Dataset Information

Glypican-3 Enhances Reprogramming of Glucose Metabolism in Liver Cancer Cells.

ABSTRACT: Glypican-3(GPC3) is a transmembrane protein which has been found to be frequently overexpressed on the surfaces of liver cancer (LC) cells, which contributes to both the growth and metastasis of LC cells. Recently, the expression of GPC3 has been reported to be inversely associated with glucose metabolism activity in LC patients, suggesting that GPC3 may play a role in the regulation of glucose metabolism in LC. However, the role of GPC3 in glucose metabolism reprogramming, as well as in LC cell growth and metastasis, is unknown. Here, we found that GPC3 significantly contributed to the reprogramming of glucose metabolism in LC cells. On the one hand, GPC3 enhanced the glycolysis of LC cells through upregulation of the glycolytic genes of Glut1, HK2, and LDH-A. On the other hand, GPC3 repressed mitochondrial respiration through downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1?), which has been well known as a crucial regulator in mitochondrial biogenesis. Mechanistic investigations revealed that HIF-1? was involved in both GPC3-regulated upregulation of glycolytic genes of HK2, PKM2, and Glut1 and downregulation of mitochondrial biogenesis regulator PGC-1? in LC cells. Additionally, GPC3-regulated reprogramming of glucose metabolism played a critical role in the growth and metastasis of LC cells. Conclusion. Our findings demonstrate that GPC3 is a critical regulator of glucose metabolism reprogramming in LC cells, which provides a strong line of evidence for GPC3 as an important therapeutic target to normalize glucose metabolic aberrations responsible for LC progression.

SUBMITTER: Yao G

PROVIDER: S-EPMC6875211 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Glypican-3 Enhances Reprogramming of Glucose Metabolism in Liver Cancer Cells.

Yao Gebing G Yin Jikai J Wang Qing Q Dong Rui R Lu Jianguo J

BioMed research international 20191106

Glypican-3(GPC3) is a transmembrane protein which has been found to be frequently overexpressed on the surfaces of liver cancer (LC) cells, which contributes to both the growth and metastasis of LC cells. Recently, the expression of GPC3 has been reported to be inversely associated with glucose metabolism activity in LC patients, suggesting that GPC3 may play a role in the regulation of glucose metabolism in LC. However, the role of GPC3 in glucose metabolism reprogramming, as well as in LC cell ...[more]

PMID: 31781603

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Project description:Autoimmune hepatitis (AIH) is an inflammatory liver disease caused by a dysregulated immune response. Although the pathogenesis of AIH remains unclear, impaired regulatory T cells (Tregs) have been considered a driver of AIH development. Unlike autoreactive T cells, Tregs mainly utilize oxidative phosphorylation (OXPHOS) as their energy supply. Elevated glycolysis has been reported to limit the suppressive functions of Tregs. However, whether glucose metabolism reprogramming in Tregs is involved in AIH etiology remains unknown. The aim of this study was to examine alternations in Treg numbers and functions in AIH patients and concanavalin A (Con A)-induced hepatitis, while exploring associations between impaired Tregs and glucose metabolism. The frequency of Tregs was decreased in the peripheral blood but increased in liver biopsies of AIH patients. Moreover, immunosuppressive therapy rescued circulating Tregs in AIH. In Con A-induced immune hepatitis, enhanced intrahepatic Treg accumulation was observed over time, accompanied by reduced splenic Treg numbers. To investigate whether functional impairment of Tregs occurs in AIH, Tregs were isolated from experimental AIH (EAH) model mice and normal controls and the former displayed downregulated mRNA levels of FOXP3, CTLA4, CD103, TIGIT, CD39, and CD73. EAH model-derived Tregs also produced fewer anti-inflammatory mediators (TGF-β and IL-35) than control Tregs. Moreover, enhanced glycolysis and reduced OXPHOS were found in Tregs from EAH model mice, as reflected by elevated levels of key glycolytic enzymes (HK2, PK-M2, and LDH-A) and a decreased ATP concentration. This study revealed a decreased peripheral Treg frequency and abnormal intrahepatic Treg infiltration in AIH. It is first reported that glucose metabolism reprogramming is associated with decreases and functional impairments in the Treg population, promoting AIH development. Targeting glucose metabolism may provide novel insights for the treatment of AIH.

Dataset Information

Glypican-3 Enhances Reprogramming of Glucose Metabolism in Liver Cancer Cells.

Publications

Glypican-3 Enhances Reprogramming of Glucose Metabolism in Liver Cancer Cells.

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