miR‑433 accelerates acquired chemoresistance of gallbladder cancer cells by targeting cyclin M

Abstract

Abstract. Resistance to chemotherapy is associated with dismal prognosis in patients with gallbladder cancer. Cyclin-dependent kinase 10 (CDK10) influences the chemosensitivity of gallbladder cancer cells, and cyclin M is the activating factor and binding partner of CDK10. To determine the effect of CDK10 or cyclin M overexpression on chemosensitivity, gemcitabine-resistant (GR) subclones were established from CDK10 or cyclin M stable transfectants. Stable overexpression of CDK10 increased the sensitivity to gemcitabine in non-resistant cells and did not further increase the sensitivity to gemcitabine in the GR subclones. GR subclones exhibited a significantly decreased expression of cyclin M while maintaining the expression levels of CDK10, compared with the non-resistant cells. MicroRNA (miR)-433 was identified as a candidate factor involved in the mechanism of the downregulation of M cyclin in GR subclones. Luciferase assays confirmed the interaction between miR-433 and the 3' untranslated region (3'UTR) of cyclin M. Additionally, ectopic expression of miR-433 significantly decreased the expression of cyclin M. Finally, increased expression of circulating miR-433 was associated with poor outcome of chemotherapy. The results of the present study suggest that miR-433 is a potential biomarker for evaluating chemosensitivity in gallbladder cancer. IntroductionGallbladder cancer is a relatively rare disease, with an estimated annual incidence of between 2 and 3 individuals/100,000; however, it is the most frequently encountered malignancy of the biliary tract (1,2). Complete surgical resection is the only potentially curative approach in early stages of the disease; however, the majority of cases are diagnosed in advanced stages. Additionally, because the aggressive malignancy tolerates traditional chemotherapy and radiotherapy, these cases have a dismal prognosis with an overall 5-year survival rate of <5% (3). Therefore, improving the diagnostic accuracy during the early stages and identifying the molecular mechanisms associated with chemotherapy or radiation resistance may provide a potential therapeutic approach for the treatment of gallbladder cancer.Cyclin M, also known as FAM58A, is a member of the cyclin family, which serves important regulatory functions in the cell cycle and transcription (4). Mutations in cyclin M cause toe syndactyly, telecanthus and anogenital and renal malformations syndrome, a human developmental anomaly (4,5). However, the function of cyclin M in other diseases remains unclear. Cyclin M has been identified as the binding partner for cyclin-dependent kinase 10 (CDK10) (5). CDK10 is involved in the regulation of cell division and function in various types of tumor (6-10). It was confirmed that CDK10 functions as a tumor suppressor gene and regulates the survivability of biliary tract cancer cells, including gallbladder cancer cells (8). These results suggest that cyclin M may also be involved in cancer development through binding to CDK10.MicroRNAs (miRNAs) are key negative regulator...

RETRACTED ARTICLE: Long noncoding RNA LINC00657 enhances the malignancy of pancreatic ductal adenocarcinoma by acting as a competing endogenous RNA on microRNA-433 to increase PAK4 expression

“…Bioinformatics analysis was then conducted to search for the miRNA targets of LINC00657. The latter contains a complementary binding site for miR-433 (Figure 3(b)), and this miRNA was selected for further investigation because this miRNA frequently participates in the malignancy of many types of human cancer [32][33][34]. After validation of the efficacy of miR-433 mimics transfection (Figure 3(c), P < 0.05), a luciferase reporter assay was performed to test whether LINC00657 can bind to miR-433 in PDAC cells.…”

A CREB1/miR-433 reciprocal feedback loop modulates proliferation and metastasis in colorectal cancer

“…On the one hand, Gotanda and colleagues reported that miR-433 increased sensitivity to 5-FU in HeLa cells by regulating of thymidylate synthase [19]. However, Yu et al and Weiner-Gorzel et al respectively demonstrated that miR-433 could promote resistance to gemcitabine or paclitaxel in gallbladder and ovarian cancer cells [20,21]. On the other hand, Lin and colleagues observed that miR-433 suppressed hematopoietic cell differentiation in myeloproliferative neoplasms [22].…”

CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene

“…In HCC, overexpression of CDK10 increased chemosensitivity to cisplatin and epirubicin in SMMC-7721 cells but not HepG2 cells ( 31 ). Furthermore, overexpression of CDK10 increased gall bladder cancer sensitivity to gemcitabine ( 69 ). Anticipating a mechanism similar to endocrine therapy resistance in breast cancer, CDK10 expression was shown to downregulate c-Raf levels in BTC ( 64 , 69 ).…”

“…Furthermore, overexpression of CDK10 increased gall bladder cancer sensitivity to gemcitabine ( 69 ). Anticipating a mechanism similar to endocrine therapy resistance in breast cancer, CDK10 expression was shown to downregulate c-Raf levels in BTC ( 64 , 69 ). Furthermore, in gall bladder cancer, knockdown of c-Raf resulted in a significant increase in gemcitabine sensitivity in cells overexpressing CDK10 ( 69 ).…”

“…Anticipating a mechanism similar to endocrine therapy resistance in breast cancer, CDK10 expression was shown to downregulate c-Raf levels in BTC ( 64 , 69 ). Furthermore, in gall bladder cancer, knockdown of c-Raf resulted in a significant increase in gemcitabine sensitivity in cells overexpressing CDK10 ( 69 ). Downregulation of CDK10 increased ETS2-mediated transcription of c-Raf, resulting in activation of the MAPK pathway.…”