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.SignificanceOur results provide new mechanistic insight for mitochondrial deregulation in HCC and present MRPS31 as a novel biomarker of HCC malignancy.
Highlights
Mitochondria are essential cytoplasmic organelles that generate and supply most of the cellular energy required for maintaining the cell’s biochemical activities
We show that somatic copy number alteration (SCNA) of mitoribosomal protein (MRP) genes is a key mechanism of bioenergetic deregulation in hepatocellular carcinoma (HCC)
MRPS31 is the key SCNA-dependent MRP suppressed in HCC Previously, we reported that deregulation of MRPs primes a favorable cancer microenvironment, promoting HCC progression [7]
Summary
Mitochondria are essential cytoplasmic organelles that generate and supply most of the cellular energy required for maintaining the cell’s biochemical activities. Mitoribosome defects due to collectively deregulated MRP expression was shown to promote an aggressive phenotype of hepatocellular carcinoma (HCC) by suppressing immune surveillance [7] These results suggest that deregulation of MRPs may be responsible for bioenergetic dysregulation and crucially involved in tumor progression. We identified eight key SCNA-dependent MRPs by analyzing genomic and transcriptomic data from The Cancer Genome Atlas-Liver HCC database (TCGA-LIHC). MRPs with DCN-gain (n = 12) or -loss (n = 5) were identified by SCNA analysis (FC > 0 or FC < 0). The fraction of HCC samples for each genes’ status (gain or loss) was calculated, generating SCNA frequency, MATERIALS AND METHODS Cell culture and cell growth rate HepG2 and Hep3B cells were purchased from American Tissue Culture Collections (ATCC, Rockville, MD). Monitoring cellular oxygen consumption rate To monitor mitochondrial respiratory activity, OCR was measured using Seahorse XF24 analyzer (Seahorse Bioscience Inc., MA) as described in the previous report [29]
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