Abstract
MicroRNAs (miRNAs) are powerful regulators in the tumorigenesis of cholangiocarcinoma (CCA). Previous studies report that miR‐551b‐3p acts as an oncogenic factor in ovarian cancer, but plays a tumour suppressive role in gastric cancer. However, the expression pattern and potential function of miR‐551b‐3p were still unclear in CCA. Therefore, this study aimed to explore the expression of miR‐551b‐3p and its role as well as molecular mechanism in CCA. Analysis of TCGA dataset suggested that miR‐551b‐3p was under‐expressed in CCA tissues compared to normal bile duct tissues. Furthermore, our data confirmed the decreased levels of miR‐551b‐3p in CCA samples and cell lines. Interestingly, TCGA data suggested that low miR‐551b‐3p level indicated reduced overall survival of CCA patients. Gain‐ and loss‐of‐function experiments found that miR‐551b‐3p inhibited the proliferation, G1‐S phase transition and induced apoptosis of CCA cells. In vivo experiments revealed that ectopic expression of miR‐551b‐3p inhibited tumour growth of CCA in mice. Further investigation demonstrated that miR‐551b‐3p directly bond to the 3′‐UTR of Cyclin D1 (CCND1) mRNA and negatively regulated the abundance of CCND1 in CCA cells. An inverse correlation between miR‐551b‐3p expression and the level of CCND1 mRNA was detected in CCA tissues from TCGA dataset. Notably, CCND1 knockdown showed similar effects to miR‐551b‐3p overexpression in HuCCT‐1 cells. CCND1 restoration rescued miR‐551b‐3p‐induced inhibition of proliferation, G1 phase arrest and apoptosis in HuCCT‐1 cells. In summary, miR‐551b‐3p inhibits the expression of CCND1 to suppress CCA cell proliferation and induce apoptosis, which may provide a theoretical basis for improving CCA treatment.
Highlights
Cholangiocarcinoma (CCA) is a common and aggressive malig‐ nancy with rising morbidity and mortality.[1]
Overexpression of miR‐551b‐3p inhibited cholangiocar‐ cinoma (CCA) cell proliferation and resulted in cell cycle arrest at G1 phase and apoptosis by targeting Cyclin D1 (CCND1), which might benefit for finding new treatment modalities to improve prevention and treatment of CCA
We explored miR‐551b‐3p expression in TCGA Data Portal from starBase V3.0,14 the data discovered that the level of miR‐551b‐3p was down‐regulated in CCA samples compared to normal bile duct tissues (P = 0.00041, Figure 1A)
Summary
Cholangiocarcinoma (CCA) is a common and aggressive malig‐ nancy with rising morbidity and mortality.[1]. MiR‐551b‐3p expression is markedly up‐regulated in papillary thyroid carcinoma (PTC) as compared with that in normal thyroid tissue.[10] miR‐551b‐3p functions as an oncogenic factor via en‐ hancing chemoresistance, invasion and proliferation of ovarian cancer (OVCa) by targeting forkhead box O3 (FOXO3) and tripar‐ tite motif containing 31 (TRIM31).[11] Interestingly, the expression level of miR‐551b‐3p is reduced in gastric cancer and its mimics suppresses invasiveness, metastasis and epithelial‐mesenchymal transition of tumour cells by targeting erb‐b2 receptor tyrosine kinase 4 (ERBB4).[12] Recently, a study reports that miR‐551b‐3p is reversely regulated by long non‐coding RNA (lncRNA) SMARCC2 and mediates the tumour promoting role of SMARCC2 through regulating transmembrane serine protease 4 (TMPRSS4) in gas‐ tric cancer.[13] the functional role of miR‐551b‐3p and its underlying molecular mechanism in the tumorigenesis of CCA remain largely unclear. Overexpression of miR‐551b‐3p inhibited CCA cell proliferation and resulted in cell cycle arrest at G1 phase and apoptosis by targeting Cyclin D1 (CCND1), which might benefit for finding new treatment modalities to improve prevention and treatment of CCA
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