Abstract
The activation of the Ras signaling pathway is a crucial process in hepatocarcinogenesis. Till now, no reports have scrutinized the role of dynamic metabolic changes in Ras oncogene-induced transition of the normal and precancerous liver cells to hepatocellular carcinoma in vivo. In the current study, we attempted a comprehensive investigation of Hras12V transgenic mice (Ras-Tg) by concatenating nontargeted metabolomics, transcriptomics analysis, and targeted-metabolomics incorporating [U-13C] glucose. A total of 631 peaks were detected, out of which 555 metabolites were screened. Besides, a total of 122 differently expressed metabolites (DEMs) were identified, and they were categorized and subtyped with the help of variation tendency analysis of the normal (W), precancerous (P), and hepatocellular carcinoma (T) liver tissues. Thus, the positive or negative association between metabolites and the hepatocellular carcinoma and Ras oncogene were identified. The bioinformatics analysis elucidated the hepatocarcinogenesis-associated significant metabolic pathways: glycolysis, mitochondrial citrate-malate shuttle, lipid biosynthesis, pentose phosphate pathway (PPP), cholesterol and bile acid biosynthesis, and glutathione metabolism. The key metabolites and enzymes identified in this analysis were further validated. Moreover, we confirmed the PPP, glycolysis, and conversion of pyruvate to cytosol acetyl-CoA by mitochondrial citrate-malate shuttle, in vivo, by incorporating [U-13C] glucose. In summary, the current study presented the comprehensive bioinformatics analysis, depicting the Ras oncogene-induced dynamic metabolite variations in hepatocarcinogenesis. A significant finding of our study was that the mitochondrial citrate-malate shuttle plays a crucial role in detoxification of lactic acid, maintenance of mitochondrial integrity, and enhancement of lipid biosynthesis, which, in turn, promotes hepatocarcinogenesis.
Highlights
Metabolism is a fundamental biological process in the normal as well as cancerous cells, and metabolic alterations are perceived as a hallmark of cancer [1]
We demonstrated the global metabolic alterations related to Ras oncogene-induced hepatic tumorigenesis with the help of the Ras-Tg and nontargeted metabolomics and transcriptomics analysis
We identified significantly changed metabolites (Table S2)—56 metabolites in the W/P, 69 metabolites in the P/T, and 90 metabolites in the W/T—in the orthogonal projections to latent structures-discriminant analysis (OPLS-DA) analysis with the criterion of p < 0.05 (Figure S4C; Tables S1 and S2)
Summary
Metabolism is a fundamental biological process in the normal as well as cancerous cells, and metabolic alterations are perceived as a hallmark of cancer [1]. The complex biochemical pathways regulation, as well as cellular and molecular heterogeneities within and across tumor entities, impede the elucidation of altered metabolism in cancer cells [1]. Deepening molecular mechanisms underlying the tumor’s metabolic characteristics will lead to improved tumor categorization and identification of the potential therapeutic agent in cancer [2]. Apart from being highly malignant, recurrent, and drug-resistant, it is often diagnosed at an advanced stage [5]. For these reasons, the need to identify molecular features that uniquely define or contribute to HCC progression remains clinically urgent. As the liver functions as a major digestive gland and is the center of systemic metabolism in the body, liver cancer transformation is coupled with prominent metabolic alterations
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