Extracellular vesicles-derived OncomiRs mediate communication between cancer cells and cancer-associated hepatic stellate cells in hepatocellular carcinoma microenvironment.

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.

Li J ，Yan Y ，Ang L ，Li X ，Liu C ，Sun B ，Lin X ，Peng Z ，Zhang X ，Zhang Q ，Wu H ，Zhao M ，Su C ... -  《-》

HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK/ERK and PI3K/AKT signaling pathways.

Li Q ，Wang C ，Wang Y ，Sun L ，Liu Z ，Wang L ，Song T ，Yao Y ，Liu Q ，Tu K ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts.

Zhou Y ，Ren H ，Dai B ，Li J ，Shang L ，Huang J ，Shi X ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Tumor cells derived-extracellular vesicles transfer miR-3129 to promote hepatocellular carcinoma metastasis by targeting TXNIP.

Hepatocellular carcinoma (HCC) is the most predominant primary liver cancer. Extracellular vesicles (EV)-mediated microRNA (miRNA) delivery is critical in cancer metastasis. We aimed to identify the mechanism of HCC cell-derived EVs-mediated miR-3129 in HCC. After EVs isolation and identification, miR-3129 expression in plasma EVs was evaluated and its diagnostic efficiency was analyzed. miR-3129 inhibitor was transfected into HepG2 and SMMC7721 cells, and cell malignant episodes were assessed. HCC cells were incubated with EVs from MHCC-97H cells and transfected with miR-3129 inhibitor and/or TXNIP. The nude mice were injected with MHCC-97H cells-EV or MHCC-97H cells-EV/miR-3129 inhibitor, and HCC growth and metastasis were assessed. miR-3129 was highly expressed in plasma EVs from HCC patients, which was the essential diagnostic biomarker for HCC. miR-3129 downregulation inhibited the malignant episodes of HCC cells. MHCC-97H cell-EVs were absorbed by HCC cells and transferred miR-3129 to HCC cells. EVs-carried miR-3129 promoted malignant episodes of HCC cells, which were weakened by miR-3129 inhibition in EVs. miR-3129 targeted TXNIP. TXNIP overexpression averted the effect of EVs-carried miR-3129 in HCC. In vivo, MHCC-97H cell-EVs transferred miR-3129 to facilitate HCC growth and metastasis. MHCC-97H cell-EVs transferred miR-3129 to promote HCC metastasis by targeting TXNIP.

Yang Y ，Mao F ，Guo L ，Shi J ，Wu M ，Cheng S ，Guo W ... -  《-》

Highly-metastatic colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment.

Liver metastasis of colorectal cancer (CRLM) is the most common cause of CRC-related mortality, and is typically caused by interactions between CRC cells and the tumour microenvironment (TME) in the liver. However, the molecular mechanisms underlying the crosstalk between tumour-derived extracellular vesicle (EV) miRNAs and the TME in CRLM have yet to be fully elucidated. The present study demonstrated that highly metastatic CRC cells released more miR-181a-5p-rich EVs than cells which exhibit a low metastatic potential, in-turn promoting CRLM. Additionally, we verified that FUS mediated packaging of miR-181a-5p into CRC EVs, which in-turn persistently activated hepatic stellate cells (HSCs) by targeting SOCS3 and activating the IL6/STAT3 signalling pathway. Activated HSCs could secrete the chemokine CCL20 and further activate a CCL20/CCR6/ERK1/2/Elk-1/miR-181a-5p positive feedback loop, resulting in reprogramming of the TME and the formation of pre-metastatic niches in CRLM. Clinically, high levels of serum EV containing miR-181a-5p was positively correlated with liver metastasis in CRC patients. Taken together, highly metastatic CRC cells-derived EVs rich in miR-181a-5p could activate HSCs and remodel the TME, thereby facilitating liver metastasis in CRC patients. These results provide novel insight into the mechanism underlying liver metastasis in CRC.

Zhao S ，Mi Y ，Zheng B ，Wei P ，Gu Y ，Zhang Z ，Xu Y ，Cai S ，Li X ，Li D ... -  《Journal of Extracellular Vesicles》