318 Glut1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis

Amann, Thomas; Maegdefrau, Ulrike; Kreuz, Markus; Hartmann, Anne; Schöelmerich, Juergen; Bosserhoff, A. K.; Hellerbrand, Claus

doi:10.1016/s0168-8278(08)60320-7

Cited by 4 publications

(3 citation statements)

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“…Previous studies suggested that high expression of HIF1α [38][39][40] and GLUT1 41,42 in HCC are major causative factors for metastasis. The rapid growth rate of cancer cells induces blood vessel leakage, chaotic structure, and non-laminar blood flow.…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Jeon

et al. 2020

Sci Rep

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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.Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide and is associated with various risk factors such as hepatitis virus infection, aflatoxin exposure, fatty liver, or alcohol abuse 1,2 . HCC is a clinical, metabolic, and heterogeneous tumor with various phenotypes 1-6 . Tumors include proliferating, slow dividing, quiescent or necrotic/apoptotic tumor cell populations, as well as fast-or slow-migrating tumor cells 7,8 . Genetic heterogeneity in solitary disseminated tumor cells and metastasis has been shown by genetic and expression profiling studies 9-15 . One of the known causes of heterogeneity related to rapid cellular proliferation is the formation of abnormal vascular networks characterized by leaking and compressed blood and lymphatic vessels, creating hypoxic areas in the tumors. Tumor hypoxia induces metabolic reprogramming from mitochondrial oxidation to glycolysis and drug resistance by activating pathways controlled by hypoxia-inducible factor (HIF) 16,17 . Moreover, there is a close relationship between hypoxia and tumor metastasis that leads to poor prognosis 18-20 .Epithelial-mesenchymal transition (EMT) is a complex trans-differentiation process that increases the migratory and invasive ...

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Section: Discussionmentioning

confidence: 99%

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

Lee

Jeon

et al. 2020

Sci Rep

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“…This imply the Hypoxia-TME classifier could be applied for preimmunotherapy stratification of cancer patients. Additionally, statistically higher CA9 expression in Hypoxia high /TME low subgroup indicates an acidic extracellular milieu favoring tumor growth, poor tumor differentiation and development,55,56 which further exhibits the predictive ability of this classifier.Apart from the above results, the observed different patterns between subgroups in terms of tumor somatic genome alterations revealed that the mRNA-based Hypoxia-TME classifier also reflects DNA molecular heterogeneity in tumor. Our results further support the observations that CCTNB1 mutation is associated with favorable prognosis and low-stage HCC57 and TP53 mutation is an indicator for poor prognosis 40.…”

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confidence: 88%

The combined signatures of hypoxia and cellular landscape provides a prognostic and therapeutic biomarker in hepatitis B virus‐related hepatocellular carcinoma

Chen

Gao

Wang

et al. 2022

Intl Journal of Cancer

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Prognosis and treatment options of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) are generally based on tumor burden and liver function. Yet, tumor growth and therapeutic resistance of HBV-HCC are strongly influenced by intratumoral hypoxia and cells infiltrating the tumor microenvironment (TME). We, therefore, studied whether linking parameters associated with hypoxia and TME cells could have a better prediction of prognosis and therapeutic responses. Quantification of 109 hypoxia-related genes and 64 TME cells was performed in 452 HBV-HCC tumors. Prognostic hypoxia and TME cells signatures were determined based on Cox regression and meta-analysis for generating the Hypoxia-TME classifier. Thereafter, the prognosis, tumor, and immune characteristics as well as the benefit of therapies in Hypoxia-TME defined subgroups were analyzed. Patients in the Hypoxia low / TME high subgroup showed a better prognosis and therapeutic responses than any other subgroups, which can be well elucidated based on the differences in terms of immune-related molecules, tumor somatic mutations, and cancer cellular signaling pathways. Notably, our analysis furthermore demonstrated the synergistic influence of hypoxia and TME on tumor metabolism and proliferation. Besides, the classifier allowed a further subdivision of patients with early-and late-HCC stages. In addition, the Hypoxia-TME classifier was validated in another independent HBV-HCC cohort (n = 144) and several pan-cancer cohorts. Overall, the Hypoxia-TME classifier

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“…12 In HCC, GLUT1 mRNA is overexpressed by 68.2%, which correlates significantly with invasiveness and metastasis. 13 The enhanced expression of GLUT1 in HCC and its lower expression in corresponding normal and benign hepatic tissue suggests that this transporter is involved in the increased glucose uptake by HCC cells, acting as a tumor-promoting target with prognostic and diagnostic significance. 13 GLUT2, the major isoform in normal hepatocytes, is crucial in glucose sensing, and hepatic glucose output is also upregulated in HCC and is positively correlated with poor prognosis in patients.…”

Section: Glucose Uptakementioning

confidence: 99%

Unraveling the Sweet Secrets of HCC: Glucometabolic Rewiring in Hepatocellular Carcinoma

Bhat,

Farooq,

Ismail

et al. 2023

Technol Cancer Res Treat

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Hepatocellular carcinoma (HCC) is the primary form of liver cancer. It causes ∼ 800 000 deaths per year, which is expected to increase due to increasing rates of obesity and metabolic dysfunction associated steatotic liver disease (MASLD). Current therapies include immune checkpoint inhibitors, tyrosine kinase inhibitors, and monoclonal antibodies, but these therapies are not satisfactorily effective and often come with multiple side effects and recurrences. Metabolic reprogramming plays a significant role in HCC progression and is often conserved between tumor types. Thus, targeting rewired metabolic pathways could provide an attractive option for targeting tumor cells alone or in conjunction with existing treatments. Therefore, there is an urgent need to identify novel targets involved in cancer-mediated metabolic reprogramming in HCC. In this review, we provide an overview of molecular rewiring and metabolic reprogramming of glucose metabolism in HCC to understand better the concepts that might widen the therapeutic window against this deadly cancer.

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318 Glut1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis

Cited by 4 publications

References 0 publications

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

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

The combined signatures of hypoxia and cellular landscape provides a prognostic and therapeutic biomarker in hepatitis B virus‐related hepatocellular carcinoma

Unraveling the Sweet Secrets of HCC: Glucometabolic Rewiring in Hepatocellular Carcinoma

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