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Multiomics Integration Reveals the Landscape of Prometastasis Metabolism in Hepatocellular Carcinoma.

ABSTRACT: The systematic investigation of gene mutation and expression is important to discover novel biomarkers and therapeutic targets in cancers. Here, we integrated genomics, transcriptomics, proteomics, and metabolomics to analyze three hepatocellular carcinoma (HCC) cell lines with differential metastatic potentials. The results revealed the profile of the prometastasis metabolism potentially associated with HCC metastasis. The multiomic analysis identified 12 genes with variations at multiple levels from three metabolic pathways, including glycolysis, starch, and sucrose metabolism, and glutathione metabolism. Furthermore, uridine diphosphate (UDP)-glucose pyrophosphorylase 2 (UGP2), was observed to be persistently up-regulated with increased metastatic potential. UGP2 overexpression promoted cell migration and invasion and enhanced glycogenesis in vitro The role of UGP2 in metastasis was further confirmed using a tumor xenograft mouse model. Taken together, the compendium of multiomic data provides valuable insights in understanding the roles of shifted cellular metabolism in HCC metastasis.

SUBMITTER: Li Y

PROVIDER: S-EPMC5880115 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Multiomics Integration Reveals the Landscape of Prometastasis Metabolism in Hepatocellular Carcinoma.

Li Yongmei Y Zhuang Hao H Zhang Xinran X Li Yuan Y Liu Yun Y Yi Xianfu X Qin Guoxuan G Wei Wen W Chen Ruibing R

Molecular & cellular proteomics : MCP 20180125 4

The systematic investigation of gene mutation and expression is important to discover novel biomarkers and therapeutic targets in cancers. Here, we integrated genomics, transcriptomics, proteomics, and metabolomics to analyze three hepatocellular carcinoma (HCC) cell lines with differential metastatic potentials. The results revealed the profile of the prometastasis metabolism potentially associated with HCC metastasis. The multiomic analysis identified 12 genes with variations at multiple level ...[more]

PMID: 29371291

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Project description:Rationale: The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC). However, plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance. Methods: Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients. Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib. Patient-derived xenograft models were employed to determine the role of TP53 in response to sorafenib. Lentiviruses harboring wild-type and c.G52C-mutant OCT4 were applied to explore the function of OCT4 in resistance to sorafenib. ChIP-PCR assay for analysis of OCT4 transcriptional activity was performed to explore the affinity with the KITLG promoter. Statistical analyses were used to associate levels of p53 and OCT4 with tumor features and patient outcomes. Results: Total 1,050 somatic mutations and 26 significant driver genes were identified. SiRNA screening in 7 HCC cell lines was further performed to identify mutations associated with differential responses to sorafenib. A recurrent nonsynonymous mutation c.G52C in OCT4 (OCT4 mut) was strongly associated with good response to sorafenib, whereas the stop-gain mutation in TP53 showed the opposite outcome both in vitro and in vivo. OCT4 wt-induced stem cell factor (encoded by KITLG gene, SCF) expression and cross-activation of c-KIT/FLT3-BRAF signals were identified indispensably for sorafenib resistance, which could be reversed by the combination of c-KIT tyrosine kinase inhibitors or neutralizing antibody against SCF. Mechanistically, an OCT4 binding site in upstream of KITLG promoter was identified with a higher affinity to wildtype of OCT4 rather than G52C-mutant form, which is indispensable for OCT4-induced expression of KITLG and sorafenib resistance. Conclusion: Our study reported a novel somatic mutation in OCT4 (c.G52C) responsible for the sorafenib effect, and also shed new light on the treatment of HCC through the combination of specific tyrosine kinase inhibitors according to individual genetic patterns.

Dataset Information

Multiomics Integration Reveals the Landscape of Prometastasis Metabolism in Hepatocellular Carcinoma.

Publications

Multiomics Integration Reveals the Landscape of Prometastasis Metabolism in Hepatocellular Carcinoma.

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