Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4
Yu‐Shui Ma, Jibin Liu, Lan Lin, Hui Zhang, Jian-Jun Wu, Yi Shi, Chengyou Jia, Dandan Zhang, Fei Yu, Huimin Wang, Yuzhen Yin, Xiaohui Jiang, Pei‐Yao Wang, Linlin Tian, Ping‐Sheng Cao, Xuming Wu, Haimin Lu, Li‐Peng Gu, Jiajia Zhang, Gujun Cong, Pei Luo, Xiaoming Zhong, Bo Cai, Minxin Shi, Suqing Zhang, Li Liu, Wenjie Zhang, Yu Liu, Zhizhen Li, Ting‐Miao Wu, Zhijun Wu, Gao‐Ren Wang, Zhongwei Lv, Chang‐Chun Ling, Kai-Jian Chu, Da Fu
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.