Liu Xiao, Guo Lei, Chen Xi, Liu Zi-Tao, Zhu Yan-Hua, Xiao Mei, Liu Jie-Zhen, Chen Xu, Zhang Yan-Liang
Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University Kunming 650032, Yunnan, China.
Yunnan Key Laboratory of Laboratory Medicine Kunming 650032, Yunnan, China.
Am J Transl Res. 2024 Nov 15;16(11):6399-6422. doi: 10.62347/JAHC2715. eCollection 2024.
This study aims to elucidate the role of cAMP responsive element binding protein 3 like 4 (CREB3L4) in the pathogenesis of lung adenocarcinoma (LUAD) and to provide new insights and approaches for its effective treatment. An analysis was conducted on the expression and prognostic implications of CREB3L4 in LUAD.
Potential downstream target genes regulated by CREB3L4 were identified through chromatin immunoprecipitation assay sequencing and mRNA sequencing analyses, and the regulatory relationship, mechanism, and prognostic significance of the identified target gene in LUAD were subsequently confirmed. Moreover, immune microenvironment analysis, the identification of immunotherapy targets, and chemotherapy drug sensitivity analyses were performed for LUAD with different levels of CREB3L4 expression.
CREB3L4 is upregulated in LUAD and is significantly associated with tumor staging and poor prognosis, influencing cell proliferation and migration. Comprehensive analysis through chromatin immunoprecipitation assay sequencing and mRNA sequencing highlighted RAS and EF-hand domain containing (RASEF) as a potential target gene under the regulation of CREB3L4, which was found to be overexpressed in LUAD and linked to tumor staging, as well as cell proliferation and migration. Notably, the knockdown of CREB3L4 markedly reduced RASEF promoter-driven luciferase activity. The aberrant expression of CREB3L4 in LUAD was intricately related to the complex tumor microenvironment and immune therapy targets, including PD-L1, CTLA-4, CD28, CD80, and demonstrated increased sensitivity to chemotherapy drugs such as osimertinib, gefitinib, and afatinib.
These findings provide preliminary evidence for the involvement of the CREB3L4/RASEF signaling pathway in LUAD pathogenesis and suggest its potential as a novel biomarker for accurate diagnosis and targeted therapy.
本研究旨在阐明环磷腺苷反应元件结合蛋白3样4（CREB3L4）在肺腺癌（LUAD）发病机制中的作用，并为其有效治疗提供新的见解和方法。对CREB3L4在LUAD中的表达及预后意义进行分析。
通过染色质免疫沉淀测序和mRNA测序分析鉴定受CREB3L4调控的潜在下游靶基因，随后证实所鉴定靶基因在LUAD中的调控关系、机制及预后意义。此外，对不同CREB3L4表达水平的LUAD进行免疫微环境分析、免疫治疗靶点鉴定及化疗药物敏感性分析。
CREB3L4在LUAD中上调，与肿瘤分期及预后不良显著相关，影响细胞增殖和迁移。通过染色质免疫沉淀测序和mRNA测序的综合分析突出显示含RAS和EF手结构域（RASEF）作为CREB3L4调控下的潜在靶基因，发现其在LUAD中过表达并与肿瘤分期以及细胞增殖和迁移相关。值得注意的是，敲低CREB3L4显著降低RASEF启动子驱动的荧光素酶活性。CREB3L4在LUAD中的异常表达与复杂的肿瘤微环境和免疫治疗靶点密切相关，包括程序性死亡受体1（PD-L1）、细胞毒性T淋巴细胞相关蛋白4（CTLA-4）、CD28、CD80，并显示出对奥希替尼、吉非替尼和阿法替尼等化疗药物的敏感性增加。
这些发现为CREB3L4/RASEF信号通路参与LUAD发病机制提供了初步证据，并表明其作为准确诊断和靶向治疗的新型生物标志物的潜力。
