Zhao Guang, Qi Jun, Li Fang, Ma Haotian, Wang Rui, Yu Xiuyi, Wang Yufei, Qin Sida, Wu Jie, Huang Chen, Ren Hong, Zhang Boxiang
Department of Thoracic Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Xi'an, Shaanxi, 710061, China.
Department of Thoracic Surgery, Sichuan Provincial People's Hospital: Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan, 610072, China.
Adv Sci (Weinh). 2025 May;12(17):e2411020. doi: 10.1002/advs.202411020. Epub 2025 Mar 11.
TNF receptor-associated factor 3 interacting protein 3 (TRAF3IP3/T3JAM) exhibits dual roles in cancer progression. While upregulated in most malignancies and critical for immune regulation. However, the specific effects and molecular mechanisms of TRAF3IP3 on the progression of lung adenocarcinoma (LUAD) remains poorly understood. This study reveals TRAF3IP3 is upregulated in several tumor tissues but exclusively decreased in LUAD and Lung squamous cell carcinoma (LUSC) tissues, consequential in a favorable overall survival (OS) in LUAD rather than LUSC. Herein, it is reported that TRAF3IP3 can suppress cell proliferation and promote the apoptosis rate of LUAD cells by inducing excessive ER stress-related apoptosis. Importantly, TRAF3IP3 triggers ER stress via the PERK/ATF4/CHOP pathway, accompanied by stimulated ER stress-induced cytoprotective autophagy in LUAD cells. Through IP-MS analysis, STRN3 is identified as a direct downstream interactor with TRAF3IP3 and corroborated to regulate ER stress positively. Mechanistically, TRAF3IP3 facilitates the recruitment of STRN3 to the ER lumen through its transmembrane domain and fulfills its functional role in ER stress in an STRN3-dependent manner in LUAD cells. Given its dual role in orchestrating ER stress-associated apoptosis and autophagy in LUAD cell fate determination, the importance of TRAF3IP3 is highlighted as novel therapeutic target for LUAD treatment.
肿瘤坏死因子受体相关因子3相互作用蛋白3（TRAF3IP3/T3JAM）在癌症进展中发挥双重作用。虽然在大多数恶性肿瘤中上调且对免疫调节至关重要。然而，TRAF3IP3对肺腺癌（LUAD）进展的具体影响和分子机制仍知之甚少。本研究表明，TRAF3IP3在几种肿瘤组织中上调，但在LUAD和肺鳞状细胞癌（LUSC）组织中却专门下调，这使得LUAD患者的总生存期（OS）良好，而非LUSC患者。在此报告中，TRAF3IP3可通过诱导过度的内质网应激相关凋亡来抑制LUAD细胞增殖并提高其凋亡率。重要的是，TRAF3IP3通过PERK/ATF4/CHOP途径触发内质网应激，同时在LUAD细胞中刺激内质网应激诱导的细胞保护性自噬。通过免疫沉淀-质谱分析，STRN3被确定为与TRAF3IP3直接相互作用的下游分子，并证实其对内质网应激起正向调节作用。机制上，TRAF3IP3通过其跨膜结构域促进STRN3向内质网腔的募集，并以STRN3依赖的方式在LUAD细胞中在内质网应激中发挥其功能作用。鉴于TRAF3IP3在协调内质网应激相关凋亡和自噬以决定LUAD细胞命运方面的双重作用，其作为LUAD治疗新靶点的重要性得以凸显。
