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Solid tumors often suffer from suboptimal oxygen and nutrient supplies. This stress underlies the requirement for metabolic adaptation. Aberrantly activated de novo lipogenesis is critical for development and progression of human hepatocellular carcinoma (HCC). However, whether de novo lipogenesis influences biological behaviors of HCCs under conditions of metabolic stress are still poorly understood. Here, we show that HCCs display distinct levels of glucose-derived de novo lipogenesis, which are positively correlated with their survival responses to glucose limitation. The enhanced lipogenesis in HCCs is characterized by an increased expression of rate-limiting enzyme acetyl-coenzyme A carboxylase alpha (ACCa). ACCa-mediated fatty acid (FA) synthesis determines the intracellular lipid content that is required to maintain energy hemostasis and inhibit cell death by means of FA oxidation (FAO) during metabolic stress. In accord, overexpression of ACCa facilitates tumor growth. ACCa forms a complex with carnitine palmitoyltransferase 1A (CPT1A) and prevents its mitochondria distribution under nutrient-sufficient conditions. During metabolic stress, phosphorylation of ACCa leads to dissociation of the complex and mitochondria localization of CPT1A, thus promoting FAO-mediated cell survival. Therefore, ACCa could provide both the substrate and enzyme storage for FAO during glucose deficiency. Up-regulation of ACCa is also significantly correlated with poorer overall survival and disease recurrence postsurgery. Multivariate Cox's regression analysis identified ACCa as an effective predictor of poor prognosis. Conclusion: ACCa plays a pivotal role in maintaining HCC survival under metabolic stress. It could be exploited as a novel diagnostic marker and therapeutic target. (HEPATOLOGY 2016;63:1272-1286 H epatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide.(1,2) Most HCC patients are considered to be incurable as a result of extensive heterogeneity in clinical presentations and tumor biology, which complicates the classification for therapy. (3,4) Identifying distinct subgroups in the HCC population with similar tumor biology is thus imperative to improve responses to various types of cancer treatment.Although many malignant tumors share common metabolic transformations, such as aerobic glycolysis, (5,6) the cellular metabolic phenotypes of cancer cellsAbbreviations: 2-DG, 2-deoxyglucose; 2-NBDG, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxyglucose; ACC, acetyl-CoA carboxylase;

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Background. Survival after liver resection of hepatocellular carcinoma (HCC) remains poor because of a high incidence of recurrence. We sought to investigate risk factors, patterns, and long-term prognosis among patients with early and late recurrence after liver resection for hepatitis B virus (HBV)-associated HCC. Methods. Data of consecutive patients undergoing curative resection for HBV-associated HCC were analyzed. According to the time to recurrence after surgery, recurrence was divided into early (≤2 years) and late recurrence (>2 years). Characteristics, patterns of initial recurrence, and postrecurrence survival (PRS) were compared between patients with early and late recurrence. Risk factors of early and late recurrence and predictors of PRS were identified by univariable and multivariable Cox regression analyses. Results. Among 894 patients, 322 (36.0%) and 282 (31.5%) developed early and late recurrence, respectively. On multivariable analyses, preoperative HBV-DNA >10 4 copies/mL

Hepatocellular carcinoma (HCC) is one of the most frequent and deadly malignancies worldwide. Studies are urgently needed on its molecular pathogenesis and biological characteristics. Dysregulation of fatty acid (FA) metabolism, in which aberrant activation of oncogenic signaling pathways alters the expression and activity of lipid-metabolizing enzymes, is an emerging hallmark of cancer cells, and it may be involved in HCC development and progression. The current review summarizes what is known about dysregulated FA metabolism in HCC and pathways through which this dysregulation may regulate HCC survival and growth. Our understanding of dysregulated FA metabolism and associated signaling pathways may contribute to the development of novel and efficient antitumor approaches for patients with HCC.

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