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RASAL1 inhibits HepG2 cell growth via HIF-2? mediated gluconeogenesis.

ABSTRACT: RAS protein activator like 1 (RASAL1) is a member of the RAS GTPase-activating protein (GAP) family, and has been identified as a tumor suppressor in various types of cancer. In the present study, it was determined that decreased levels of RASAL1 were accompanied by a higher pathological stage and larger tumor size in human liver cancer. Therefore, it was hypothesized that RASAL1 may serve an inhibitory role in liver cancer. In the present study, the following was demonstrated: i) Exogenous expression of RASAL1 may inhibit the proliferation and invasion ability of HepG2 cells; ii) overexpression of RASAL1 may downregulate HIF-2? transcription activity and HIF-2?-mediated gluconeogenesis through extracellular signal-related kinase 1/2 activation; iii) RASAL1 may reduce the xenograft tumor size in nude mice by inhibiting the expression of hypoxia-inducible factor (HIF)-2? and gluconeogenesis enzymes. These data suggest that the RASAL1/HIF-2? axis may serve an essential role in the growth of HepG2 cells, and that this signaling cascade may be a novel therapeutic target for the treatment of liver cancer.

SUBMITTER: Meng F

PROVIDER: S-EPMC5755015 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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RASAL1 inhibits HepG2 cell growth via HIF-2α mediated gluconeogenesis.

Meng Fanhua F Zhang Wei W Wang Yufeng Y

Oncology letters 20171003 6

RAS protein activator like 1 (RASAL1) is a member of the RAS GTPase-activating protein (GAP) family, and has been identified as a tumor suppressor in various types of cancer. In the present study, it was determined that decreased levels of RASAL1 were accompanied by a higher pathological stage and larger tumor size in human liver cancer. Therefore, it was hypothesized that RASAL1 may serve an inhibitory role in liver cancer. In the present study, the following was demonstrated: i) Exogenous expr ...[more]

PMID: 29344173

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Project description:BackgroundChronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions.MethodsExperimental mice were exposed to prolonged normobaric hypoxic air (15% pO2, 1 atm, 2 weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia-inducible factors HIF-1α and HIF-2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin-induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC-specific HIF-2α knockout mice, and mice treated with HIF-2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia- and HIF-2α-dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann-Whitney U tests.ResultsChronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P < 0.001; Soleus: 11.5% reduction in weight, P < 0.001) and weakness (10.0% reduction in peak-isometric torque, P < 0.001), along with impaired muscle regeneration characterized by diminished myofibre cross-sectional areas, increased fibrosis (P < 0.001), and incomplete strength recovery (92.3% of pre-injury levels, P < 0.05). HIF-2α stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi, P < 0.01). HIF-2α ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi, P < 0.01), while HIF-1α ablation did not have the same effect. HIF-2α stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF-2α. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase, P < 0.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi, P < 0.05), suggesting their therapeutic potential for alleviating chronic hypoxia-associated muscle atrophy.ConclusionsChronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia.

Dataset Information

RASAL1 inhibits HepG2 cell growth via HIF-2? mediated gluconeogenesis.

Publications

RASAL1 inhibits HepG2 cell growth via HIF-2α mediated gluconeogenesis.

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