Effects of hypoxia‐inducible factor‐1α and hypoxia‐inducible factor‐2α overexpression on hepatocellular carcinoma survival: A systematic review with meta‐analysis

Ding, Zi-Niu; Dong, Zhao‐Ru; Chen, Zhiqiang; Yang, Yafei; Yan, Lun-Jie; Li, Haichao; Liu, Kaixuan; Yao, Cheng-Yu; Yan, Yu-Chuan; Yang, Chuncheng; Li, Tao

doi:10.1111/jgh.15395

Cited by 9 publications

(6 citation statements)

References 64 publications

(80 reference statements)

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“…The present results demonstrated that the HIF1α-VEGF-C axis was upregulated by increased Jnk1 mRNA and JNK expression by the FA-rich diets in HCVcpTg mice. Overexpressions of JNK1 and HIF1α have been detected in human HCC samples and were correlated with unfavorable patient outcomes [62, 63]. FA reportedly activated JNK through SRC non-receptor tyrosine kinase and might be related to the Warburg effect [60, 64]; however, the precise mechanism of how FA enhances Jnk1 mRNA expression requires clarification in future investigations.…”

Section: Discussionmentioning

confidence: 99%

Dietary Fat Composition Affects Hepatic Angiogenesis and Lymphangiogenesis in Hepatitis C Virus Core Gene Transgenic Mice

Diao¹,

Wang²,

Jia³

et al. 2022

Liver Cancer

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Introduction: Previous research has demonstrated that an isocaloric diet rich in trans-fatty acid (TFA), saturated fatty acid (SFA), and cholesterol (Chol) promoted steatosis-derived hepatic tumorigenesis in hepatitis C virus core gene transgenic (HCVcpTg) mice in different manners. Growth factor signaling and ensuing angiogenesis/lymphangiogenesis are key factors in hepatic tumorigenesis that have become recent therapeutic targets for hepatocellular carcinoma. However, the influence of dietary fat composition on these factors remains unclear. This study investigated whether the type of dietary fat would have a specific impact on hepatic angiogenesis/lymphangiogenesis in HCVcpTg mice. Methods: Male HCVcpTg mice were treated with a control diet, an isocaloric diet containing 1.5% cholesterol (Chol diet), or a diet replacing soybean oil with hydrogenated coconut oil (SFA diet) for a period of 15 months or with shortening (TFA diet) for 5 months. The degree of angiogenesis/lymphangiogenesis and the expression of growth factors, including fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), were evaluated in non-tumorous liver tissues using quantitative mRNA measurement, immunoblot analysis, and immunohistochemistry. Results: Long-term feeding of SFA and TFA diets to HCVcpTg mice increased the expressions of vascular endothelial cell indicators, such as CD31 and TEK receptor tyrosine kinase, in addition to lymphatic vessel endothelial hyaluronan receptor 1, indicating that angiogenesis/lymphangiogenesis were upregulated only by these fatty acid-enriched diets. This promoting effect correlated with elevated VEGF-C and FGF receptor 2 and 3 levels in the liver. c-Jun N-terminal kinase (JNK) and hypoxia-inducible factor (HIF) 1α, both key regulators of VEGF-C expression, were enhanced in the SFA- and TFA-rich diet groups as well. The Chol diet significantly increased the expressions of such growth factors as FGF2 and PDGF subunit B, without any detectable impact on angiogenesis/lymphangiogenesis. Conclusion: This study revealed that diets rich in SFA and TFA, but not Chol, might stimulate hepatic angiogenesis/lymphangiogenesis mainly through the JNK-HIF1α-VEGF-C axis. Our observations indicate the importance of dietary fat species for preventing hepatic tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Dietary Fat Composition Affects Hepatic Angiogenesis and Lymphangiogenesis in Hepatitis C Virus Core Gene Transgenic Mice

Diao¹,

Wang²,

Jia³

et al. 2022

Liver Cancer

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“…Overexpression of HIF-1α was also associated with clinicopathologic features including BCLC, intrahepatic metastasis, lymph node metastasis, tumor-to-lymph node metastasis (TNM), tumor differentiation, tumor number, tumor size, vascular invasion, and angiogenesis (5). Another meta-analysis involving 3,238 patients in 22 studies also showed poor prognosis in HCC patients presenting with overexpression of HIF-1α (45). However, other studies showed that HIF-1α protein expression was associated with tumor differentiation, and intrahepatic and extrahepatic metastases, but not with the presence of portal vein tumor embolism, prognosis, or hepatitis B surface antigen (HBsAg) status (41).…”

Section: Expression and Prognosis Of Hif-1α In Hepatocellular Carcinomamentioning

confidence: 95%

Hypoxia‑inducible factor‑1α: A critical target for inhibiting the metastasis of hepatocellular carcinoma (Review)

Chen

Yuan

et al. 2022

Oncol Lett

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Metastasis is one of the major reasons for patient mortality in hepatocellular carcinoma (HCC), and the progression of HCC to a metastatic state depends on the local microenvironment. Hypoxia is a key condition affecting the microenvironment of HCC. Currently, various studies have shown that the expression of hypoxia-ainducible factor-1α (HIF-1α) is associated with the invasion and metastasis of HCC. High expression of HIF-1α often leads to poor prognosis in patients with HCC. In this review, the molecular structure of HIF-1α is described, and the expression pattern of HIF-1α in HCC under hypoxia, which is associated with metastasis and poor prognosis in HCC, is explained. The molecular mechanisms of HIF-1α function and the metastasis of HCC are further discussed. The modulation of HIF-1α can reduce sorafenib resistance and improve the prognosis of patients after TACE. Therefore, HIF-1α may be a critical target for inhibiting HCC metastasis in the future. Contents1. Introduction 2. The structure and biological function of HIF-1α 3. Expression and prognosis of HIF-1α in hepatocellular carcinoma 4. HIF-1α promotes metastasis of hepatocellular carcinoma 5. HIF-1α: A new target for the treatment of HCC 6. Prospects

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“…In fact, the expression of the most important rate limiting enzymes involved in glycolysis is frequently altered in liver cancer [23]. Most of these genes are regulated by the O 2sensitive transcription factor hypoxia inducible factor 1 (HIF1α) that was reported to be stabilized and activated in HCCs [24]. Of note, HIF1α also regulates the expression of the glucose transporter GLUT1 which resulted to be upregulated in HCC and to be associated with tumor histological grade [25].…”

Section: Glycolysismentioning

confidence: 99%

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Fan

Kam

Ramadori

2021

Cancers

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Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.

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Effects of hypoxia‐inducible factor‐1α and hypoxia‐inducible factor‐2α overexpression on hepatocellular carcinoma survival: A systematic review with meta‐analysis

Cited by 9 publications

References 64 publications

Dietary Fat Composition Affects Hepatic Angiogenesis and Lymphangiogenesis in Hepatitis C Virus Core Gene Transgenic Mice

Dietary Fat Composition Affects Hepatic Angiogenesis and Lymphangiogenesis in Hepatitis C Virus Core Gene Transgenic Mice

Hypoxia‑inducible factor‑1α: A critical target for inhibiting the metastasis of hepatocellular carcinoma (Review)

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

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