Department of Gastroenterology, First Affiliated Hospital of Xi'an Medical College, Xi'an, Shaanxi 710077, P.R. China.
General Surgery, The Fourth People's Hospital of Shaanxi Province, Xi'an, Shaanxi 710000, P.R. China.
Int J Oncol. 2019 Sep;55(3):671-683. doi: 10.3892/ijo.2019.4852. Epub 2019 Jul 30.
Aberrant activation of Wnt/β‑catenin signaling is observed in >90% of colorectal cancer cases. microRNAs (miRNAs) regulate the expression of key genes in Wnt/β‑catenin signaling. As a result, abnormal expression of miRNAs regulates the activation of Wnt/β‑catenin signaling in several types of cancer. In the current study, it was demonstrated that miR‑501‑3p was overexpressed in colorectal tumor tissues compared to the adjacent normal tissues. Downregulation of miR‑501‑3p inhibited cell proliferation and sphere formation, while it induced cell cycle arrest at the G1 phase in colorectal cancer cells. Bioinformatics analysis results predicted that adenomatous polyposis coli (APC), a negative regulator of Wnt/β‑catenin signaling, was a potential target gene of miR‑501‑3p. Inhibition of miR‑501‑3p increased APC expression in colorectal cancer cells. Additionally, β‑catenin was destabilized following miR‑501‑3p inhibition; immunofluorescence analysis revealed that β‑catenin translocated from nucleus to cytoplasm. In addition, cyclin D1 and c‑Myc, two well‑characterized target genes of Wnt/β‑catenin signaling, were downregulated following miR‑501‑3p inhibition. Transfection of APC small interfering RNA re‑activated β‑catenin and stimulated the expression of cyclin D1 and c‑Myc. Furthermore, silencing of APC reversed the miR‑501‑3p inhibitor‑induced cell cycle disruption, and the inhibition of cell proliferation and sphere formation in colorectal cancer cells. In conclusion, the present study identified miR‑501‑3p as a novel regulator of Wnt/β‑catenin signaling in colorectal cancer cells via targeting APC, suggesting that miR‑501‑3p may act as a novel oncogenic miRNA in colorectal cancer.
异常激活的 Wnt/β-连环蛋白信号通路存在于 >90%的结直肠癌病例中。微小 RNA (miRNA) 可调节 Wnt/β-连环蛋白信号通路中的关键基因表达。因此，miRNA 的异常表达可调节几种类型癌症中 Wnt/β-连环蛋白信号通路的激活。在本研究中，结果表明 miR-501-3p 在结直肠肿瘤组织中的表达高于相邻正常组织。下调 miR-501-3p 抑制了结直肠癌细胞的增殖和球体形成，同时诱导细胞周期停滞在 G1 期。生物信息学分析结果预测，腺瘤性息肉病基因（APC），Wnt/β-连环蛋白信号通路的负调节剂，是 miR-501-3p 的一个潜在靶基因。抑制 miR-501-3p 增加了结直肠癌细胞中 APC 的表达。此外，miR-501-3p 抑制后β-连环蛋白失稳；免疫荧光分析显示β-连环蛋白从核转位到细胞质。此外，Wnt/β-连环蛋白信号通路的两个公认靶基因 cyclin D1 和 c-Myc 的表达在 miR-501-3p 抑制后下调。APC 小干扰 RNA 的转染使β-连环蛋白重新激活，并刺激 cyclin D1 和 c-Myc 的表达。此外，沉默 APC 逆转了 miR-501-3p 抑制剂诱导的细胞周期紊乱，并抑制了结直肠癌细胞的增殖和球体形成。综上所述，本研究通过靶向 APC 鉴定出 miR-501-3p 是结直肠癌细胞中 Wnt/β-连环蛋白信号的新型调节因子，提示 miR-501-3p 可能在结直肠癌中作为一种新型致癌 miRNA 发挥作用。
