Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect

Huining Tian,1 Xiaoyu Zhu,2 You Lv,1 Yan Jiao,3 Guixia Wang1 1Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin, People’s Republic of China; 2Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, People’s Republic of ChinaCorrespondence: Guixia WangDepartment of Endocrinology and Metabolism, The First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun 130021, Jilin, People’s Republic of ChinaTel +86 158 0438 1103Fax +86 431 8878 6259Email gwang168@jlu.edu.cnYan JiaoDepartment of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun 130021, Jilin, People’s Republic of ChinaTel/ Fax +86 13843101157Email lagelangri1@126.comAbstract: Hepatocellular carcinoma (HCC) is a tumor that exhibits glucometabolic reprogramming, with a high incidence and poor prognosis. Usually, HCC is not discovered until an advanced stage. Sorafenib is almost the only drug that is effective at treating advanced HCC, and promising metabolism-related therapeutic targets of HCC are urgently needed. The “Warburg effect” illustrates that tumor cells tend to choose aerobic glycolysis over oxidative phosphorylation (OXPHOS), which is closely related to the features of the tumor microenvironment (TME). The HCC microenvironment consists of hypoxia, acidosis and immune suppression, and contributes to tumor glycolysis. In turn, the glycolysis of the tumor aggravates hypoxia, acidosis and immune suppression, and leads to tumor proliferation, angiogenesis, epithelial–mesenchymal transition (EMT), invasion and metastasis. In 2017, a mechanism underlying the effects of gluconeogenesis on inhibiting glycolysis and blockading HCC progression was proposed. Treating HCC by increasing gluconeogenesis has attracted increasing attention from scientists, but few articles have summarized it. In this review, we discuss the mechanisms associated with the TME, glycolysis and gluconeogenesis and the current treatments for HCC. We believe that a treatment combination of sorafenib with TME improvement and/or anti-Warburg therapies will set the trend of advanced HCC therapy in the future.Keywords: hepatocellular carcinoma, tumor microenvironment, glycolysis, gluconeogenesis, Warburg effect