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The critical role of glucose deprivation in epithelial-mesenchymal transition in hepatocellular carcinoma under hypoxia

 Hanhee Jo  ;  Jongsook Lee  ;  Jeongyong Jeon  ;  Seon Yoo Kim  ;  Jee-In Chung  ;  Hae Yong Ko  ;  Misu Lee  ;  Mijin Yun 
 SCIENTIFIC REPORTS, Vol.10(1) : 1538, 2020-12 
Journal Title
Issue Date
Adult ; Animals ; Carcinoma, Hepatocellular / metabolism* ; Carcinoma, Hepatocellular / pathology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Epithelial-Mesenchymal Transition / physiology* ; Female ; Fluorodeoxyglucose F18 ; Gene Expression Regulation, Neoplastic / genetics ; Glucose / metabolism* ; Hep G2 Cells ; Humans ; Hypoxia / metabolism ; Hypoxia / physiopathology ; Liver Neoplasms / metabolism ; Liver Neoplasms / pathology ; Male ; Mice ; Mice, Inbred BALB C ; Middle Aged ; Positron Emission Tomography Computed Tomography ; Tumor Microenvironment / physiology
Imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is used to determine sites of abnormal glucose metabolism to predict high tumor grade, metastasis, and poor patient survival. However, not all tumors with increased 18F-FDG uptake show aggressive tumor biology, as evident from the moderate correlation between metastasis and high FDG uptake. We hypothesized that metastasis is likely attributable to the complexity and heterogeneity of the cancer microenvironment. To identify the cancer microenvironment that induces the epithelial-mesenchymal transition (EMT) process, tumor areas of patients with HCC were analyzed by immunostaining. Our data demonstrated the induction of EMT process in HCC cells with low proliferation under hypoxic conditions. To validate our finding, among HCC cell lines, HepG2 cells with highly increased expression of HIF1α under hypoxia were employed in vitro and in vivo. Major changes in EMT-associated protein expression, such as the up-regulation of N-cadherin and snail/slug are associated with decreased proliferation-related protein (PCNA) caused by glucose deprivation under hypoxia. Indeed, PCNA knockdown-HepG2 cells under hypoxia showed the induction of more EMT process compare to the control. Thus, HCC cells with low proliferative potential under glucose-deprived and hypoxic conditions show high probability for induced EMT process and promote cell invasion. This study investigates reasons as to why an EMT process cannot fully be predicted. Our observations indicate that rather than analyzing a single factor, an integrated analysis of hypoxia with low glucose metabolism and low cell proliferation might be helpful to predict the potential impact on induction of EMT process and promotion of cell invasion.
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1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
Yonsei Authors
Yun, Mi Jin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Jeon, Jeong Yong(전정용)
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