MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming
Authors: Dong-Mei Gao
Li-Li Lu
Jian Zhou
Yang Liu
Jia Fan
Duo Wen
Li-Li Dong
Xin-Yu Bian
Wei-Zhong Wu
Dong-Li Liu
Journal: Journal of Hematology & Oncology (2020)
Discipline: CLINICAL MEDICINE
Keywords: Hepatocellular carcinoma; Invadopodia; Metastasis; miR-612; β-Oxidation.
Affiliations: Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 180 Fenglin Road, Shanghai, 200032, China., Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China., Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China., Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China., Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China., Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. ., Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .

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 HCCLM3miR-612-OE and HCCLM3hadha-KD cells were decreased nearly by 40% and 60% of their counterparts (p &lt; 0.05). The levels of acetyl CoA were significantly decreased, about 1/3 (p &gt; 0.05) or 1/2 (p &lt; 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 &lt; 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 HCCLM3miR-612-OE (p &lt; 0.05) and HCCLM3hadha-KD (p &lt; 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. 

Retracted: No

PubPeer comments:
 Fig 3 as example ![file] , 
 Fig 3, more duplications ![file] , 
 #2 Erratum published [4 May 2020] . -------------------------------------- The original article [1] contains an error in Fig. 3c and Fig. 3g whereby the image of group WT and NC in HCCLM3 cell lines were repeated. The correct presentations of Fig. 3c and Fig. 3g can be seen ahead. ![] ,