title: Downregulation of Foxc2 enhances apoptosis induced by 5-fluorouracil through activation of MAPK and AKT pathways in colorectal cancer.
abstract: The chemotherapy drug 5-fluorouracil (5-FU) is fundamental for the treatment of colorectal cancer (CRC); however, drug resistance to 5-FU may occasionally occur. Abnormal expression of Forkhead box C2 gene (Foxc2) has been identified in several human cancers, but the role of Foxc2 in the progression of CRC remains unclear. The present study established a stable Foxc2-short hairpin (sh)RNA cell line, which was confirmed by western blot analysis and quantitative polymerase chain reaction. The Foxc2-shRNA cells were treated with 5-FU and the cell viability was determined by an MTT assay. Western blot analysis was performed to investigate the signaling pathway involved in 5-FU treatment. The present study identified that 5-FU increased the percentage of apoptotic CRC cells among the Foxc2/RNA interference-transfected cells compared with cells transfected with an empty vector. Therefore, the downregulation of Foxc2, induced by 5-FU, may enhance apoptosis by the downregulation of apoptotic factors, including B cell lymphoma-2 and pro-caspase-3, in Foxc2-shRNA CRC cells. Furthermore, the mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinases/protein kinase B (PI3K/AKT) pathways were essential for the sensitization effect of Foxc2 to 5-FU treatment. Overall, these findings reveal the mechanisms behind Foxc2 depletion and 5-FU treatment of CRC and suggest that Foxc2 enhances resistance to apoptosis, induced by 5-FU, through the activation of MAPK and P13K/AKT pathways, and may serve as a valuable clinical prognostic marker for CRC.
authors.affiliation: Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China; Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Liao
keywords: AKT; Foxc2; MAPK; apoptosis; colorectal cancer