GPR81核运输对肺癌和其他实体癌的生长和进展至关重要。

IF 3.2 Q3 ONCOLOGY
LiBang Yang, Thomas Kono, Adam Gilbertsen, Yingming Li, Bo Sun, Blake A Jacobson, Sabine Karam, Scott M Dehm, Craig A Henke, Robert A Kratzke
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引用次数: 0

摘要

背景:Warburg效应在癌症中很常见。乳酸及其受体GPR81在癌症进展中起重要作用。膜受体核易位在肿瘤病理中起着新的作用,已被广泛接受。乳酸/GPR81轴调控恶性肿瘤的机制尚不清楚。目的:探讨外源性乳酸促进GPR81核转运的机制。方法:用外源性乳酸刺激肺癌细胞,采用免疫荧光法和western blot法检测细胞膜、细胞质和细胞核中GPR81水平。用突变型GPR81核定位信号(NLS)构建体、野生型GPR81或空载体转导肺癌细胞,在体外和体内研究GPR81核转运对肺癌细胞恶性的影响。免疫沉淀蛋白质组学分析和染色质免疫沉淀(ChIP)测序检测GPR81相互作用蛋白和基因。结果:在缺氧/乳酸刺激下,GPR81在肺癌细胞核内易位积累。功能上,GPR81核易位促进癌细胞增殖和运动。GPR81 NLS的缺失减少了GPR81核水平,降低了体外癌细胞的生长和侵袭,以及体内癌细胞的恶性程度。蛋白质组学分析显示,包括SFPQ在内的一组蛋白与癌细胞细胞核中的GPR81相互作用。值得注意的是,GPR81与SFPQ的相互作用促进了癌细胞的生长和运动。ChIP测序分析发现GPR81有一组靶向基因。结论:GPR81与SFPQ相互作用促进肿瘤细胞恶性。GPR81核易位对癌症进展至关重要,可能是限制癌症进展的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
GPR81 nuclear transportation is critical for cancer growth and progression in lung and other solid cancers.

Background: The Warburg effect is common in cancers. Lactate and its receptor GPR81 play an important role in cancer progression. It is widely accepted that membrane receptor nuclear translocation plays some novel role in cancer pathology. The mechanism by which the lactate/GPR81 axis regulates cancer malignancy remains unclear.

Aim: To elucidate the mechanism of GPR81 nuclear transportation promoted by exogenous lactate.

Methods: Lung cancer cells were stimulated with exogenous lactate and GPR81 levels were measured by immunofluoresence and western blot analysis in membrane, cytoplasmic, and nuclear fractions. Lung cancer cells were transduced with a mutant GPR81 nuclear localization signal (NLS) construct, wild type GPR81 or empty vector and used to examine how GPR81 nuclear transportation affects lung cancer cells malignancy in vitro and in vivo. Immunoprecipitation Proteomics analysis and Chromatin immunoprecipitation (ChIP) sequencing were used to determine GPR81 interacting proteins and genes.

Results: In response to hypoxia/Lactate stimulation, GPR81 translocates and accumulates in the nucleus of lung cancer cells. Functionally, GPR81 nuclear translocation promotes cancer cell proliferation and motility. Depletion of the GPR81 NLS depletes GPR81 nuclear levels and decreases cancer cell growth and invasion in vitro, as well as cancer cell malignancy in vivo. Proteomics analysis revealed a set of proteins including SFPQ, that interact with GPR81 in the cancer cell nucleus. Notably, the interaction of GPR81 with SFPQ promotes cancer cell growth and motility. ChIP sequencing analysis discovered that there is a set of genes targeted by GPR81.

Conclusion: The interaction of GPR81 with SFPQ promotes cancer cell malignancy. GPR81 nuclear translocation is critical in conferring cancer progression and may be a potential therapeutic target for limiting cancer progression.

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来源期刊
自引率
0.00%
发文量
585
期刊介绍: The WJCO is a high-quality, peer reviewed, open-access journal. The primary task of WJCO is to rapidly publish high-quality original articles, reviews, editorials, and case reports in the field of oncology. In order to promote productive academic communication, the peer review process for the WJCO is transparent; to this end, all published manuscripts are accompanied by the anonymized reviewers’ comments as well as the authors’ responses. The primary aims of the WJCO are to improve diagnostic, therapeutic and preventive modalities and the skills of clinicians and to guide clinical practice in oncology. Scope: Art of Oncology, Biology of Neoplasia, Breast Cancer, Cancer Prevention and Control, Cancer-Related Complications, Diagnosis in Oncology, Gastrointestinal Cancer, Genetic Testing For Cancer, Gynecologic Cancer, Head and Neck Cancer, Hematologic Malignancy, Lung Cancer, Melanoma, Molecular Oncology, Neurooncology, Palliative and Supportive Care, Pediatric Oncology, Surgical Oncology, Translational Oncology, and Urologic Oncology.
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