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01-12-2020 | Metastasis | Research

MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming

Authors: Yang Liu, Li-Li Lu, Duo Wen, Dong-Li Liu, Li-Li Dong, Dong-Mei Gao, Xin-Yu Bian, Jian Zhou, Jia Fan, Wei-Zhong Wu

Published in: Journal of Hematology & Oncology | Issue 1/2020

Abstract

Background

MicroRNA-612 (miR-612) has been proven to suppress EMT, stemness, and tumor metastasis of hepatocellular carcinoma (HCC) via PI3K/AKT2 and Sp1/Nanog signaling. However, its biological roles on HCC progression are far from elucidated.

Methods

We found direct downstream target of miR-612, hadha by RNA immunoprecipitation and sequencing. To explore its biological characteristic, potential molecular mechanism, and clinical relevance in HCC patients, we performed several in-vitro and in-vivo models, as well as human tissue chip.

Results

Ectopic expression of miR-612 could partially reverse the level of HADHA, then suppress function of pseudopods, and diminish metastatic and invasive potential of HCC by lipid reprogramming. In detail, miR-612 might reduce invadopodia formation via HADHA-mediated cell membrane cholesterol alteration and accompanied with the inhibition of Wnt/β-catenin regulated EMT occurrence. Our results showed that the maximum oxygen consumption rates (OCR) of HCCLM3^miR-612-OE and HCCLM3^hadha-KD cells were decreased nearly by 40% and 60% of their counterparts (p < 0.05). The levels of acetyl CoA were significantly decreased, about 1/3 (p > 0.05) or 1/2 (p < 0.05) of their controls, in exogenous miR-612 or hadha-shRNA transfected HCCLM3 cell lines. Besides, overexpression of hadha cell lines had a high expression level of total cholesterol, especially 27-hydroxycholesterol (p < 0.005). SREBP2 protein expression level as well as its downstream targets, HMGCS1, HMGCR, MVD, SQLE were all deregulated by HADHA. Meanwhile, the ATP levels were reduced to 1/2 and 1/4 in HCCLM3^miR-612-OE (p < 0.05) and HCCLM3^hadha-KD (p < 0.01) respectively. Moreover, patients with low miR-612 levels and high HADHA levels had a poor prognosis with shorter overall survival.

Conclusion

miR-612 can suppress the formation of invadopodia, EMT, and HCC metastasis and by HADHA-mediated lipid programming, which may provide a new insight of miR-612 on tumor metastasis and progression.

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Title: MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming
Authors: Yang Liu
Li-Li Lu
Duo Wen
Dong-Li Liu
Li-Li Dong
Dong-Mei Gao
Xin-Yu Bian
Jian Zhou
Jia Fan
Wei-Zhong Wu
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Metastasis
Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-019-0841-3

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