Department of Respiratory and Critical Care Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine Central South University, Changsha 410008, China.
Department of Pulmonary and Critical Care Medicine 1, The Affiliated Zhuzhou Hospital Xiangya Medical College CSU, Central South University, Zhuzhou 412000, China.
Int Immunopharmacol. 2023 Sep;122:110580. doi: 10.1016/j.intimp.2023.110580. Epub 2023 Jul 5.
Lung adenocarcinoma (LUAD) is a malignant respiratory disease, resulting in a heavy social burden. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance and tumor immune microenvironment are important directions in the treatment of LUAD. In this study, we confirmed the role of ADAM metallopeptidase domain 12 (ADAM12) in LUAD development and progression. Our bioinformatic analysis was conducted to screen ADAM12 was correlated with EGFR-TKI and immune infiltration in LUAD patients. Our results showed that the transcription and post-transcription level of ADAM12 is significantly increased in tumor samples compared to normal samples, and ADAM12 correlated with poor prognosis in LUAD patients. High level of ADAM12 accelerated the LUAD progression via promoting proliferation, cell cycle, apoptosis escaping, immune escaping, EGFR-TKI resistance, angiogenesis, invasion and migration based on experiment validation in vitro and in vivo, which could be attenuated by ADAM12 knockdown. Further mechanistic studies suggested that the PI3K/Akt/mTOR and RAS signaling pathways were activated after ADAM12 knockdown. Therefore, ADAM12 might be validated as a possible molecular therapy target and prognostic marker for patients with LUAD.
肺腺癌 (LUAD) 是一种恶性呼吸系统疾病，给社会带来了沉重的负担。表皮生长因子受体酪氨酸激酶抑制剂 (EGFR-TKI) 耐药和肿瘤免疫微环境是 LUAD 治疗的重要方向。在本研究中，我们证实了 ADAM 金属肽酶结构域 12 (ADAM12) 在 LUAD 发展和进展中的作用。我们通过生物信息学分析筛选出 ADAM12 与 LUAD 患者的 EGFR-TKI 和免疫浸润相关。结果表明，与正常组织相比，肿瘤组织中 ADAM12 的转录和转录后水平显著升高，ADAM12 与 LUAD 患者的不良预后相关。高水平的 ADAM12 通过促进增殖、细胞周期、逃避凋亡、免疫逃避、EGFR-TKI 耐药、血管生成、侵袭和迁移，在体外和体内实验中加速 LUAD 的进展，这些可以通过 ADAM12 敲低来减弱。进一步的机制研究表明，ADAM12 敲低后激活了 PI3K/Akt/mTOR 和 RAS 信号通路。因此，ADAM12 可能被验证为 LUAD 患者的一种潜在的分子治疗靶点和预后标志物。
