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.
Keywords: 5-fluorouracil; FOXA1; KRT7; gastric cancer.