Abstract
A marked increase in the rate of glycolysis is a key event in the pathogenesis of hepatocellular carcinoma (HCC), the main type of primary liver cancer. Liver cirrhosis is considered to be a key player in HCC pathogenesis as it precedes HCC in up to 90% of patients. Intriguingly, the biochemical events that underlie the progression of cirrhosis to HCC are not well understood. In this study, we examined the expression profile of metabolic gene transcripts in liver samples from patients with HCC and patients with cirrhosis. We found that gene expression of glycolytic enzymes is up-regulated in precancerous cirrhotic livers and significantly associated with an elevated risk for developing HCC. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in HCC compared to normal livers but remain unchanged in cirrhosis. Our findings suggest that key glycolytic enzymes such as hexokinase 2 (HK2), aldolase A (ALDOA), and pyruvate kinase M2 (PKM2) may represent potential markers and molecular targets for early detection and chemoprevention of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the main type of primary liver cancer and the second leading cause of cancer-related mortality worldwide, with more than 700,000 deaths every year (El-Serag, 2011; Jemal et al, 2011; Forner et al, 2018)
To have a complete overview of the metabolic genes expressed in HCC and premalignant stages of disease, we analyzed the transcription profiling of enzymes involved in glycolysis, phosphate pathway (PPP), tricarboxylic acid (TCA), and oxidative phosphorylation (OXPHOS) in liver samples from patients with HCC and patients with cirrhosis
The decreased expression and activity of LDHA would favor the routing of pyruvate into mitochondria where it can be further metabolized through TCA and oxidative phosphorylation
Summary
Hepatocellular carcinoma (HCC) is the main type of primary liver cancer and the second leading cause of cancer-related mortality worldwide, with more than 700,000 deaths every year (El-Serag, 2011; Jemal et al, 2011; Forner et al, 2018). Treatment options mainly consist of tumor resection, liver transplant, chemotherapies and radiologic intervention, all of which are limited to patients with early-stage disease. The large majority of HCC patients are usually diagnosed at advanced stages, which lack of curative therapies (Llovet et al, 2008; Ulahannan et al, 2014; Forner et al, 2018). Early HCC detection and prevention are required for reducing the high mortality rate. A better understanding of the molecular basis of HCC formation and the identification of markers are essential for the development of preventive therapies targeting the specific HCC-promoting factors and thereby improvement prognosis
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