MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming
Open Access
- 7 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Hematology & Oncology
- Vol. 13 (1), 1-19
- https://doi.org/10.1186/s13045-019-0841-3
Abstract
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. 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. 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 < 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 HCCLM3miR-612-OE (p < 0.05) and HCCLM3hadha-KD (p < 0.01) respectively. Moreover, patients with low miR-612 levels and high HADHA levels had a poor prognosis with shorter overall survival. 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.Keywords
Funding Information
- National Natural Science Foundation of China (81272437, 81472675)
- National Key Research and Development Plan (2016YFC0902400)
- Shanghai Municipal Health Commission, Collaborative Innovation Cluster Project (2019CXJQ02)
This publication has 55 references indexed in Scilit:
- The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and functionNature Reviews Molecular Cell Biology, 2011
- Regulation of cancer cell metabolismNature Reviews Cancer, 2011
- Regulation of Integrin β1 Recycling to Lipid Rafts by Rab1a to Promote Cell MigrationJournal of Biological Chemistry, 2010
- Network organization of the human autophagy systemNature, 2010
- Understanding the Warburg Effect: The Metabolic Requirements of Cell ProliferationScience, 2009
- Mitochondrial trifunctional protein defects: Clinical implications and therapeutic approachesAdvanced Drug Delivery Reviews, 2008
- Endogenous human microRNAs that suppress breast cancer metastasisNature, 2008
- A Mammalian microRNA Expression Atlas Based on Small RNA Library SequencingCell, 2007
- Molecular mechanisms of invadopodium formationThe Journal of cell biology, 2005
- The functions of animal microRNAsNature, 2004