Controversial roles of cold‑inducible RNA‑binding protein in human cancer (Review)

  • Authors:
    • Young-Mi Kim
    • Suntaek Hong
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  • Published online on: September 24, 2021
  • Article Number: 91
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Cold‑inducible RNA‑binding protein (CIRBP) is a cold‑shock protein comprised of an RNA‑binding motif that is induced by several stressors, such as cold shock, UV radiation, nutrient deprivation, reactive oxygen species and hypoxia. CIRBP can modulate post‑transcriptional regulation of target mRNA, which is required to control DNA repair, circadian rhythms, cell growth, telomere integrity and cardiac physiology. In addition, the crucial function of CIRBP in various human diseases, including cancers and inflammatory disease, has been reported. Although CIRBP is primarily considered to be an oncogene, it may also serve a role in tumor suppression. In the present study, the controversial roles of CIRBP in various human cancers is summarized, with a focus on the interconnectivity between CIRBP and its target mRNAs involved in tumorigenesis. CIRBP may represent an important prognostic marker and therapeutic target for cancer therapy.

1. Introduction

Cold-inducible RNA-binding protein (CIRBP; also called CIRP and hnRNP A18) was identified as a cold-shock protein and an RNA-binding protein (RBP) expressed following a variety of stressors, such as hypoxia, cold shock and UV radiation (1-3). In total, two major CRIBP transcripts are expressed in cells through N6-methyladenosine modification-mediated alternative splicing (2,4-6). The large isoform of CIRBP (CIRBP-L) contains 297 amino acids and another short one (CIRBP-S) encodes 172 amino acids (Fig. 1). CIRBP is translated in the nucleus and migrates to the cytoplasm following stimulation (1,7). CIRBP contains an RNA-recognition motif (RRM) in the N-terminal domain and an arginine-rich motif (RGG) in the C-terminal region (1); it interacts with the 5′ or 3′-UTR of partner mRNAs through its RRM and regulates its expression post-transcriptionally (1,8). The RGG domain of CIRBP induces the protein-protein interaction, thereby modulating the protein-RNA interaction. Therefore, it is likely that CIRBP acts as a chaperone protein to interact and support RNA structure, assembly and transport of various proteins (9).

Moreover, CIRBP participates in multiple cellular signaling pathways as a crucial regulator. In the apoptosis pathway, mild hypothermia can protect cells from death in part through CIRBP, which activates the MAPK and NF-κB pathways (3). This indicates that CIRBP functions as a regulator of cell viability by activating survival signaling. Under mild hypothermia and UV radiation, CIRBP upregulates the expression of thioredoxin (TRX), which protects cells from oxidative damage by sequestering reactive oxygen species (ROS) (10,11). These findings indicate that CIRBP can induce anti-senescence signaling through TRX-mediated antioxidant activity. In addition, CIRBP is involved in various biological processes, including DNA repair, circadian clock regulation, telomere integrity, nutrient deficiency, inflammatory response signaling and cardiac electrophysiology (12-18). Furthermore, CIRBP is also involved in various human diseases, including sepsis, Alzheimer's disease and pancreatitis (19-24).

In recent years, numerous studies have suggested the involvement of CIRBP in several forms of human cancer. In the present review, the roles of CIRBP and its target mRNAs in cancer are summarized, and its potential as a therapeutic target is evaluated.

2. Controversial roles of CIRBP in regulating hallmarks of cancer

RBPs not only serve important roles in multiple physiological signaling pathways, but also act as important regulators of cancer genesis and progression. Several studies have reported that RBPs influence cancer progression by acting as either oncogenes or tumor suppressors (25,26). In order for normal cells to develop into cancer cells, they must go through a multi-step process to acquire the hallmarks of cancer. Hallmarks of cancer have been previously described and updated with newly identified characteristics of cancer (27). In the present review, the role of CIRBP in human cancers was summarized based on the hallmarks of cancer. Similar to other RBPs, CIRBP has a promotive or inhibitory regulatory effect on carcinogenesis, depending on the cancer subtype (Table I).

Table I

Expression and controversial roles of CIRBP in human cancers.

Table I

Expression and controversial roles of CIRBP in human cancers.

First author(s), yearCancer typeExperimental methodExpression in cancerRole of CIRBP in cancerCohort/cell line(Refs.)
Guo et al, 2010BreastRT-qPCR and western blottingUpregulatedPromoting proliferation and decreasing apoptosisBreast cancer cells(69)
Chang et al, 2016BreastIHCUpregulatedPromoting proliferation, migration and invasion91 TMA samples(30)
Indacochea et al, 2021BreastWestern blottingUpregulatedPromoting proliferationBreast cancer cells(31)
Chang et al, 2016MelanomaIHC and western blottingUpregulatedPromoting migration and invasion77 TMA samples; melanoma cells(30)
Biade et al, 2006OvarianMicroarray and RT-qPCRDownregulatedReducing cell doubling time86 specimens(81)
Artero-Castro et al, 2009ColonWestern blotting and RT-qPCRUpregulatedPromoting proliferation31 patients(73)
Sakurai et al, 2015LiverIHCUpregulatedIncreasing HCC recurrence12 patients who underwent hepatectomy(53)
Lu et al, 2018BladderIF and western blottingUpregulatedPromoting proliferation and migrationBladder cancer and paracancerous tissue samples (n=20); bladder cancer cells(29)
Hamid et al, 2003Endometrial carcinomaIHC and western blottingDownregulatedDecreasing proliferationEndometrial carcinomas (n-39); normal endometria (n=27)(36)
Lin et al, 2019Nasopharyngeal carcinomaIHC, RT-qPCR and GEO datasetDownregulatedDecreasing proliferationNP and NPC samples; GSE53819, GSE12452 and GSE13597(56)

[i] CIRBP, cold-inducible RNA-binding protein; GEO, Gene Expression Omnibus; HCC, hepatocellular carcinoma; IF, immunofluorescence; IHC, immunohistochemistry; NP, nasopharyngeal epithelial tissues; NPC, nasopharyngeal cancer; RT-qPCR, reverse transcription-quantitative PCR; TMA, tissue microarray.

CIRBP in proliferative signaling

The most fundamental characteristic of cancer cells is the capacity to maintain unlimited proliferation. Healthy tissues maintain structure and function by carefully regulating cell growth to ensure cell number homeostasis, whereas cancer cells exhibit excessive proliferation (28). CIRBP significantly promotes the proliferation of breast and bladder cancer cells (29,30). Recently, it has been reported that CIRBP expression is elevated in luminal breast cancer, promoting cell proliferation and clonogenicity (31). Notably, CIRBP levels are closely associated with a less favorable survival rate in patients with the luminal subtype (31). Moreover, CIRBP enhances the proliferation of immature male germ cells through its interaction with dual-specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) in mice (32).

In addition to its role in carcinoma, CIRBP expression is also increased in pituitary corticotroph adenoma, which promotes cell proliferation and tumor growth via Erk signaling (33). However, certain reports have revealed that CIRBP can suppress the tumorigenesis of breast cancer cells (34,35). High expression of CIRBP in breast tissue has been correlated with a more favorable prognosis in postmenopausal women with breast cancer who have experienced childbirth (34). Another study also reported that CIRBP overexpression interferes with cell proliferation during mammary gland development (35). In addition, CIRBP expression is highest in normal endometrium, but significantly reduced in endometrial carcinoma (36). Recently, CIRBP was also reported to induce translation of p27, a CDK inhibitor, thereby reducing cell proliferation (37).

CIRBP in replicative immortality

Telomeres are essential for genome stability, as they protect the fusion of linear chromosomes (38). Telomeres are extended and maintained by telomerase, which is comprised of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC). Although it is virtually silent in somatic cells, TERT expression is activated in numerous tumor types, giving cancer cells the hallmark feature of replicative immortality (39). For the maintenance of telomere length, CIRBP has been identified as a telomerase-associating protein through its RRG domain (40). Upon direct interaction with TERC, CIRBP promotes the formation of the telomerase complex. In addition, CIRBP enhances the telomerase activity through stabilization of TERT mRNA. As activated TERT is a common trait in most cancer types, this may represent an important approach to understanding the exact role of CIRBP in the regulation of telomerase activity.

CIRBP in the cell death pathway

Apoptosis acts as a natural barrier to tumorigenesis and is suppressed in tumors that have successfully progressed to a treatment-resistant state (41). Previous studies have reported an association between CIRBP and apoptosis. For example, CIRBP-overexpressing cells have a reduced rate of apoptosis owing to reduced DNA damage (42,43). A recent study reported that CIRBP inhibits amyloid β-induced activation of apoptosis via anti-oxidative pathways in cortical neurons (44). Notably, CIRBP stimulates NLRP3 inflammasome activation and simultaneously induces caspase-1 activation and IL-1β release, resulting in pyroptosis, a type of inflammatory cell death (45). Additionally, cancer cells must evade pathways involving tumor suppressor genes, such as p53 and retinoblastoma protein, which negatively regulate proliferation (46). It has been reported that CIRBP inhibits p53, thereby reducing apoptosis (42) and suppressing the damage of testicular tissue (47), but the exact mechanism is still unknown.

CIRBP in tumor-promoting inflammation

Cancer cells use the inflammatory microenvironment to promote tumor growth. Tumor-promoting inflammation is closely associated with tumor progression and metastasis (48). Certain studies have reported that CIRBP acts as a mediator of cancer-associated inflammation in numerous cancer types. Chronic inflammation is known to increase the risk of intestinal cancer in patients with inflammatory bowel disease (IBD) (49). In patients with IBD, CIRBP is positively correlated with IL-23A (50), a known oncogenic cytokine, and IL-17, which is known to enhance cancer-induced inflammation (51,52). Moreover, CIRBP expression is higher in inflammatory cells compared with epithelial cells in patients with IBD, and the same result is observed in patients with colitis-associated colorectal cancer (CAC) (52). In another study, CIRBP deficiency resulted in decreased expression of inflammatory cytokines in liver-specific macrophages and attenuated tumorigenesis in mice (53). Oral chronic inflammation is a crucial part of oral squamous cell carcinoma (OSCC) promotion (54). The expression of CIRBP and toll-like receptor 4 (TLR4) is high, and a positive correlation in their expression levels has been reported in patients with OSCC (55). In a previous study, it was reported that CIRBP induced an inflammatory response through TLR4 (15). Overall, these findings indicate that CIRBP can modulate the development of cancer through the regulation of the inflammatory response.

CIRBP in invasion and metastasis

A major characteristic that distinguishes cancer cells from normal cells is their ability to spread through invasion and metastasis. Metastasis is the major cause of cancer-related mortality in patients. In addition to the previously mentioned role of CIRBP in proliferative signaling, several studies have reported that CIRBP is involved in the metastasis of multiple cancer types (56,57). CIRBP is upregulated in 57% of human bladder cancer tissues and cancer cell lines, and it is reported to enhance migration and metastasis in vivo and in vitro (29). Breast cancer is one of the leading causes of cancer-associated mortality in women (58). Notably, progressive breast cancer is virtually incurable and the cause of a high mortality rate in patients. CIRBP downregulation was shown to reduce the invasion and migration capacity of breast cancer cells, and CIRBP upregulation was observed in more aggressive breast cancer subtypes compared with ductal carcinoma, in situ (30). Moreover, CIRBP exhibited strong metastasis-promoting activity in invasive ductal carcinoma (59) and invasive brain metastases (60). In addition, epithelial-mesenchymal transition (EMT) is a crucial process for cancers metastasizing from the original site to other organs (61). During TGF-β-induced EMT, CIRBP silencing was shown to inhibit the upregulation of the master regulator, Snail, thereby suppressing the migration of hepatocellular carcinoma cells (62). This indicates that CIRBP is involved in metastasis of HCC and, therefore, the low survival rate of patients with HCC. However, in contrast to its oncogenic role in certain cancer types, several studies have shown that CIRBP can suppress cancer metastasis (56,63). CIRBP is negatively correlated with distant metastasis in nasopharyngeal cancer (56), and is downregulated in patients with aggressive metastatic TNBC (63).

CIRBP in angiogenesis

Angiogenesis is regulated by chemical signals such as VEGF, which binds to endothelial cell receptors and initiates intracellular signaling to promote the growth of new blood vessels (64). Neoangiogenesis represents an important step in cancer and is required to supply nutrients and oxygen to the tumoral cells, and to remove the waste products (65). Melanoma tumors with decreased CIRBP expression exhibit specifically downregulated VEGF expression compared with controls when using the angiogenesis proteome profiler array (30). Conversely, strong staining of CD31, an angiogenesis marker, was observed in a skin wound-healing sample of CIRBP-knockout mice compared with wild-type mice (66). Moreover, a recent study demonstrated that knockdown of CIRBP enhances the regeneration of ischemic muscle tissues, damaged by unilateral ligation of the hindlimb femoral artery, through acceleration of angiogenesis and M2-like macrophage polarization (67). These studies strongly indicate that CIRBP serves a role in angiogenesis, which may modulate tumor growth.

3. Molecular mechanism of CIRBP for regulating target RNAs

CIRBP is commonly overexpressed in a number of cancer tissues and cell lines. It acts as an oncogene by increasing the stability and translation of cancer-associated mRNA targets. However, several studies have also suggested the potential of CIRBP as a tumor suppressor by modulating the stability of target mRNAs (Fig. 1; Table II). CIRBP can bind the 5′ and 3′-UTRs of mRNAs, as well as poly U sequences at the 3′-ends (68). It has been suggested that its binding is important for the translation of interacting mRNAs by regulating polyadenylation and 3′-end cleavage (7,37). In the context of stress-induced regulation, abnormal upregulation of CIRBP promotes hypoxia inducible factor (HIF)-1α expression (29). Due to stabilization of the HIF-1α mRNA transcript, increased HIF-1α can bind to the promoter region of prostaglandin I2 synthase, a tumor suppressor, resulting in its downregulation (29) and an increase in the growth and invasion of cancer cells. An in vitro study demonstrated that CIRBP can also increase the mRNA stability of cyclin E1 in breast cancer (69). Responding to DNA damage, CIRBP can bind to the 3′-UTRs of TRX, replication protein A2 and ATR serine/threonine kinase mRNAs and increase their translational efficiencies (7,10,70). A recent study reported that, in luminal breast cancer, CIRBP is upregulated and enhances oncogenic properties by downregulating the CST3 mRNA expression levels (31). Notably, CIRBP can also enhance telomere maintenance by upregulating TERT mRNA levels (40). In most human cancer cells, active telomerase is upregulated, highlighting the importance of TERT expression and telomerase activity in promoting cancer progression (71,72). Other CIRBP-mediated regulatory effects have also been reported in human cancers. For example, CIRBP can increase phosphorylation of ribosomal protein S6, and eukaryotic translation initiation factor 4E-binding protein1, a protein that regulates the elongation phases of translation (73). In addition, CIRBP can promote cell proliferation by upregulating cyclin D1 and downregulating p27 via ERK signaling (33). Within the MAPK pathway, ERK signaling is involved in various human diseases, including inflammatory-related diseases and cancer (74,75). Additionally, CIRBP reduces phosphorylation of p27 by interacting with DYRK1B and inhibiting its binding to p27 in mouse germ cells (32). CIRBP also interferes with the phosphorylation of cyclin D1 by DYRK1B, thereby stabilizing cyclin D1 and ultimately increasing proliferation (32). Conversely, another study showed that CIRBP had an anti-proliferative function by binding to the 5′-UTR of p27 and increasing p27 expression in mouse embryonic fibroblasts (37).

Table II

Target mRNAs of CIRBP.

Table II

Target mRNAs of CIRBP.

Author, yearTarget mRNABinding siteRegulation of CIRBP for target mRNABiological roles of target mRNACell lines(Refs.)
Guo et al, 2010Cyclin E13′-UTR and CDSStabilization of the transcriptRegulating G1/S phase transitionBreast cancer cells(69)
Lu et al, 2018HIF-1α3′-UTRStabilization of the transcriptResponse to hypoxiaBladder cancer cells(29)
Chang et al, 2016TRX3′-UTRStabilization of the transcriptCellular redox metabolismMelanoma cells(30)
Chang et al, 2016ATR and RPA23′-UTRStabilization of the transcriptDNA repairBreast cancer cells(30)
Zhang et al, 2016TERT3′-UTRStabilization of the transcriptTelomerase componentsUterus, cervix cells(40)
Morf et al, 2012CLOCK3′-UTRStabilization of the transcriptCircadian geneFibroblasts(13)
Roilo et al, 2018p275′-UTRIncreasing translationCyclin-dependent kinase inhibitorBreast cancer cells(37)
Indacochea et al, 2021CST3UnknownDecreasing translationTumor suppressorBreast cancer cells(31)
Jian et al, 2016Cyclin D1 p27Unknown UnknownIncreasing translation Decreasing translationRegulating G1/S phase transition Cyclin-dependent kinase inhibitorPituitary corticotroph cells(33)
Artero-Castro et al, 2009S6 and 4E-BP1UnknownIncreasing translationInitiation and elongation phases of translationMEFs(73)

[i] 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; ATR, ATR serine/threonine kinase; CDS, coding sequence; CIRBP, cold-inducible RNA-binding protein; CST3, cystatin C; HIF-1α, hypoxia inducible factor-1α; MEF, mouse embryonic fibroblast; RPA2, replication protein A2; TERT, telomerase reverse transcriptase; TRX, thioredoxin; UTR, untranslated region; CLOCK, clock circadian regulator.

The association between cancer and inflammation has been reported in numerous studies. In chronic airway inflammation disease, CIRBP upregulates mucin-5AC, which is associated with pulmonary disease via NF-κB/TLR4 signaling (76). In a CAC mouse model, CIRBP depletion reduced the level of inflammation markers, such as TNF-α and IL-23, and consequently decreased the susceptibility to CAC development (52). CIRBP can induce ROS accumulation by increasing the expression of inflammatory cytokines (IL-6 and IL-1β) in liver-specific macrophages. Conversely, CIRBP-knockout mice exhibited a decreased level of inflammatory cytokines with attenuated ROS accumulation (53). Together, these studies suggest that CIRBP may function as a tumor promoter or tumor suppressor by modulating the expression of inflammatory mediators.

4. CIRBP as a prognostic marker in cancer

Applicable prognostic cancer biomarkers in cancer are crucial for better tumor prediction and treatment planning. Several studies have shown the potential of RBPs as prognostic markers for various types of cancer, such as gastric or breast cancer (77,78). Consequently, databases such as TCGA ( and GEO ( containing the expression level of CIRBP in samples from patients with cancer were selected, and the potential of CIRBP as a prognostic marker in human cancers was presented (Table III).

Table III

CIRBP as a prognostic biomarker in human cancer.

Table III

CIRBP as a prognostic biomarker in human cancer.

Author, yearCancer typeType of evidenceStatisticsCutoff point for prognosis(Refs.)
He and Zuo, 2019NSCLCCox analysis of 1,331 early-stage NSCLC specimens (TCGA and GEO)GSE31210: HR, 0.25 (CI, 0.13-0.48), P=3x10-5; GSE37745: HR, 0.65 (CI, 0.45-095), P=2.7x10-2; GSE50081: HR, 0.6 (CI, 0.39- 0.96), P=2.3x10-2; TCGA: HR, 0.67 (CI, 0.53-0.85), P=8.4x10-4Cox regression analysis; HR<1 and P<0.05; good prognosis(80)
Chen et al, 2020NSCLCMethylation sequencing of 119 patients with NSCLC with or without LN metastasisAUC of the LN metastasis: 88.6% (95% CI, 87.8-89.4) in plasma samples and 74.9% (95% CI, 72.2-77.6) in tissue samples of malignant lung nodulesFDR cutoff <0.2; poor prognosis(57)
Ren et al, 2014OSCCIHC of 61 specimens from patients with OSCCT stage, P=0.028; Clinical stage, P=0.002; Histological classification, P=0.022; Lymph node metastasis, P=0.033Univariate analysis; P<0.05; poor prognosis(55)
Biade et al, 2006Ovarian cancerMicroarray of benign (n=29), borderline (n=34) and malignant (n=57) ovarian tumor specimensPAM Score: Benign, 0.2298; Malignant, 0PAM score>0; good prognosis(81)
Lin et al, 2019NPCRT-qPCR of NPC tissue (n=38) and non-cancerous NP tissue (n=23); TMA of NPC tissue (n=177) and non-cancerous NP tissue (n=61)Univariate analysis: T1-T2 vs. T3-T4: HR, 0.474 (CI, 0.253-0.887), P=0.020; N0-N1 vs. N2-N3: HR, 0.475 (CI, 0.256-0.881), P=0.018; M: No vs. Yes: HR, 0.146 (CI, 0.067-0.318), P<0.001; C: I-II vs. III-IV: HR, 0.481 (CI, 0.255-0.907), P=0.024Univariate analysis; P<0.05; good prognosis(56)
Mangé et al, 2012Breast cancerMicroarray of DCIS (n=20) and patients with IBC (n=20); ELISA of DCIS (n=61) and patients with IBC (n=59); IHC of DCIS and IBC specimens (n=20)AUC in the difference between DCIS and IBC: HR, 0.794 (95% CI, 0.674-0.877)Log-rank test; P<0.05; good prognosis(83)
Dankner et al, 2021 Breast/lung/otherIHC and TMA, RNA seq of 164 patients with, minimally invasive brain metastasis (n=56) or highly invasive brain metastasis (n=108); breast (n=83); lung (n=38); other (n=43)IHC H score: MI<HI, P=0.0096Log-rank test; P<0.05; poor prognosis(60)

[i] AUC, area under the ROC curve; C, clinical; CI, confidence interval; CIRBP, cold-inducible RNA-binding protein; DCIS, ductal carcinoma in situ; GEO, gene expression omnibus; HR, hazard ratio; IBC, invasive breast carcinoma; FDR, false discovery rate; IHC, immunohistochemistry; M, distant metastasis; N, regional lymph nodes; NPC, nasopharyngeal carcinoma; NSCLC, non-small cell lung cancer; PAM, prediction analysis of microarrays; OSCC, oral squamous cell carcinoma; T, primary tumor; TCGA, The Cancer Genome Atlas; TMA, tissue microarray; MI, minimally invasive lesion; HI, highly invasive lesion.

A recent study indicated that CIRBP is methylated in the plasma of non-small cell lung carcinoma (NSCLC) with occult lymph node metastasis. RNA sequencing data obtained from The Cancer Genome Atlas (TCGA) also revealed that the mRNA expression levels of CIRBP are higher in metastatic tissues compared with primary breast tumor samples (79). Similar to previous RNA sequencing data, CIRBP is upregulated in invasive ductal carcinoma (59) and in patient with brain metastases with a high recurrence rate (60). These studies suggest that CIRBP can promote cancer metastasis. Conversely, CIRBP is inversely correlated with lymph node invasion and distant metastasis in nasopharyngeal carcinoma (56). Additionally, CIRBP is differentially upregulated in non-triple negative breast cancer (TNBC) compared with metastasis-related TNBC (63). Although the evidence of CIRBP involvement in metastasis is still incomplete, CIRBP may potentially represent a crucial component of the metastatic process.

To overcome low survival rate of patients with metastatic cancer, it is necessary to identify the biomarkers for early diagnosis before metastasis to distant organs. Recently, genomic profiling analysis using Gene Expression Omnibus and TCGA datasets revealed that high expression levels of CIRBP are correlated with good prognosis in patients with early-stage NSCLC with low metastasis (80). Stratification according to TNM classification revealed that a higher CIRBP expression level is frequently detected in T1-T2, M0 and I-II tumors compared with T3-T4, M1 and III-IV nasopharyngeal carcinoma tissues, respectively (56). Likewise, gene expression profiles based on microarrays have demonstrated that CIRBP is significantly upregulated in benign tumors compared with malignant ovarian cancers (81). Conversely, CIRBP is significantly associated with histological classification, clinical stages and lymph node metastasis in OSCC samples (55). Although it is important to classify the subtypes of breast cancer, there is currently no good parameter to distinguish invasive breast carcinoma (IBC) from ductal carcinoma in situ (DCIS) (82). By screening autoantibodies using protein microarrays with DCIS and IBC samples, CIRBP was identified as an autoantibody signature that could discriminate DCIS from IBC. This result indicates that CIRBP may represent a novel prognostic marker in breast cancer (83). CIRBP is also a splicing factor (SF), which are important factors in cancer progression (84,85). By comparing RNA expression levels of various SFs between primary cancer and their metastatic counterparts from TCGA, it was found that CIRBP expression is higher in metastatic tissues compared with original tumors (79). Along with SF, alternative splicing events (ASEs) are also responsible for cancer development and progression (86,87). RNA sequencing and ASE-related datasets of breast cancer samples obtained from TCGA revealed that CIRBP, may serve as a predictor for survival in prognostic-related ASE (59). Together, these results suggest that CIRBP may function as a prognostic marker in a number of cancer types.

5. CIRBP as a therapeutic target for cancer therapy

The use of cytotoxic drugs is the main treatment method for advanced and aggressive cancers, and cancers without specific therapeutic targets. However, resistance to cytotoxic chemotherapy and drug side effects are major barriers to attaining a complete response (88). Several studies have reported that resistance to chemotherapy is enhanced by secretory molecules that can promote the repair signaling coordinated by TLR4 (89,90). CIRBP can trigger the secretion of TNF-α through the activation of TLR4 and NF-κB in macrophages. Several studies have also reported that CIRBP can mediate inflammatory signaling via regulation of TLR4 signaling (76,91). Based on these results, CIRBP-derived oligopeptides or neutralizing antibodies were demonstrated to ameliorate sepsis-mediated injury of the lung and kidney (15,92,93). These CIRBP antagonists can block the interaction of extracellular CIRBP with TLR4/myeloid differentiation 2 receptor complex to inhibit the downstream signaling (15).

The circadian clock is an important molecular mechanism for the maintenance of homeostasis and its imbalance facilitates tumor progression (94). In various cancer types, circadian genes are associated with chemoresistance and cancer progression (95,96). Thus, there is a novel approach that indirectly or directly targets circadian clock genes to remove cancer and improve survival rates (97,98). Several studies have suggested that CIRBP can be used in cancer treatment by regulating circadian genes (13,68). Chemotherapeutic drugs can induce apoptosis, necrosis and autophagy in cancerous tissues (99,100). As CIRBP exerts a protective role in apoptosis in neurons and cardiac cells, combined therapy of cytotoxic drugs with anti-CIRBP therapeutics may improve the response efficacy and survival rate in patients with neuronal and cardiac abnormalities (101,102).

Small molecules that complement biologics, such as antibodies, have advantages of cost effectiveness and cell permeability for applications in cancer therapy. Several chemical probes targeting specific RBPs have been shown to be able to function as selective inhibitors by modulating RBP-target mRNA interactions (103-107). Recently, it has been reported that a probe can interfere with CIRBP-RNA associations, inhibit cytotoxic T-lymphocyte protein-4 and TRX expression, and suppress the progression of various cancer types without side effects (108). Further studies are needed to apply these CIRBP antagonists for cancer therapy in the future.

6. Conclusions

The present review summarized recent findings about the roles of CIRBP in cancer development, metastasis and cancer therapy (Fig. 2). During cancer proliferation and metastasis, the function of CIRBP appears to be driven primarily by promoting the stability and translation of target mRNAs. Conversely, certain studies have demonstrated that CIRBP serves as a tumor suppressor in cancer progression by modulating the multiple steps of cell proliferation. These controversial roles of CIRBP in human cancers may originate from the alternative splicing of the CIRBP transcript (2,4-6). Differentially expressed splicing variants may interact and modulate the different target mRNAs, depending on cancer subtypes or cell contexts. To understand the exact role of CIRBP in cancers, target mRNAs of each splicing isoform should be identified and the regulatory mechanism analyzed in human cancers. Clinical studies have shown that CIRBP may represent a prognostic marker of cancer progression. Although numerous studies have reported roles of CIRBP in cancer biology, further detailed studies are required to elucidate the exact role of CIRBP in human cancers and to evaluate the potential of the application of CIRBP-targeted cancer therapy.

Availability of data and materials

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Author's contributions

Y-MK and SH designed and discussed the contents and wrote the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

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Patient consent for publication

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Competing interests

The authors declare that they have no competing interests.


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De Leeuw F, Zhang T, Wauquier C, Huez G, Kruys V and Gueydan C: The cold-inducible RNA-binding protein migrates from the nucleus to cytoplasmic stress granules by a methylation-dependent mechanism and acts as a translational repressor. Exp Cell Res. 313:4130–4144. 2007. View Article : Google Scholar : PubMed/NCBI


Al-Fageeh MB and Smales CM: Cold-inducible RNA binding protein (CIRP) expression is modulated by alternative mRNAs. RNA. 15:1164–1176. 2009. View Article : Google Scholar :


Kaneko T and Kibayashi K: Mild hypothermia facilitates the expression of cold-inducible RNA-binding protein and heat shock protein 70.1 in mouse brain. Brain Res. 1466:128–136. 2012. View Article : Google Scholar


Horii Y, Shimaoka H, Horii K, Shiina T and Shimizu Y: Mild hypothermia causes a shift in the alternative splicing of cold-inducible RNA-binding protein transcripts in Syrian hamsters. Am J Physiol Regul Integr Comp Physiol. 317:R240–R247. 2019. View Article : Google Scholar : PubMed/NCBI


Gokhale NS, McIntyre AB, Mattocks MD, Holley CL, Lazear HM, Mason CE and Horner SM: Altered m6A modification of specific cellular transcripts affects flaviviridae infection. Mol Cell. 77:542–555.e8. 2020. View Article : Google Scholar


Liao Y, Tong L, Tang L and Wu S: The role of cold-inducible RNA binding protein in cell stress response. Int J Cancer. 141:2164–2173. 2017. View Article : Google Scholar


Yang C and Carrier F: The UV-inducible RNA-binding protein A18 (A18 hnRNP) plays a protective role in the genotoxic stress response. J Biol Chem. 276:47277–47284. 2001. View Article : Google Scholar


Sheikh MS, Carrier F, Papathanasiou MA, Hollander MC, Zhan Q, Yu K and Fornace AJ Jr: Identification of several human homologs of hamster DNA damage-inducible transcripts. Cloning and characterization of a novel UV-inducible cDNA that codes for a putative RNA-binding protein. J Biol Chem. 272:26720–26726. 1997. View Article : Google Scholar


Fujita J: Cold shock response in mammalian cells. J Mol Microbiol Biotechnol. 1:243–255. 1999.


Yang R, Weber DJ and Carrier F: Post-transcriptional regulation of thioredoxin by the stress inducible heterogenous ribonucleoprotein A18. Nucleic Acids Res. 34:1224–1236. 2006. View Article : Google Scholar


Lu J, Shen Y, Qian HY, Liu LJ, Zhou BC, Xiao Y, Mao JN, An GY, Rui MZ, Wang T and Zhu CL: Effects of mild hypothermia on the ROS and expression of caspase-3 mRNA and LC3 of hippocampus nerve cells in rats after cardiopulmonary resuscitation. World J Emerg Med. 5:298–305. 2014. View Article : Google Scholar :


Haley B, Paunesku T, Protić M and Woloschak GE: Response of heterogeneous ribonuclear proteins (hnRNP) to ionising radiation and their involvement in DNA damage repair. Int J Radiat Biol. 85:643–655. 2009. View Article : Google Scholar


Morf J, Rey G, Schneider K, Stratmann M, Fujita J, Naef F and Schibler U: Cold-inducible RNA-binding protein modulates circadian gene expression posttranscriptionally. Science. 338:379–383. 2012. View Article : Google Scholar : PubMed/NCBI


Denning NL, Aziz M, Murao A, Gurien SD, Ochani M, Prince JM and Wang P: Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis. JCI Insight. 5:e1341722020. View Article : Google Scholar :


Qiang X, Yang WL, Wu R, Zhou M, Jacob A, Dong W, Kuncewitch M, Ji Y, Yang H, Wang H, et al: Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. 19:1489–1495. 2013. View Article : Google Scholar


Zhong P, Peng J, Yuan M, Kong B and Huang H: Cold-inducible RNA-binding protein (CIRP) in inflammatory diseases: Molecular insights of its associated signalling pathways. Scand J Immunol. 93:e129492021. View Article : Google Scholar


Xie D, Geng L, Wang S, Xiong K, Zhao T, Wang G, Feng Z, Lv F, Wang C, Liang D, et al: Cold-inducible RNA-binding protein modulates atrial fibrillation onset by targeting multiple ion channels. Heart Rhythm. 17:998–1008. 2020. View Article : Google Scholar


Xie D, Geng L, Xiong K, Zhao T, Wang S, Xue J, Wang C, Wang G, Feng Z, Zhou H, et al: Cold-Inducible RNA-binding protein prevents an excessive heart rate response to stress by targeting phosphodiesterase. Circ Res. 126:1706–1720. 2020. View Article : Google Scholar


Aziz M, Brenner M and Wang P: Extracellular CIRP (eCIRP) and inflammation. J Leukoc Biol. 106:133–146. 2019. View Article : Google Scholar


Zhou Y, Dong H, Zhong Y, Huang J, Lv J and Li J: The cold-inducible RNA-binding protein (CIRP) level in peripheral blood predicts sepsis outcome. PLoS One. 10:e01377212015. View Article : Google Scholar :


Gong JD, Qi XF, Zhang Y and Li HL: Increased admission serum cold-inducible RNA-binding protein concentration is associated with prognosis of severe acute pancreatitis. Clin Chim Acta. 471:135–142. 2017. View Article : Google Scholar


Sharma A, Brenner M and Wang P: Potential role of extracellular CIRP in alcohol-induced Alzheimer's disease. Mol Neurobiol. 57:5000–5010. 2020. View Article : Google Scholar : PubMed/NCBI


Yoo IS, Lee SY, Park CK, Lee JC, Kim Y, Yoo SJ, Shim SC, Choi YS, Lee Y and Kang SW: Serum and synovial fluid concentrations of cold-inducible RNA-binding protein in patients with rheumatoid arthritis. Int J Rheum Dis. 21:148–154. 2018. View Article : Google Scholar


Lujan DA, Ochoa JL and Hartley RS: Cold-inducible RNA binding protein in cancer and inflammation. Wiley Interdiscip Rev RNA. Jan 11–2018.Epub ahead of print. View Article : Google Scholar


Kanemura Y, Mori K, Sakakibara S, Fujikawa H, Hayashi H, Nakano A, Matsumoto T, Tamura K, Imai T, Ohnishi T, et al: Musashi1, an evolutionarily conserved neural RNA-binding protein, is a versatile marker of human glioma cells in determining their cellular origin, malignancy, and proliferative activity. Differentiation. 68:141–152. 2001. View Article : Google Scholar


Wang Q, Wang F, Zhong W, Ling H, Wang J, Cui J, Xie T, Wen S and Chen J: RNA-binding protein RBM6 as a tumor suppressor gene represses the growth and progression in laryngocarcinoma. Gene. 697:26–34. 2019. View Article : Google Scholar


Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar


Kong N, Zhang H, Feng C, Liu C, Xiao Y, Zhang X, Mei L, Kim JS, Tao W and Ji X: Arsenene-mediated multiple independently targeted reactive oxygen species burst for cancer therapy. Nat Commun. 12:47772021. View Article : Google Scholar :


Lu M, Ge Q, Wang G, Luo Y and Wang X, Jiang W, Liu X, Wu CL, Xiao Y and Wang X: CIRBP is a novel oncogene in human bladder cancer inducing expression of HIF-1α. Cell Death Dis. 9:10462018. View Article : Google Scholar


Chang ET, Parekh PR, Yang Q, Nguyen DM and Carrier F: Heterogenous ribonucleoprotein A18 (hnRNP A18) promotes tumor growth by increasing protein translation of selected transcripts in cancer cells. Oncotarget. 7:10578–10593. 2016. View Article : Google Scholar


Indacochea A, Guerrero S, Ureña M, Araujo F, Coll O, LLeonart ME and Gebauer F: Cold-inducible RNA binding protein promotes breast cancer cell malignancy by regulating Cystatin C levels. RNA. 27:190–201. 2021. View Article : Google Scholar


Masuda T, Itoh K, Higashitsuji H, Higashitsuji H, Nakazawa N, Sakurai T, Liu Y, Tokuchi H, Fujita T, Zhao Y, et al: Cold-inducible RNA-binding protein (Cirp) interacts with Dyrk1b/Mirk and promotes proliferation of immature male germ cells in mice. Proc Natl Acad Sci USA. 109:10885–10890. 2012. View Article : Google Scholar


Jian F, Chen Y, Ning G, Fu W, Tang H, Chen X, Zhao Y, Zheng L, Pan S, Wang W, et al: Cold inducible RNA binding protein upregulation in pituitary corticotroph adenoma induces corticotroph cell proliferation via Erk signaling pathway. Oncotarget. 7:9175–9187. 2016. View Article : Google Scholar : PubMed/NCBI


Peri S, de Cicco RL, Santucci-Pereira J, Slifker M, Ross EA, Russo IH, Russo PA, Arslan AA, Belitskaya-Lévy I, Zeleniuch-Jacquotte A, et al: Defining the genomic signature of the parous breast. BMC Med Genomics. 5:462012. View Article : Google Scholar


Lujan DA, Garcia S, Vanderhoof J, Sifuentes J, Brandt Y, Wu Y, Guo X, Mitchell T, Howard T, Hathaway HJ and Hartley RS: Cold-inducible RNA binding protein in mouse mammary gland development. Tissue Cell. 48:577–587. 2016. View Article : Google Scholar


Hamid AA, Mandai M, Fujita J, Nanbu K, Kariya M, Kusakari T, Fukuhara K and Fujii S: Expression of cold-inducible RNA-binding protein in the normal endometrium, endometrial hyperplasia, and endometrial carcinoma. Int J Gynecol Pathol. 22:240–247. 2003. View Article : Google Scholar


Roilo M, Kullmann MK and Hengst L: Cold-inducible RNA-binding protein (CIRP) induces translation of the cell-cycle inhibitor p27Kip1. Nucleic Acids Res. 46:3198–3210. 2018. View Article : Google Scholar


Roake CM and Artandi SE: Regulation of human telomerase in homeostasis and disease. Nat Rev Mol Cell Biol. 21:384–397. 2020. View Article : Google Scholar


Yuan X, Larsson C and Xu D: Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: Old actors and new players. Oncogene. 38:6172–6183. 2019. View Article : Google Scholar


Zhang Y, Wu Y, Mao P, Li F, Han X, Zhang Y, Jiang S, Chen Y, Huang J, Liu D, et al: Cold-inducible RNA-binding protein CIRP/hnRNP A18 regulates telomerase activity in a temperature-dependent manner. Nucleic Acids Res. 44:761–775. 2016. View Article : Google Scholar


Adams JM and Cory S: The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 26:1324–1337. 2007. View Article : Google Scholar


Lee HN, Ahn SM and Jang HH: Cold-inducible RNA-binding protein, CIRP, inhibits DNA damage-induced apoptosis by regulating p53. Biochem Biophys Res Commun. 464:916–921. 2015. View Article : Google Scholar


Sun W, Bergmeier AP, Liao Y, Wu S and Tong L: CIRP sensitizes cancer cell responses to ionizing radiation. Radiat Res. 195:93–100. 2021.


Su F, Yang S, Wang H, Qiao Z, Zhao H and Qu Z: CIRBP ameliorates neuronal amyloid toxicity via antioxidative and antiapoptotic pathways in primary cortical neurons. Oxid Med Cell Longev. 2020:27861392020. View Article : Google Scholar


Yang WL, Sharma A, Wang Z, Li Z, Fan J and Wang P: Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome. Sci Rep. 6:265712016. View Article : Google Scholar


Li H, Han X, Yang S, Wang Y, Dong Y and Tang T: FOXP1 drives osteosarcoma development by repressing P21 and RB transcription downstream of P53. Oncogene. 40:2785–2802. 2021. View Article : Google Scholar


Zhou KW, Zheng XM, Yang ZW, Zhang L and Chen HD: Overexpression of CIRP may reduce testicular damage induced by cryptorchidism. Clin Invest Med. 32:E103–E111. 2009. View Article : Google Scholar


Cho SY, Oh Y, Jeong EM, Park S, Lee D, Wang X, Zeng Q, Qin H, Hu F, Gong H, et al: Amplification of transglutaminase 2 enhances tumor-promoting inflammation in gastric cancers. Exp Mol Med. 52:854–864. 2020. View Article : Google Scholar


Means AL, Freeman TJ, Zhu J, Woodbury LG, Marincola-Smith P, Wu C, Meyer AR, Weaver CJ, Padmanabhan C, An H, et al: Epithelial Smad4 Deletion Up-regulates inflammation and promotes inflammation-associated cancer. Cell Mol Gastroenterol Hepatol. 6:257–276. 2018. View Article : Google Scholar :


Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y, Harris T, Drake C, Pardoll D and Yu H: Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 15:114–123. 2009. View Article : Google Scholar


Wu D, Wu P, Huang Q, Liu Y, Ye J and Huang J: Interleukin-17: A promoter in colorectal cancer progression. Clin Dev Immunol. 2013:4363072013. View Article : Google Scholar


Sakurai T, Kashida H, Watanabe T, Hagiwara S, Mizushima T, Iijima H, Nishida N, Higashitsuji H, Fujita J and Kudo M: Stress response protein cirp links inflammation and tumorigenesis in colitis-associated cancer. Cancer Res. 74:6119–6128. 2014. View Article : Google Scholar


Sakurai T, Yada N, Watanabe T, Arizumi T, Hagiwara S, Ueshima K, Nishida N, Fujita J and Kudo M: Cold-inducible RNA-binding protein promotes the development of liver cancer. Cancer Sci. 106:352–358. 2015. View Article : Google Scholar


Feller L, Altini M and Lemmer J: Inflammation in the context of oral cancer. Oral Oncol. 49:887–892. 2013. View Article : Google Scholar


Ren WH, Zhang LM, Liu HQ, Gao L, Chen C, Qiang C, Wang XL, Liu CY, Li SM, Huang C, et al: Protein overexpression of CIRP and TLR4 in oral squamous cell carcinoma: An immunohistochemical and clinical correlation analysis. Med Oncol. 31:1202014. View Article : Google Scholar


Lin TY, Chen Y, Jia JS, Zhou C, Lian M, Wen YT, Li XY, Chen HW, Lin XL, Zhang XL, et al: Loss of Cirbp expression is correlated with the malignant progression and poor prognosis in nasopharyngeal carcinoma. Cancer Manag Res. 11:6959–6969. 2019. View Article : Google Scholar


Chen Z, Xiong S, Li J, Ou L, Li C, Tao J, Jiang Z, Fan J, He J and Liang W: DNA methylation markers that correlate with occult lymph node metastases of non-small cell lung cancer and a preliminary prediction model. Transl Lung Cancer Res. 9:280–287. 2020. View Article : Google Scholar


Fahad Ullah M: Breast cancer: Current perspectives on the disease status. Adv Exp Med Biol. 1152:51–64. 2019. View Article : Google Scholar


Huang R, Guo J, Yan P, Zhai S, Hu P, Zhu X, Zhang J, Qiao Y, Zhang Y, Liu H, et al: The construction of bone metastasis-specific prognostic model and co-expressed network of alternative splicing in breast cancer. Front Cell Dev Biol. 8:7902020. View Article : Google Scholar


Dankner M, Caron M, Al-Saadi T, Yu W, Ouellet V, Ezzeddine R, Maritan SM, Annis MG, Le PU, Nadaf J, et al: Invasive growth associated with Cold-Inducible RNA-Binding Protein expression drives recurrence of surgically resected brain metastases. Neuro Oncol. 23:1470–1480. 2021. View Article : Google Scholar


Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar


Lee HN, Ahn SM and Jang HH: Cold-inducible RNA-binding protein promotes epithelial-mesenchymal transition by activating ERK and p38 pathways. Biochem Biophys Res Commun. 477:1038–1044. 2016. View Article : Google Scholar


Joe S and Nam H: Prognostic factor analysis for breast cancer using gene expression profiles. BMC Med Inform Decis Mak. 16(Suppl 1): 562016. View Article : Google Scholar


Carmeliet P: VEGF as a key mediator of angiogenesis in cancer. Oncology. 69(Suppl 3): S4–S10. 2005. View Article : Google Scholar


Hashemi Goradel N, Ghiyami-Hour F, Jahangiri S, Negahdari B, Sahebkar A, Masoudifar A and Mirzaei H: Nanoparticles as new tools for inhibition of cancer angiogenesis. J Cell Physiol. 233:2902–2910. 2018. View Article : Google Scholar


Idrovo JP, Jacob A, Yang WL, Wang Z, Yen HT, Nicastro J, Coppa GF and Wang P: A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing. Int J Mol Med. 37:423–428. 2016. View Article : Google Scholar


Kübler M, Beck S, Fischer S, Götz P, Kumaraswami K, Ishikawa-Ankerhold H, Lasch M and Deindl E: Absence of cold-inducible RNA-binding protein (CIRP) promotes angiogenesis and regeneration of ischemic tissue by inducing M2-Like macrophage polarization. Biomedicines. 9:3952021. View Article : Google Scholar : PubMed/NCBI


Liu Y, Hu W, Murakawa Y, Yin J, Wang G, Landthaler M and Yan J: Cold-induced RNA-binding proteins regulate circadian gene expression by controlling alternative polyadenylation. Sci Rep. 3:20542013. View Article : Google Scholar :


Guo X, Wu Y and Hartley RS: Cold-inducible RNA-binding protein contributes to human antigen R and cyclin E1 deregulation in breast cancer. Mol Carcinog. 49:130–140. 2010. View Article : Google Scholar


Yang R, Zhan M, Nalabothula NR, Yang Q, Indig FE and Carrier F: Functional significance for a heterogenous ribonucleo-protein A18 signature RNA motif in the 3′-untranslated region of ataxia telangiectasia mutated and Rad3-related (ATR) transcript. J Biol Chem. 285:8887–8893. 2010. View Article : Google Scholar :


Ouellette MM, Liao M, Herbert BS, Johnson M, Holt SE, Liss HS, Shay JW and Wright WE: Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J Biol Chem. 275:10072–10076. 2000. View Article : Google Scholar


Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Tahara E, Ide T and Ishikawa F: Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet. 18:65–68. 1998. View Article : Google Scholar


Artero-Castro A, Callejas FB, Castellvi J, Kondoh H, Carnero A, Fernández-Marcos PJ, Serrano M, Ramón y Cajal S and Lleonart ME: Cold-inducible RNA-binding protein bypasses replicative senescence in primary cells through extracellular signal-regulated kinase 1 and 2 activation. Mol Cell Biol. 29:1855–1868. 2009. View Article : Google Scholar


García-Gómez R, Bustelo XR and Crespo P: Protein-protein interactions: Emerging oncotargets in the RAS-ERK pathway. Trends Cancer. 4:616–633. 2018. View Article : Google Scholar


Kim JY, Lee SG, Chung JY, Kim YJ, Park JE, Koh H, Han MS, Park YC, Yoo YH and Kim JM: Ellipticine induces apoptosis in human endometrial cancer cells: the potential involvement of reactive oxygen species and mitogen-activated protein kinases. Toxicology. 289:91–102. 2011. View Article : Google Scholar


Chen L, Ran D, Xie W, Xu Q and Zhou X: Cold-inducible RNA-binding protein mediates cold air inducible airway mucin production through TLR4/NF-κB signaling pathway. Int Immunopharmacol. 39:48–56. 2016. View Article : Google Scholar


Li J, Zhou W, Wei J, Xiao X, An T, Wu W and He Y: Prognostic value and biological functions of RNA binding proteins in stomach adenocarcinoma. Onco Targets Ther. 14:1689–1705. 2021. View Article : Google Scholar


Zhang J, Xu A, Miao C, Yang J, Gu M and Song N: Prognostic value of Lin28A and Lin28B in various human malignancies: A systematic review and meta-analysis. Cancer Cell Int. 19:792019. View Article : Google Scholar : PubMed/NCBI


Koedoot E, Smid M, Foekens JA, Martens JWM, Le Dévédec SE and van de Water B: Co-regulated gene expression of splicing factors as drivers of cancer progression. Sci Rep. 9:54842019. View Article : Google Scholar : PubMed/NCBI


He R and Zuo S: A robust 8-gene prognostic signature for early-stage non-small cell lung cancer. Front Oncol. 9:6932019. View Article : Google Scholar :


Biade S, Marinucci M, Schick J, Roberts D, Workman G, Sage EH, O'Dwyer PJ, Livolsi VA and Johnson SW: Gene expression profiling of human ovarian tumours. Br J Cancer. 95:1092–1100. 2006. View Article : Google Scholar


Virnig BA, Tuttle TM, Shamliyan T and Kane RL: Ductal carcinoma in situ of the breast: A systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 102:170–178. 2010. View Article : Google Scholar


Mangé A, Lacombe J, Bascoul-Mollevi C, Jarlier M, Lamy PJ, Rouanet P, Maudelonde T and Solassol J: Serum autoantibody signature of ductal carcinoma in situ progression to invasive breast cancer. Clin Cancer Res. 18:1992–2000. 2012. View Article : Google Scholar


Sveen A, Kilpinen S, Ruusulehto A, Lothe RA and Skotheim RI: Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes. Oncogene. 35:2413–2427. 2016. View Article : Google Scholar


Anczuków O and Krainer AR: Splicing-factor alterations in cancers. RNA. 22:1285–1301. 2016. View Article : Google Scholar


Zhao D, Zhang C, Jiang M, Wang Y, Liang Y, Wang L, Qin K, Rehman FU and Zhang X: Survival-associated alternative splicing signatures in non-small cell lung cancer. Aging (Albany NY). 12:5878–5893. 2020. View Article : Google Scholar


Anczuków O, Akerman M, Cléry A, Wu J, Shen C, Shirole NH, Raimer A, Sun S, Jensen MA, Hua Y, et al: SRSF1-regulated alternative splicing in breast cancer. Mol Cell. 60:105–117. 2015. View Article : Google Scholar


Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, Shabafrouz K, Ribi C, Cairoli A, Guex-Crosier Y, et al: Adverse effects of immune-checkpoint inhibitors: Epidemiology, management and surveillance. Nat Rev Clin Oncol. 16:563–580. 2019. View Article : Google Scholar


Rajput S, Volk-Draper LD and Ran S: TLR4 is a novel determinant of the response to paclitaxel in breast cancer. Mol Cancer Ther. 12:1676–1687. 2013. View Article : Google Scholar


Perera PY, Mayadas TN, Takeuchi O, Akira S, Zaks-Zilberman M, Goyert SM and Vogel SN: CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol. 166:574–581. 2001. View Article : Google Scholar


Bolognese AC, Sharma A, Yang WL, Nicastro J, Coppa GF and Wang P: Cold-inducible RNA-binding protein activates splenic T cells during sepsis in a TLR4-dependent manner. Cell Mol Immunol. 15:38–47. 2018. View Article : Google Scholar


Khan MM, Yang WL, Brenner M, Bolognese AC and Wang P: Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress. Sci Rep. 7:413632017. View Article : Google Scholar


Zhang F, Brenner M, Yang WL and Wang P: A cold-inducible RNA-binding protein (CIRP)-derived peptide attenuates inflammation and organ injury in septic mice. Sci Rep. 8:30522018. View Article : Google Scholar


Sulli G, Lam MTY and Panda S: Interplay between circadian clock and cancer: New frontiers for cancer treatment. Trends Cancer. 5:475–494. 2019. View Article : Google Scholar


Hadadi E, Taylor W, Li XM, Aslan Y, Villote M, Rivière J, Duvallet G, Auriau C, Dulong S, Raymond-Letron I, et al: Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice. Nat Commun. 11:31932020. View Article : Google Scholar


Fang L, Yang Z, Zhou J, Tung JY, Hsiao CD, Wang L, Deng Y, Wang P, Wang J and Lee MH: Circadian clock gene CRY2 degradation is involved in chemoresistance of colorectal cancer. Mol Cancer Ther. 14:1476–1487. 2015. View Article : Google Scholar : PubMed/NCBI


Rosenberg LH, Lafitte M, Quereda V, Grant W, Chen W, Bibian M, Noguchi Y, Fallahi M, Yang C, Chang JC, et al: Therapeutic targeting of casein kinase 1δ in breast cancer. Sci Transl Med. 7:318ra2022015. View Article : Google Scholar


Oshima T, Niwa Y, Kuwata K, Srivastava A, Hyoda T, Tsuchiya Y, Kumagai M, Tsuyuguchi M, Tamaru T, Sugiyama A, et al: Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. Sci Adv. 5:eaau90602019. View Article : Google Scholar


Ricci MS and Zong WX: Chemotherapeutic approaches for targeting cell death pathways. Oncologist. 11:342–357. 2006. View Article : Google Scholar : PubMed/NCBI


Carneiro BA and El-Deiry WS: Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 17:395–417. 2020. View Article : Google Scholar


Chen M, Fu H, Zhang J, Huang H and Zhong P: CIRP downregulation renders cardiac cells prone to apoptosis in heart failure. Biochem Biophys Res Commun. 517:545–550. 2019. View Article : Google Scholar


Li S, Zhang Z, Xue J, Liu A and Zhang H: Cold-inducible RNA binding protein inhibits H2O2-induced apoptosis in rat cortical neurons. Brain Res. 1441:47–52. 2012. View Article : Google Scholar


Wang L, Rowe RG, Jaimes A, Yu C, Nam Y, Pearson DS, Zhang J, Xie X, Marion W, Heffron GJ, et al: Small-molecule inhibitors disrupt let-7 oligouridylation and release the selective blockade of let-7 processing by LIN28. Cell Rep. 23:3091–3101. 2018. View Article : Google Scholar


Minuesa G, Albanese SK, Xie W, Kazansky Y, Worroll D, Chow A, Schurer A, Park SM, Rotsides CZ, Taggart J, et al: Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia. Nat Commun. 10:26912019. View Article : Google Scholar : PubMed/NCBI


Wu X, Gardashova G, Lan L, Han S, Zhong C, Marquez RT, Wei L, Wood S, Roy S, Gowthaman R, et al: Targeting the interaction between RNA-binding protein HuR and FOXQ1 suppresses breast cancer invasion and metastasis. Commun Biol. 3:1932020. View Article : Google Scholar


François-Moutal L, Felemban R, Scott DD, Sayegh MR, Miranda VG, Perez-Miller S, Khanna R, Gokhale V, Zarnescu DC and Khanna M: Small molecule targeting TDP-43's RNA recognition motifs reduces locomotor defects in a drosophila model of amyotrophic lateral sclerosis (ALS). ACS Chem Biol. 14:2006–2013. 2019. View Article : Google Scholar


Baker JD, Uhrich RL, Strovas TJ, Saxton AD and Kraemer BC: Targeting pathological tau by small molecule inhibition of the poly(A):MSUT2 RNA-protein interaction. ACS Chem Neurosci. 11:2277–2285. 2020. View Article : Google Scholar


Solano-Gonzalez E, Coburn KM, Yu W, Wilson GM, Nurmemmedov E, Kesari S, Chang ET, MacKerell AD, Weber DJ and Carrier F: Small molecules inhibitors of the heterogeneous ribonuclear protein A18 (hnRNP A18): A regulator of protein translation and an immune checkpoint. Nucleic Acids Res. 49:1235–1246. 2021. View Article : Google Scholar

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Kim Y and Kim Y: Controversial roles of cold‑inducible RNA‑binding protein in human cancer (Review). Int J Oncol 59: 91, 2021
Kim, Y., & Kim, Y. (2021). Controversial roles of cold‑inducible RNA‑binding protein in human cancer (Review). International Journal of Oncology, 59, 91.
Kim, Y., Hong, S."Controversial roles of cold‑inducible RNA‑binding protein in human cancer (Review)". International Journal of Oncology 59.5 (2021): 91.
Kim, Y., Hong, S."Controversial roles of cold‑inducible RNA‑binding protein in human cancer (Review)". International Journal of Oncology 59, no. 5 (2021): 91.