School of Medical Technology, Jiangsu College of Nursing, Huaian City, China.
Department of Gastroenterology, The First Hospital of Jilin University, Changchun City, China.
J Biol Regul Homeost Agents. 2019 Jul-Aug;33(4):1041-1050.
Gastric cancer (GC) is the fourth leading cause of gynecological malignancies worldwide. 5-fluorouracil (5-FU)-mediated chemotherapy is the adjuvant treatment for patients with GC following surgical resection. Many studies have indicated the cancer-type specific roles of forkhead box protein A1 (FOXA1) and keratin 7 (KRT7) in human malignancies. However, the potential mechanism underlying the involvement of FOXA1 and KRT7 in the pathogenesis and chemoresistance of GC are still not entirely clear. In our study, gain- and loss-of-function experiments proved that FOXA1 promoted cell proliferation, migration and invasion in AGS and SGC-7901 cells. Consequently, KRT7 was identified to be transcriptional activated by FOXA1 using Dual luciferase reporter assay. Our results also indicated that FOXA1 exerted its functions in enhancing viability and invasion of AGS and SGC-7901 cells through activating KRT7. Finally, interference of FOXA1 or KRT7 increased the chemosensitivity of AGS and SGC-7901 cells to 5-fluorouracil (5-Fu) treatment by suppressing cell proliferation. In conclusion, these data indicate that FOXA1 promoted proliferation, migration, invasion, and decreased chemosensitivity of GC cells to 5-Fu treatment through transcriptional activator KRT7. The present study provides a novel therapeutic strategy for the enhancement of efficacy in GC treatment and provides important insights into the molecular mechanism underlying 5-FU-mediated chemoresistance.
胃癌（GC）是全球第四大妇科恶性肿瘤。氟尿嘧啶（5-FU）介导的化疗是 GC 患者手术后的辅助治疗。许多研究表明叉头框蛋白 A1（FOXA1）和角蛋白 7（KRT7）在人类恶性肿瘤中具有癌症类型特异性作用。然而，FOXA1 和 KRT7 参与 GC 发病机制和化学耐药性的潜在机制尚不完全清楚。在我们的研究中，功能获得和功能丧失实验证明 FOXA1 促进了 AGS 和 SGC-7901 细胞的增殖、迁移和侵袭。因此，双荧光素酶报告基因检测证实 KRT7 是 FOXA1 的转录激活子。我们的结果还表明，FOXA1 通过激活 KRT7 发挥其增强 AGS 和 SGC-7901 细胞活力和侵袭的功能。最后，干扰 FOXA1 或 KRT7 通过抑制细胞增殖，增加 AGS 和 SGC-7901 细胞对 5-氟尿嘧啶（5-Fu）治疗的化疗敏感性。总之，这些数据表明，FOXA1 通过转录激活子 KRT7 促进 GC 细胞的增殖、迁移、侵袭，并降低对 5-Fu 治疗的化疗敏感性。本研究为提高 GC 治疗效果提供了一种新的治疗策略，并为 5-FU 介导的化学耐药性的分子机制提供了重要的见解。
