Liao Yuhan, Chen Xinhua, Xu Hao, Zhi Yunfei, Zhuo Xinghua, Yu Jiang, Zhao Liang
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Pathology &, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
J Transl Med. 2025 Mar 13;23(1):320. doi: 10.1186/s12967-025-06340-6.
Extracellular vesicles (EVs) produced in the tumor microenvironment in response to chemotherapy promote chemotherapy-resistant phenotypes. However, the role of EVs proteins induced by gastric cancer (GC) cell chemotherapy in regulating chemotherapy resistance remains unclear.
Immunohistochemistry was used to verify the relationship between brain-specific angiogenesis inhibitor 1-associated protein-2-like protein 2 (BAIAP2L2) expression and chemotherapy resistance in advanced GC. The relationship between BAIAP2L2 and chemotherapy resistance was verified using a subcutaneous tumor model in nude mice. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were performed to detect purified EVs. Tandem mass tag (TMT) analysis was used to detect differential labels. The interaction between YTH domain-containing family protein1 (YTHDF1) and BAIAP2L2 in GC cells was confirmed by RIP-qPCR analysis using a YTHDF1-specific antibody.
We found that BAIAP2L2 was associated with chemotherapy resistance to GC in clinical samples and was increased in chemotherapy-resistant GC cells. Mechanistically, BAIAP2L2 promotes the transfer of chemotherapy resistance from resistant GC cells to sensitive cells through EVs proteins, such as ANXA4. Furthermore, ANXA4 promoted platinum-based chemical resistance in GC by mediating autophagy. Interestingly, YTHDF1 facilitates the translation of BAIAP2L2 and ANXA4 through mA modifications.
Our findings reveal the key role of BAIAP2L2 as a potential prognostic marker and therapeutic target for chemotherapy resistance in GC.
肿瘤微环境中因化疗产生的细胞外囊泡（EVs）可促进化疗耐药表型。然而，胃癌（GC）细胞化疗诱导的EVs蛋白在调节化疗耐药中的作用仍不清楚。
采用免疫组织化学法验证脑特异性血管生成抑制因子1相关蛋白2样蛋白2（BAIAP2L2）表达与晚期GC化疗耐药之间的关系。利用裸鼠皮下肿瘤模型验证BAIAP2L2与化疗耐药的关系。进行透射电子显微镜、纳米颗粒跟踪分析和蛋白质免疫印迹法检测纯化的EVs。采用串联质谱标签（TMT）分析检测差异标记。使用YTHDF1特异性抗体通过RIP-qPCR分析证实GC细胞中含YTH结构域家族蛋白1（YTHDF1）与BAIAP2L2之间的相互作用。
我们发现BAIAP2L2与临床样本中GC的化疗耐药相关，且在化疗耐药的GC细胞中表达增加。机制上，BAIAP2L2通过EVs蛋白（如膜联蛋白A4，ANXA4）促进化疗耐药从耐药GC细胞转移至敏感细胞。此外，ANXA4通过介导自噬促进GC对铂类药物的耐药。有趣的是，YTHDF1通过m⁶A修饰促进BAIAP2L2和ANXA4的翻译。
我们的研究结果揭示了BAIAP2L2作为GC化疗耐药潜在预后标志物和治疗靶点的关键作用。
