MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

Qing Xia; Tao Han; Pinghua Yang; Ruoyu Wang; Hengyu Li; Jin Zhang; Xinfeng Zhou

doi:10.1155/2019/8734362

MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

Stem Cells Int. 2019 Dec 1:2019:8734362. doi: 10.1155/2019/8734362. eCollection 2019.

Authors

Qing Xia^#¹, Tao Han^#², Pinghua Yang^#³, Ruoyu Wang^#³, Hengyu Li⁴, Jin Zhang³, Xinfeng Zhou¹

Affiliations

¹ Department of General Surgery, Hua Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.
² Department of Oncology, General Hospital of Northern Theater Command, Shenyang, Liaoning Province, China.
³ Department of General Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China.
⁴ Department of General Surgery, First Affiliated Hospital of Second Military Medical University, Shanghai, China.

^# Contributed equally.

Abstract

Background: MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated.

Methods: Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs).

Results: Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC's self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC's self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients.

Conclusion: Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.