Role of insulin receptor substrates in the progression of hepatocellular carcinoma

Sakurai, Yoshitaka; Kubota, Naoto; Takamoto, Iseki; Obata, Atsushi; Iwamoto, Masahiko; Hayashi, Takanori; Aihara, Masakazu; Kubota, Tetsuya; Nishihara, Hiroshi; Kadowaki, Takashi

doi:10.1038/s41598-017-03299-3

Cited by 43 publications

(36 citation statements)

References 48 publications

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“…Eventually, the increased β-catenin is transported to the nucleus and leads to the increase or decrease in the expression of specific genes. Much research has shown that altered Wnt signaling is involved in HCC occurrence and development [ 29 – 31 ]. Recently, it was reported that Wnt signaling activation can increase colon cancer cell glycolysis and promote colon cancer cell proliferation [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells

Fan

Yang

Zhang

et al. 2018

J Exp Clin Cancer Res

168

111

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BackgroundAutophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Autophagy can regulate the migration and invasive ability in cancer cells. However, the connection between autophagy and metabolism is unclear. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H+ clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation.MethodsAutophagic activity was evaluated using western blotting, immunoblotting, and transmission electron microscopy. The underlying mechanisms of autophagy activation on HCC cell glycolysis were studied via western blotting, and Transwell, lactate, and glucose assays. MCT1 expression was detected using quantitative reverse transcription–PCR (real-time PCR), western blotting, and immunostaining of HCC tissues and the paired adjacent tissues.ResultsAutophagy promoted HCC cell glycolysis accompanied by MCT1 upregulation. Wnt/β-catenin signaling pathway activation mediated the effect of autophagy on HCC cell glycolysis. β-Catenin downregulation inhibited the autophagy-induced glycolysis in HCC cells, and reduced MCT1 expression in the HCC cells. MCT1 was highly expressed in HCC tissues, and high MCT1 expression correlated positively with the expression of microtubule-associated protein light chain 3 (LC3).ConclusionActivation of autophagy can promote metastasis and glycolysis in HCC cells, and autophagy induces MCT1 expression by activating Wnt/β-catenin signaling. Our study describes the connection between autophagy and glucose metabolism in HCC cells and may provide a potential therapeutic target for HCC treatment.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0673-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells

Fan

Yang

Zhang

et al. 2018

J Exp Clin Cancer Res

168

111

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“…Expression of IRS1 can be directly activated by β-catenin, and IRS1 is highly expressed in many cancers with constitutive stabilization of β-catenin. Sakurai et al reported that the upregulation of IRS1 by Wnt/β-catenin signaling plays a crucial role in the progression of HCC [ 45 ]. At the same time, Zhang et al reported that the loss of β-catenin impairs the liver’s ability to counteract N -nitrosodiethylamine (DEN)-induced oxidative stress and enhances tumorigenesis [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients

et al. 2018

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BackgroundNonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes. Our aim was to investigate the relationship between NAFLD and impaired glucose metabolism in terms of insulin receptor substrate 1 and 2 (IRS1 and IRS2) expression in the liver.MethodsLiver biopsy was performed at the University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD who were not being treated with any diabetes or dyslipidemia drugs. Among them, 63 underwent liver biopsy after an overnight fast, and 83 at 5 h after an oral glucose tolerance test (OGTT). Differences in messenger RNA (mRNA) levels of several glucose metabolism-related factors were determined and correlated with hepatic histological changes assessed by NAFLD activity score. We prospectively followed up with the patients until May 2017.ResultsHepatic necroinflammation was significantly correlated with serum insulin levels and inversely correlated with IRS1 mRNA levels. In specimens obtained after an OGTT, hepatic necroinflammation and IRS1 expression correlated significantly with both peripheral and hepatic insulin resistance. We also found that hepatic β-catenin and glucokinase mRNA levels were elevated in patients undergoing liver biopsy after an OGTT, especially in those with less hepatic necroinflammation and a lower degree of fibrosis. A prospective cohort study showed that ballooning is the most significant risk factor for developing diabetes.ConclusionsThe decreased hepatic expression of IRS1 and β-catenin in NAFLD is linked to histological progression such as ballooning, and might lead to diabetes as a result of impaired glucose metabolism.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1472-0) contains supplementary material, which is available to authorized users.

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“…In addition to these studies, Sakurai et al showed that inhibiting the tyrosine phosphorylation of IRS1 significantly decreased diethynitrosamine-induced hepatocellular carcinoma cell proliferation through the inhibition of AKT activation [24]. Another study also suggested that insulin-induced AKT activation promotes the cell survival in primary glioblastoma cells [12].…”

Section: Discussionmentioning

confidence: 98%

Insulin receptor substrate 1 overexpression promotes survival of glioblastoma cells through AKT1 activation

Görgişen¹,

Yaren²

2020

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Glioblastoma multiforme (GBM) is the most common and malignant type of central nervous system tumours in adults. Strict regulation of glucose homeostasis has a significant role in GBM pathogenesis. Insulin receptor substrate 1 (IRS1) protein is the most important adaptor molecule involved in the regulation of glucose metabolism. It interacts with many cancer-related receptors and its overexpression is strongly associated with cell proliferation and survival. Our study was aimed to understand the role of IRS1 proteins in GBM cell viability. U-87 MG cells were transfected with pcDNA3.1-flagtagged-human IRS1 expression vector. Insulin induced phosphorylation levels of IRS1, AKT1 and ERK1/2 and Grb2 expression were examined to determine the effects of ectopic IRS1 overexpression on insulin signalling and the viability levels of U-87 MG cells were determined by MTT analysis. Overexpression of IRS1 in U-87 MG cells led to an increase in cell viability. Its overexpression also increased Grb2 expression and phosphorylation of AKT1 through elevation of IRS1 tyrosine phosphorylation in IRS1-transfected U-87 MG cells compared to control and mock transfected groups. Our study showed that increased IRS1 expression and activation may promote the cell viability via AKT1 activation. IRS1 signalling may be considered as a therapeutic target for further studies.

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Role of insulin receptor substrates in the progression of hepatocellular carcinoma

Cited by 43 publications

References 48 publications

Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells

Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells

Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients

Insulin receptor substrate 1 overexpression promotes survival of glioblastoma cells through AKT1 activation

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