HDLBP Promotes Glycolysis and CD8+ T Cell Exhaustion in Lung Adenocarcinoma by Stabilizing GJB2 RNA.

IF 5.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Li Xu, Bin Zhou, Kaiqi Jin, Tao Ge, Ming Deng, Hongdou Ding, Xinnan Xu
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引用次数: 0

Abstract

Gap junction protein beta 2 (GJB2) has been associated with glycolysis and immunosuppression in human tumors. This research aims to explore the roles of GJB2 in these aspects in the context of lung adenocarcinoma (LUAD). GJB2 expression in LUAD was analyzed using bioinformatics tools and verified in human LUAD cells. RNA binding proteins (RBPs) that target GJB2 were predicted using bioinformatics and verified using RNA immunoprecipitation assays. Gain- or loss-of-function assays of GJB2 and high-density lipoprotein binding protein (HDLBP) were performed in LUAD cells, investigating their roles in glycolysis. These LUAD cells underwent co-culture with activated CD8+ T cells to examine the effect of gene interference on the exhaustion and activity of T cells. A mouse model of allograft tumor was established for in vivo validation. GJB2 exhibited aberrantly heightened expression in LUAD cells. Further overexpression of GJB2 in cancer cells increased glucose uptake, lactate production, and extracellular acidification rate, augmented aggressive phenotype of cancer cells, and increased exhaustion of the co-cultured CD8+ T cells. HDLBP, an RBP that binds to GJB2 RNA, was found to be highly expressed in LUAD as well, which enhanced GJB2 expression by stabilizing the GJB2 mRNA. Overexpression of HDLBP similarly rendered glycolysis and T cell inactivity, with these effects negated by GJB2 knockdown. Parallelly, GJB2 silencing in mouse 3LL cells suppressed tumorigenesis, glycolysis, and T cell exhaustion in mice promoted by HDLBP. This research suggests that HDLBP-mediated GJB2 RNA stabilization augments glycolysis and CD8+ T cell exhaustion in LUAD progression.

HDLBP通过稳定GJB2 RNA促进肺腺癌中糖酵解和CD8+ T细胞衰竭。
间隙连接蛋白β 2 (GJB2)在人类肿瘤中与糖酵解和免疫抑制有关。本研究旨在探讨GJB2在肺腺癌(LUAD)背景下在这些方面的作用。利用生物信息学工具分析GJB2在LUAD中的表达,并在人LUAD细胞中进行验证。利用生物信息学预测靶向GJB2的RNA结合蛋白(rbp),并利用RNA免疫沉淀法进行验证。在LUAD细胞中进行GJB2和高密度脂蛋白结合蛋白(HDLBP)的功能增加或丧失分析,研究它们在糖酵解中的作用。将这些LUAD细胞与活化的CD8+ T细胞共培养,以检测基因干扰对T细胞衰竭和活性的影响。建立小鼠同种异体移植瘤模型进行体内验证。GJB2在LUAD细胞中表达异常升高。GJB2在癌细胞中的进一步过表达增加了葡萄糖摄取、乳酸生成和细胞外酸化速率,增强了癌细胞的侵袭性表型,增加了共培养CD8+ T细胞的衰竭。HDLBP是一种结合GJB2 RNA的RBP,在LUAD中也高表达,通过稳定GJB2 mRNA来增强GJB2的表达。过表达HDLBP类似地导致糖酵解和T细胞失活,这些作用被GJB2敲除。同时,小鼠3LL细胞中GJB2的沉默抑制了HDLBP促进的小鼠肿瘤发生、糖酵解和T细胞衰竭。这项研究表明,hdlbp介导的GJB2 RNA稳定增强了LUAD进展中的糖酵解和CD8+ T细胞耗竭。
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来源期刊
CiteScore
11.20
自引率
3.10%
发文量
370
审稿时长
3-8 weeks
期刊介绍: The American Journal of Respiratory Cell and Molecular Biology publishes papers that report significant and original observations in the area of pulmonary biology. The focus of the Journal includes, but is not limited to, cellular, biochemical, molecular, developmental, genetic, and immunologic studies of lung cells and molecules.
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