MicroRNA-302a/d inhibits the self-renewal capability and cell cycle entry of liver cancer stem cells by targeting the E2F7/AKT axis

• Main Authors: Yu-Shui Ma, Zhong-Wei Lv, Fei Yu, Zheng-Yan Chang, Xian-Ling Cong, Xiao-Ming Zhong, Gai-Xia Lu, Jian Zhu, Da Fu
• Format: Article
• Language: English
• Published: BMC 2018-10-01
• Series: Journal of Experimental & Clinical Cancer Research
• Subjects: HCC; LCSCs; miRNA-302a/d; E2F7; Prognosis
• Online Access: http://link.springer.com/article/10.1186/s13046-018-0927-8

Abstract Background There is increasing evidence that liver cancer stem cells (LCSCs) contribute to hepatocellular carcinoma (HCC) initiation and progression. MicroRNA (miRNA) plays a significant functional role by directly regulating respective targets in LCSCs-triggered HCC, however, little is known about the function of the miRNA-302 family in LCSCs. Methods MiRNAs microarray was used to detect the miRNAs involved in LCSCs maintenance and differentiation. Biological roles and the molecular mechanism of miRNA-302a/d and its target gene E2F7 were detected in HCC in vitro. The expression and correlation of miRNA-302a/d and E2F7 in HCC patients was evaluated by quantitative PCR and Kaplan–Meier survival analysis. Results We found that the miRNA-302 family was downregulated during the spheroid formation of HCC cells and patients with lower miRNA-302a/d expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, E2F7 was confirmed to be directly targeted and inhibited by miRNA-302a/d. Furthermore, concomitant low expression of miRNA-302a/d and high expression of E2F7 correlated with a shorter median OS and PFS in HCC patients. Cellular functional analysis demonstrated that miRNA-302a/d negatively regulates self-renewal capability and cell cycle entry of liver cancer stem cells via suppression of its target gene E2F7 and its downstream AKT/β-catenin/CCND1 signaling pathway. Conclusions Our data provide the first evidence that E2F7 is a direct target of miRNA-302a/d and miRNA-302a/d inhibits the stemness of LCSCs and proliferation of HCC cells by targeting the E2F7/AKT/β-catenin/CCND1 signaling pathway.