PMID- 34772924 OWN - NLM STAT- MEDLINE DCOM- 20220324 LR - 20230208 IS - 2041-4889 (Electronic) VI - 12 IP - 11 DP - 2021 Nov 12 TI - MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness. PG - 1076 LID - 10.1038/s41419-021-04370-8 [doi] LID - 1076 AB - 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. CI - (c) 2021. The Author(s). FAU - Min, Seongki AU - Min S AUID- ORCID: 0000-0001-9621-0739 AD - Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Korea. AD - Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, 16499, Korea. FAU - Lee, Young-Kyoung AU - Lee YK AUID- ORCID: 0000-0003-4940-5028 AD - Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Korea. FAU - Hong, Jiwon AU - Hong J AUID- ORCID: 0000-0003-4224-6490 AD - Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Korea. AD - Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, 16499, Korea. FAU - Park, Tae Jun AU - Park TJ AUID- ORCID: 0000-0002-8862-1834 AD - Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Korea. AD - Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, 16499, Korea. FAU - Woo, Hyun Goo AU - Woo HG AUID- ORCID: 0000-0002-0916-893X AD - Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, 16499, Korea. AD - Department of Physiology, Ajou University School of Medicine, Suwon, 16499, Korea. FAU - Kwon, So Mee AU - Kwon SM AD - Department of Physiology, Ajou University School of Medicine, Suwon, 16499, Korea. smkwon@ajou.ac.kr. FAU - Yoon, Gyesoon AU - Yoon G AUID- ORCID: 0000-0002-4665-5999 AD - Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Korea. ypeace@ajou.ac.kr. AD - Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, 16499, Korea. ypeace@ajou.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211112 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Autoantigens) RN - 0 (Biomarkers, Tumor) RN - 0 (Mrps31 protein, mouse) RN - 0 (Ribosomal Proteins) SB - IM MH - Autoantigens/*metabolism MH - Biomarkers, Tumor/*metabolism MH - Carcinoma, Hepatocellular/*genetics/pathology MH - Genomics/*methods MH - Humans MH - Liver Neoplasms/*genetics/pathology MH - Ribosomal Proteins/*metabolism MH - Transfection PMC - PMC8589861 COIS- The authors declare no competing interests. EDAT- 2021/11/14 06:00 MHDA- 2022/03/25 06:00 PMCR- 2021/11/12 CRDT- 2021/11/13 05:47 PHST- 2021/08/05 00:00 [received] PHST- 2021/10/29 00:00 [accepted] PHST- 2021/10/18 00:00 [revised] PHST- 2021/11/13 05:47 [entrez] PHST- 2021/11/14 06:00 [pubmed] PHST- 2022/03/25 06:00 [medline] PHST- 2021/11/12 00:00 [pmc-release] AID - 10.1038/s41419-021-04370-8 [pii] AID - 4370 [pii] AID - 10.1038/s41419-021-04370-8 [doi] PST - epublish SO - Cell Death Dis. 2021 Nov 12;12(11):1076. doi: 10.1038/s41419-021-04370-8.