Extracellular vesicles-derived OncomiRs mediate communication between cancer cells and cancer-associated hepatic stellate cells in hepatocellular carcinoma microenvironment
Authors: Chunying Liu
Hongping Wu
Bin Sun
Zhangxiao Peng
Jiang Li
Qin Zhang
Xiaoya Li
Min Zhao
Xuejing Lin
Changqing Su
Yan Yan
Xiaofeng Zhang
Lin Ang
Journal: Carcinogenesis (2020)
Discipline: CLINICAL MEDICINE
Keywords: Tumor microenvironment; Hepatic stellate cells; HCC cells; Extracellular vesicles; OncomiRs
Affiliations: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China., Department of Pathology, The Second People's Hospital of Hefei, Hefei, Anhui Province, China.

Abstract:  Tumor microenvironment (TME) is a critical determinant for hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) are main interstitial cells in TME and play a vital role in early intrahepatic invasion and metastasis of HCC. The potential mechanism on the interactions between HSCs and HCC cells remains unclear. In this study, the effects of extracellular vesicles (EVs)-derived OncomiRs that mediate communication between HCC cells and cancer-associated hepatic stellate cells (caHSCs) and remold TME were investigated. The results found that the HCC cells-released EVs contained more various OncomiRs, which could activate HSCs (LX2 cells) and transform them to caHSCs, the caHSCs in turn exerted promotion effects on HCC cells through HSCs-released EVs. To further simulate the effects of OncomiRs in EVs on construction of pro-metastatic TME, a group of OncomiRs, miR-21, miR-221 and miR-151 was transfected into HCC cells and LX2 cells. These microRNAs in the EVs from OncomiRs-enhanced cells were demonstrated to have oncogenic effects on HCC cells by upregulating the activities of protein kinase B (AKT)/extracellular signal-regulated kinase (ERK) signal pathways. Equivalent results were also found in HCC xenografted tumor models. The findings suggested that the OncomiR secretion and transference by cancer cells-released EVs can mediate the communication between HCC cells and HSCs. HCC cells and caHSCs, as well as their secreted EVs, jointly construct a pro-metastatic TME suitable for invasion and metastasis of cancer cells, all these TME components form a positive feedback loop to promote HCC progression and metastasis. 

Retracted: No

PubPeer comments:
 Figure 1C: Two sets of panels appear to look very similar, although they represent different timepoints or treatments. Shown with red and aqua boxes. ![file] , 
 We have found the error during the process of proof cprrection, and we have already contacted the journal editorial board to correct the error. We sincerely appreciate and thank Pubpeer s actions to point out our mistake and urging us to be more careful in our future work. , 
 Corrigendum published, [13 August 2020] . -------------------------------------------------- This manuscript has been amended to correct an error in the formatting of Figure 1C. In the original figure, two images were inadvertently overlapped during the revision process, however, this has now been corrected. The authors apologise for any confusion caused. ![file] ,