prolyl hydroxylase promoted tumorigenesis in breast cancer and was regulated by Fbw7. Following phosphorylation of GSK3β at the C-terminus of EgIN2, the latter became ubiquitylated and degraded by Fbw7 (78). In addition, Fbw7 overexpression significantly decreased the viability of the activated B cell-like diffuse large B lymphoma cell lines, SU-DHL-2 and OCI-LY-3, and increased their apoptotic rate (79). This process is caused by Fbw7 ubiquitination and degradation of STAT3 and phosphorylated STAT3^Tyr705, resulting in the dysfunction of downstream anti-apoptotic proteins, Myc, survivin, Mcl-1, serine/threonine-protein kinase pim-1, B-cell lymphoma-2 (Bcl-2) and Bcl2-associated agonist of cell death (79).

Dysfunctional Fbw7 is closely associated with the progression, invasion, metastasis and chemoresistance of tumors as a result of deficiencies in the ubiquitylation and degradation of substrates that serve as oncoproteins in tumor progression. In gastrointestinal tumors, the Fbw7 expression level is typically aberrantly downregulated, and the detailed mechanisms involved are diverse. At the genetic level, FBW7 mutations may lead to increased dysfunctional expression. At the transcriptional level, miRs bind to Fbw7 mRNA, thus the proteins are not translated. At the post-transcriptional level, the stability of Fbw7 is regulated by numerous various upstream regulatory proteins, whereas, physiological ubiquitination function is abrogated by deubiquitinases. In addition, mutations in the CPD region of substrates result in a loss of affinity to Fbw7, resulting in dysfunctional ubiquitination by Fbw7. The frequent presence of mutations in FBW7 in tumors may constitute FBW7 as an early tumor screening gene. Fbw7 may additionally be used as an essential protein target for targeted therapy to reverse chemoresistance. Approaches against Fbw7 in anti-tumor therapy may include knocking out FBW7 variant genes, targeting upstream proteins of Fbw7 and substrates of Fbw7 that have cancer-promoting effects, and exogenously upregulating the expression of Fbw7 to reverse tumorigenesis.

Bromodomain containing protein-7 (BRD7), is a subunit of switch/sucrose non-fermenting (SWI/SNF), which is an evolutionarily conserved, large (~2 MDa) multi-subunit, ATP-dependent chromatin remodeling complex that regulates epigenetic architecture and cellular identity (80). Similar to Fbw7, mutations of BRD7 may lead to SWI/SNF dysfunction, which causes aberrant gene expression leading to various diseases, including prostate cancer, breast cancer and nasopharyngeal cancer (80–82). The mechanisms include regulating the cell cycle, serving as a co-activator of p53, c-Myc, HIF-α and NF-κB, and downregulating the expression of BRD7 in cancer (83). Therefore, it was hypothesized that Fbw7 and BRD7 may be tumor suppressors, and they may be synergistic in tumor inhibition. However, the specific association between Fbw7 and BRD7 remains unknown, and requires further study.

Compared with other gastrointestinal malignancies, the survival rate for pancreatic cancer is decreased, suggesting the urgency in identifying specific targets to reduce the degree of radical surgery undertaken. Although a variety of adjuvant and neoadjuvant chemotherapeutic agents exist, the overall survival rate of pancreatic cancer has remained unaltered over the past few decades. Therefore, studies on Fbw7 may provide novel insight for targeted therapy for advanced pancreatic cancer. However, studies of the role of Fbw7 in pancreatic cancer have only gradually emerged in recent years (71,72,84). A previous study demonstrated that Fbw7 regulates the expression of NF-κB and vice versa (85). NF-κB is closely correlated with angiogenesis, invasion and metastasis of pancreatic cancer (86). However, limited studies exist on the association between Fbw7 and NF-κB in pancreatic cancer. Therefore, the regulation of Fbw7 and the NF-κB signaling pathway may become the focus of future studies in targeted therapy for pancreatic cancer.

In conclusion, the present review discusses the mechanisms of Fbw7 in the progression of gastrointestinal malignancies. Fbw7, in addition to upstream and downstream regulatory proteins, were suggested to be potential tumor therapeutic targets. Previous studies provided insight for the regulatory mechanisms of Fbw7 in gastrointestinal malignancies. However, specific issues require investigation. Upstream and downstream signaling molecules and signaling pathways that specifically affect Fbw7 expression have not yet been examined. Additionally, the diagnostic specificity and sensitivity of FBW7 as a biomarker for cancer and the veracity of prognosis prediction requires further improvement. Furthermore, large-scale clinical and multicenter trials as opposed to cell culture or animal studies require gradual implementation to examine chemotherapeutics targeting Fbw7.