Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.
Oncogene. 2023 Dec;42(49):3619-3632. doi: 10.1038/s41388-023-02873-6. Epub 2023 Oct 20.
The tripartite motif (TRIM) protein family has been investigated in multiple human cancers, including gastric cancer (GC). However, the role of TRIM69 in the anoikis resistance and metastasis of GC cells remains to be elucidated. We identified the differentially expressed genes in anoikis-resistant GC cells using RNA-sequencing analysis. The interaction between TRIM69 and PRKCD was analyzed by coimmunoprecipitation and mass spectrometry. Our results have shown that TRIM69 was significantly downregulated in anoikis-resistant GC cells. TRIM69 overexpression markedly suppressed the anoikis resistance and metastasis of GC cells in vitro and in vivo. TRIM69 knockdown had the opposite effects. Mechanistically, TRIM69 interacted with PRKCD through its B-box domain and catalyzed the K48-linked polyubiquitination of PRKCD. Moreover, TRIM69 inhibited BDNF production in a PRKCD-dependent manner. Importantly, overexpression of PRKCD or BDNF blocked the effects of TRIM69 on the anoikis resistance and metastasis of GC cells. Interestingly, a TRIM69PRKCDBDNF cell subset was positively associated with metastasis in GC patients. TRIM69-mediated suppression of the anoikis resistance and metastasis of GC cells via modulation of the PRKCD/BDNF axis, with potential implications for novel therapeutic approaches for metastatic GC.
三结构域蛋白（TRIM）家族在多种人类癌症中进行了研究，包括胃癌（GC）。然而，TRIM69 在 GC 细胞的抗失巢凋亡和转移中的作用仍有待阐明。我们使用 RNA 测序分析鉴定了抗失巢凋亡 GC 细胞中的差异表达基因。通过共免疫沉淀和质谱分析分析了 TRIM69 和 PRKCD 之间的相互作用。我们的结果表明，TRIM69 在抗失巢凋亡 GC 细胞中显著下调。TRIM69 的过表达显着抑制了 GC 细胞在体外和体内的抗失巢凋亡和转移。TRIM69 敲低则有相反的效果。在机制上，TRIM69 通过其 B 盒结构域与 PRKCD 相互作用，并催化 PRKCD 的 K48 连接多泛素化。此外，TRIM69 以 PRKCD 依赖的方式抑制 BDNF 的产生。重要的是，PRKCD 或 BDNF 的过表达阻断了 TRIM69 对 GC 细胞抗失巢凋亡和转移的影响。有趣的是，TRIM69-PRKCD-BDNF 细胞亚群与 GC 患者的转移呈正相关。TRIM69 通过调节 PRKCD/BDNF 轴抑制 GC 细胞的抗失巢凋亡和转移，这可能为转移性 GC 的新治疗方法提供了潜力。
