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Abstract
HCC is well known for low glycolysis in the tumors, whereas hypoxia induces glycolytic phenotype and tumor progression. This study was conducted to evaluate the expression of SLCs in human HCCs and investigated whether extracellular nutrient administration related to SLCs in low-glycolytic HCC can prevent hypoxic tumor progression. SLCs expression was screened according to the level of glycolysis in HCCs. Then, whether extracellular nutrient treatment can affect hypoxic tumor progression, as well as the mechanisms, were evaluated in an in vitro cell line and an in vivo animal model. Low-glycolytic HCCs showed high SLC13A5/NaCT and SLC16A1/MCT1 but low SLC2A1/GLUT1 and HIF1α/HIF1α expression. Especially, high SLC13A5 expression was significantly associated with good overall survival in the Cancer Genome Atlas (TCGA) database. In HepG2 cells with the highest NaCT expression, extracellular citrate treatment upon hypoxia induced HIF1α degradation, which led to reduced glycolysis and cellular proliferation. Finally, in HepG2-animal models, the citrate-treated group showed smaller tumor with less hypoxic areas than the vehicle-treated group. In patients with HCC, SLC13A5/NaCT is an important SLC, which is associated with low glycolysis and good prognosis. Extracellular citrate treatment induced the failure of metabolic adaptation to hypoxia and tumor growth inhibition, which can be a potential therapeutic strategy in HCCs.

Affiliations

Seon Yoo Kim  1 , Dongwoo Kim  1 , Jisu Kim  1 , Hae Young Ko  1 , Won Jin Kim  2 , Youngjoo Park  1 , Hye Won Lee  3 , Dai Hoon Han  4 , Kyung Sik Kim  4 , Sunghyouk Park  5 , Misu Lee  2   6 , Mijin Yun  1
1 Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.
2 Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon 22012, Korea.
3 Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.
4 Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.
5 Department of Manufacturing Pharmacy, Natural Product Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
6 Institute for New Drug Development, College of Life Science and Bioengineering, Incheon National University, Incheon 22012, Korea.