多组学分析显示PLEKHA6是肺腺癌中β-catenin信号传导和治疗易感的调节因子。

IF 2.9 3区 医学 Q2 ONCOLOGY
American journal of cancer research Pub Date : 2025-07-25 eCollection Date: 2025-01-01 DOI:10.62347/NVVF8441
Bing-Hua Su, Sachin Kumar, Li-Hsin Cheng, Wan-Jung Chang, Dahlak Daniel Solomon, Ching-Chung Ko, Chung-Chieh Chiao, Do Thi Minh Xuan, Juan Lorell Ngadio, Christophorus Manuel Heryanto, Bianca Tobias William, Fitria Sari Wulandari, Hao-Chien Yang, Hung-Yun Lin, Chih-Yang Wang, Ming-Cheng Tsai, Ming-Derg Lai
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引用次数: 0

摘要

肺腺癌(LUAD)仍然是最普遍和最致命的肺癌亚型,主要是由于诊断晚和治疗耐药。在这项研究中,我们进行了全面的多组学分析来表征LUAD的pleckstrin同源结构域(PLEKHA)家族基因。在8个成员中,PLEKHA6在LUAD组织中唯一过表达,且与不良预后显著相关。综合整体RNA-Seq、单细胞RNA-Seq、DNA甲基化和药物基因组学分析发现PLEKHA6是致癌过程的关键调节剂,包括Wnt/β-catenin信号传导、钙粘蛋白介导的粘附和细胞骨架重塑。A549 LUAD细胞的功能分析显示,PLEKHA6敲低可抑制β-catenin和VE-cadherin的表达,导致增殖、迁移和集落形成受损,同时增加细胞凋亡和细胞周期阻滞。单细胞RNA测序显示PLEKHA6表达与肿瘤相关巨噬细胞(TAM)浸润之间存在相关性,暗示PLEKHA6参与肿瘤微环境(TME)内的免疫重塑。药物敏感性分析和分子对接进一步确定了针对表达plekha6的LUAD细胞的潜在治疗药物。总之,我们的研究结果表明PLEKHA6在LUAD中是一种新的致癌驱动因子和免疫调节剂,支持其作为预后生物标志物和精确肿瘤学治疗靶点的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Multi-omics profiling reveals PLEKHA6 as a modulator of β-catenin signaling and therapeutic vulnerability in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) remains the most prevalent and lethal subtype of lung cancer, largely due to late diagnosis and therapeutic resistance. In this study, we conducted a comprehensive multi-omics analysis to characterize the pleckstrin homology domain-containing (PLEKHA) family gene in LUAD. Among the eight members, PLEKHA6 was uniquely overexpressed in LUAD tissues and significantly associated with poor prognosis. Integrated bulk RNA-Seq, single-cell RNA-Seq, DNA methylation, and pharmacogenomic analyses identified PLEKHA6 as a key modulator of oncogenic processes, including Wnt/β-catenin signaling, cadherin-mediated adhesion, and cytoskeletal remodeling. Functional assays in A549 LUAD cells revealed that PLEKHA6 knockdown suppressed β-catenin and VE-cadherin expression, leading to impaired proliferation, migration, and colony formation, along with enhanced apoptosis and cell cycle arrest. Single-cell RNA sequencing demonstrated a correlation between PLEKHA6 expression and tumor-associated macrophage (TAM) infiltration, implicating PLEKHA6 in immune remodeling within the tumor microenvironment (TME). Drug sensitivity analysis and molecular docking further identified potential therapeutic drugs targeting PLEKHA6-expressing LUAD cells. Collectively, our findings establish PLEKHA6 as a novel oncogenic driver and immune modulator in LUAD, supporting its potential as both a prognostic biomarker and a therapeutic target for precision oncology.

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来源期刊
自引率
3.80%
发文量
263
期刊介绍: The American Journal of Cancer Research (AJCR) (ISSN 2156-6976), is an independent open access, online only journal to facilitate rapid dissemination of novel discoveries in basic science and treatment of cancer. It was founded by a group of scientists for cancer research and clinical academic oncologists from around the world, who are devoted to the promotion and advancement of our understanding of the cancer and its treatment. The scope of AJCR is intended to encompass that of multi-disciplinary researchers from any scientific discipline where the primary focus of the research is to increase and integrate knowledge about etiology and molecular mechanisms of carcinogenesis with the ultimate aim of advancing the cure and prevention of this increasingly devastating disease. To achieve these aims AJCR will publish review articles, original articles and new techniques in cancer research and therapy. It will also publish hypothesis, case reports and letter to the editor. Unlike most other open access online journals, AJCR will keep most of the traditional features of paper print that we are all familiar with, such as continuous volume, issue numbers, as well as continuous page numbers to retain our comfortable familiarity towards an academic journal.
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