Exosomal microRNAs in the DLK1-DIO3 imprinted region derived from cancer-associated fibroblasts promote progression of hepatocellular carcinoma by targeting hedgehog interacting protein

Author:

Jin An-Li,Ding Lin,Yang Wen-Jing,Liu Te,Chen Wei,Li Tong,Zhang Chun-Yan,Pan Bai-Shen,Qiu Shuang-Jian,Zhou Jian,Fan Jia,Guo Wei,Yang Xin-Rong,Wang Bei-Li

Abstract

Abstract Background Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and third leading cause of cancer-related death worldwide in 2020. Exosomes derived from cancer-associated fibroblasts (CAFs-exo) can promote tumor progression in various human cancers. However, the underlying regulatory mechanism controlling how CAFs-exo can promote HCC progression remains poorly understood. Methods CAFs and para-cancer fibroblasts (PAFs) were isolated from HCC tissues and corresponding para-cancer tissues, then were cultured in vitro. CAFs and PAFs were characterized by immunofluorescence and western blot (WB) assays. Exosomes were isolated by ultracentrifugation, and characterized by transmission electron microscopy, nanoflow cytometry, and WB assay. The internalization of exosomes by HCC cells was observed under a fluorescence microscope. Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell proliferation. Wound healing and transwell assays were used for migration and invasion experiments. RT-PCR assay was used to examine differentially expressed microRNAs (miRNAs) in exosomes and HCC cells. The TargetScan database was used to predict miRNA target genes. Hedgehog interacting protein (HHIP) expression analysis, prognostic analysis, and enrichment analysis of HHIP-related co-expressed genes were performed using the TIMER, UALCAN, Kaplan–Meier plotter, and LinkedOmics databases. Results CAFs-exo were internalized by HCC cells. CAFs-exo contributed to the aggressive phenotype of HCC cells, while inhibiting exosome secretion reversed these effects. Mechanistically, miRNAs in the DLK1-DIO3 imprinted region (miR-329-3p, miR-380-3p, miR-410-5p, miR-431-5p) were increased in HCC cells co-cultured with CAFs-exo compared with PAFs-exo. Expression of HHIP, a possible miR-431-5p target gene, was significantly downregulated in HCC cells. Low HHIP expression level in tumor tissues could predict poor prognosis in HCC patients. HHIP-related co-expressed genes were mainly associated with cell adhesion molecules. Conclusions CAFs-exo can promote HCC progression by delivering miRNAs in the DLK1-DIO3 imprinted region to HCC cells, subsequently inhibiting HHIP expression. HHIP is a potential prognostic biomarker in HCC.

Funder

Key Medical and Health Projects of Xiamen

National Key Research & Development Program of China

State Key Program of National Natural Science of China grants

Shanghai Municipal Health Commission Collaborative Innovation Cluster Project

Constructing Project of Clinical Key Disciplines in Shanghai

Specialized Fund for the Clinical Researches of Zhongshan Hospital, Fudan University

Shanghai Medical Key Specialty

National Natural Science Foundation of China grants

Shanghai “Rising Stars of Medical Talent” Youth Development Program

Projects from Science Foundation of Zhongshan Hospital, Fudan University

Projects from the Shanghai Science and Technology Commission

Projects from the Shanghai Municipal Health Commission

Projects from Excellent backbone of Zhongshan Hospital, Fudan University

Publisher

Springer Science and Business Media LLC

Subject

Gastroenterology,General Medicine

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