MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness

Abstract Deregulated mitochondrial energetics is a metabolic hallmark of cancer cells. However, the causative mechanism of the bioenergetic deregulation is not clear. In this study, we show that somatic copy number alteration (SCNA) of mitoribosomal protein (MRP) genes is a key mechanism of bioenerg...

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Autores principales:	Seongki Min, Young-Kyoung Lee, Jiwon Hong, Tae Jun Park, Hyun Goo Woo, So Mee Kwon, Gyesoon Yoon
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/9137da938a5642118402603ae6bbad42
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spelling	oai:doaj.org-article:9137da938a5642118402603ae6bbad422021-11-14T12:06:57ZMRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness10.1038/s41419-021-04370-82041-4889https://doaj.org/article/9137da938a5642118402603ae6bbad422021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04370-8https://doaj.org/toc/2041-4889Abstract Deregulated mitochondrial energetics is a metabolic hallmark of cancer cells. However, the causative mechanism of the bioenergetic deregulation is not clear. In this study, we show that somatic copy number alteration (SCNA) of mitoribosomal protein (MRP) genes is a key mechanism of bioenergetic deregulation in hepatocellular carcinoma (HCC). Association analysis between the genomic and transcriptomic profiles of 82 MRPs using The Cancer Genome Atlas-Liver HCC database identified eight key SCNA-dependent MRPs: MRPS31, MRPL10, MRPL21, MRPL15, MRPL13, MRPL55, and DAP3. MRPS31 was the only downregulated MRP harboring a DNA copy number (DCN) loss. MRPS31 loss was associated specifically with the DCN losses of many genes on chromosome 13q. Survival analysis revealed a unique dependency of HCC on the MRPS31 deficiency, showing poor clinical outcome. Subclass prediction analysis using several public classifiers indicated that MRPS31 loss is linked to aggressive HCC phenotypes. By employing hepatoma cell lines with SCNA-dependent MRPS31 expression (JHH5, HepG2, Hep3B, and SNU449), we demonstrated that MRPS31 deficiency is the key mechanism, disturbing the whole mitoribosome assembly. MRPS31 suppression enhanced hepatoma cell invasiveness by augmenting MMP7 and COL1A1 expression. Unlike the action of MMP7 on extracellular matrix destruction, COL1A1 modulated invasiveness via the ZEB1-mediated epithelial-to-mesenchymal transition. Finally, MRPS31 expression further stratified the high COL1A1/DDR1-expressing HCC groups into high and low overall survival, indicating that MRPS31 loss is a promising prognostic marker. Significance Our results provide new mechanistic insight for mitochondrial deregulation in HCC and present MRPS31 as a novel biomarker of HCC malignancy.Seongki MinYoung-Kyoung LeeJiwon HongTae Jun ParkHyun Goo WooSo Mee KwonGyesoon YoonNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Seongki Min Young-Kyoung Lee Jiwon Hong Tae Jun Park Hyun Goo Woo So Mee Kwon Gyesoon Yoon MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness
description	Abstract Deregulated mitochondrial energetics is a metabolic hallmark of cancer cells. However, the causative mechanism of the bioenergetic deregulation is not clear. In this study, we show that somatic copy number alteration (SCNA) of mitoribosomal protein (MRP) genes is a key mechanism of bioenergetic deregulation in hepatocellular carcinoma (HCC). Association analysis between the genomic and transcriptomic profiles of 82 MRPs using The Cancer Genome Atlas-Liver HCC database identified eight key SCNA-dependent MRPs: MRPS31, MRPL10, MRPL21, MRPL15, MRPL13, MRPL55, and DAP3. MRPS31 was the only downregulated MRP harboring a DNA copy number (DCN) loss. MRPS31 loss was associated specifically with the DCN losses of many genes on chromosome 13q. Survival analysis revealed a unique dependency of HCC on the MRPS31 deficiency, showing poor clinical outcome. Subclass prediction analysis using several public classifiers indicated that MRPS31 loss is linked to aggressive HCC phenotypes. By employing hepatoma cell lines with SCNA-dependent MRPS31 expression (JHH5, HepG2, Hep3B, and SNU449), we demonstrated that MRPS31 deficiency is the key mechanism, disturbing the whole mitoribosome assembly. MRPS31 suppression enhanced hepatoma cell invasiveness by augmenting MMP7 and COL1A1 expression. Unlike the action of MMP7 on extracellular matrix destruction, COL1A1 modulated invasiveness via the ZEB1-mediated epithelial-to-mesenchymal transition. Finally, MRPS31 expression further stratified the high COL1A1/DDR1-expressing HCC groups into high and low overall survival, indicating that MRPS31 loss is a promising prognostic marker. Significance Our results provide new mechanistic insight for mitochondrial deregulation in HCC and present MRPS31 as a novel biomarker of HCC malignancy.
format	article
author	Seongki Min Young-Kyoung Lee Jiwon Hong Tae Jun Park Hyun Goo Woo So Mee Kwon Gyesoon Yoon
author_facet	Seongki Min Young-Kyoung Lee Jiwon Hong Tae Jun Park Hyun Goo Woo So Mee Kwon Gyesoon Yoon
author_sort	Seongki Min
title	MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness
title_short	MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness
title_full	MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness
title_fullStr	MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness
title_full_unstemmed	MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness
title_sort	mrps31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/9137da938a5642118402603ae6bbad42
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MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness

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