Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, Liaoning Province, China.
Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, Liaoning Province, China.
Biochem Biophys Res Commun. 2021 Jul 12;562:43-49. doi: 10.1016/j.bbrc.2021.04.106. Epub 2021 May 24.
FGD5 (faciogenital dysplasia-5), a Rho-family guanine nucleotide exchange factor, has been identified as a key regulator of endothelial cells angiogenesis and apoptosis. However, the expression and role of FGD5 in the pathogenesis of gastric cancer remain unknown. In the present study, we first detected FGD5 expression in tumor tissues of different stages by immunofluorescence and confirmed that FGD5 expression was associated with stages in human gastric cancer. Knockdown FGD5 by shRNA in 7901 and BGC823 human gastric cells lines inhibited tumorigenesis and migration in vivo and in vitro. Mechanistically, co-immunoprecipitation (Co-IP) assay showed that FGD5 interacted with EGFR and decreased EGFR ubiquitination. Additionally, FGD5 sustained the activation of EGFR downstream signaling molecules, including STAT3 and pSTAT3. Furthermore, we showed that FGD5 could induce resistance to chemotherapy 5Fu/CIS, however, a well-known STAT3 inhibitor FLL32 could reverse FGD5-induced chemotherapy resistance in vivo. In conclusion, we are the first to demonstrate that FGD5 expression was associated with tumor stage and proliferation in gastric cancer and targeting FGD5 might be a potential therapeutic target for EGFR-STAT3 resistance gastric cancer.
FGD5（颜面生殖器发育不良-5）是一种 Rho 家族鸟嘌呤核苷酸交换因子，已被确定为内皮细胞血管生成和凋亡的关键调节剂。然而，FGD5 在胃癌发病机制中的表达和作用尚不清楚。在本研究中，我们首先通过免疫荧光法检测了不同阶段肿瘤组织中的 FGD5 表达，并证实 FGD5 表达与人类胃癌的分期有关。在 7901 和 BGC823 人胃细胞系中，通过 shRNA 敲低 FGD5 可抑制体内和体外的肿瘤发生和迁移。机制上，免疫共沉淀（Co-IP）试验表明 FGD5 与 EGFR 相互作用并降低 EGFR 泛素化。此外，FGD5 还维持了 EGFR 下游信号分子的激活，包括 STAT3 和 pSTAT3。此外，我们表明 FGD5 可诱导对化疗药物 5Fu/CIS 的耐药性，然而，一种已知的 STAT3 抑制剂 FLL32 可在体内逆转 FGD5 诱导的化疗耐药性。总之，我们首次证明 FGD5 的表达与胃癌的肿瘤分期和增殖有关，靶向 FGD5 可能是治疗 EGFR-STAT3 耐药性胃癌的潜在靶点。
