title: Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis.
abstract: Cancer-associated fibroblasts (CAFs) play a pivotal role in regulating tumour progression. Therefore, understanding how CAFs communicate with hepatocellular carcinoma (HCC) is crucial for HCC therapy. Recently, exosomes have been considered an important "messenger" between cells. In this study, we performed microRNA (miRNA) sequencing of exosomes derived from CAFs and corresponding para-cancer fibroblasts (PAFs) of HCC patients. We found a significant reduction in the miR-320a level in CAF-derived exosomes. Using exogenous miRNAs, we demonstrated that stromal cells could transfer miRNA to HCC cells. In vitro and in vivo studies further revealed that miR-320a could function as an antitumour miRNA by binding to its direct downstream target PBX3 to suppress HCC cell proliferation, migration and metastasis. The miR-320a-PBX3 pathway inhibited tumour progression by suppressing the activation of the MAPK pathway, which could induce the epithelial-mesenchymal transition and upregulate cyclin-dependent kinase 2 (CDK2) and MMP2 expression to promote cell proliferation and metastasis. In xenograft experiments involving CAFs mixed with MHCC97-H cells, miR-320a overexpression in CAFs could inhibit tumourigenesis. Therefore, these data suggest that CAF-mediated HCC tumour progression is partially related to the loss of antitumour miR-320a in the exosomes of CAFs and that promoting the transfer of stromal cell-derived miR-320a might be a potential treatment option to overcome HCC progression.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Zhuochao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Yue
authors.affiliation: Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Jingyue
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Emergency, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Ben
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Pu
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Bai
authors.initials: B
authors.lastname: Ruan
authors.affiliation: Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Qike
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China. Electronic address: taokaishan0686@163.com.
authors.forename: Kaishan
authors.initials: K
authors.lastname: Tao
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China. Electronic address: gdwkgwx@fmmu.edu.cn.
authors.forename: Kefeng
authors.initials: K
authors.lastname: Dou
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D015536:Down-Regulation; D055354:Exosomes / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D018398:Homeodomain Proteins; C572916:MIRN320 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C090466:proto-oncogene protein Pbx3; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: CAFs; Exosomes; PBX3; Tumourigenesis; miR-320a