Abstract
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/β-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/β-catenin/CCND1 signaling pathway.
Highlights
There is increasing evidence that liver cancer stem cells (LCSCs) contribute to hepatocellular carcinoma (HCC) initiation and progression
Recent studies have suggested that liver cancer stem cells (LCSCs), which display the capacity for self renewal and differentiation, are located within the tumor bulk and are responsible for HCC initiation, progression, resistance to therapy
We further demonstrated that miRNA-302a/d negatively regulated cell growth and spheroid formation, and promoted apoptosis of HCC cells via suppression of its target gene E2F transcription factor 7 (E2F7), which suggested that miRNA-302a/d and E2F7 might be potential tumor biomarkers for the diagnosis and treatment of HCC patients
Summary
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, little is known about the function of the miRNA-302 family in LCSCs. Global morbidity of hepatobiliary malignancies, mainly hepatocellular carcinoma (HCC) and cholangiocarcinoma, has recently increased [1]. HCC has the third highest mortality rate out of all major malignant carcinomas worldwide [2]. The high rate of recurrence and heterogeneity are the two major features of HCC [4]. Recent studies have suggested that liver cancer stem cells (LCSCs), which display the capacity for self renewal and differentiation, are located within the tumor bulk and are responsible for HCC initiation, progression, resistance to therapy. How LCSCs sustain their self-renewal remains largely unknown and the clinical significance of LCSCs is yet to be fully established
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
