BackgroundThere 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.MethodsMiRNAs 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.ResultsWe 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/-catenin/CCND1 signaling pathway.ConclusionsOur 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/-catenin/CCND1 signaling pathway.
[1]Tongji Univ, Cent Lab Med Res, Shanghai Peoples Hosp 10, Sch Med, Shanghai 200072, Peoples R China.
[2]Tongji Univ, Dept Nucl Med, Shanghai Peoples Hosp 10, Sch Med, Shanghai 200072, Peoples R China.
[3]East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Coll Chem & Mol Engn, Shanghai 200062, Peoples R China.
[4]Tongji Univ, Dept Pathol, Shanghai Peoples Hosp 10, Sch Med, Shanghai 200072, Peoples R China.
[5]Jilin Univ, Dept Biobank, China Japan Union Hosp, Changchun 130033, Jilin, Peoples R China.
[6]Jiangxi Prov Tumor Hosp, Dept Radiol, Nanchang 330029, Jiangxi, Peoples R China.
[7]Shanghai Jiao Tong Univ, Rui Jin Hosp, Dept Digest Surg, Sch Med, Shanghai 200025, Peoples R China.
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