Forkhead‑box�A1 regulates tumor cell growth and predicts prognosis in colorectal cancer

Abstract

Forkhead box A1 (FOXA1) functions as a tumor suppressor gene or an oncogene in various types of cancer; however, the distinct function of FOXA1 in colorectal cancer is unclear. The present study aimed to evaluate whether FOXA1 affects the oncogenic behavior of colorectal cancer cells, and to investigate its prognostic value in colorectal cancer. The impact of FOXA1 on tumor cell behavior was investigated using small interfering RNA and the pcDNA6-myc vector in human colorectal cancer cell lines. To investigate the role of FOXA1 in the progression of human colorectal cancer, an immunohistochemical technique was used to localize FOXA1 protein in paraffin-embedded tissue blocks obtained from 403 patients with colorectal cancer. Tumor cell apoptosis and proliferation were evaluated using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and Ki-67 immunohistochemical staining, respectively. FOXA1 knockdown inhibited tumor cell invasion in colorectal cancer cells, and induced apoptosis and cell cycle arrest. FOXA1 knockdown activated cleaved caspase-poly (ADP-ribose) polymerase, upregulated the expression of p53 upregulated modulator of apoptosis, and downregulated BH3 interacting domain death agonist and myeloid cell leukemia-1, leading to the induction of apoptosis. FOXA1 knockdown increased the phosphorylation level of signal transducer and activator of transcription-3. By contrast, these results were reversed following the overexpression of FOXA1. The overexpression of FOXA1 was associated with differentiation, lymphovascular invasion, advanced tumor stage, depth of invasion, lymph node metastasis and poor survival rate. The mean Ki-67 labeling index value of FOXA1-positive tumors was significantly higher than that of FOXA1-negative tumors. However, no significant association was observed between the expression of FOXA1 and the mean apoptotic index value. These results indicate that FOXA1 is associated with tumor progression via the modulation of tumor cell survival in human colorectal cancer.

<p>FOXA1 Promotes Cell Proliferation and Suppresses Apoptosis in HCC by Directly Regulating miR-212-3p/FOXA1/AGR2 Signaling Pathway</p>

“…As reported in many studies, the expression of FOXA1 was increased in various types of cancers, including urothelial carcinoma, 3 colorectal cancer, 4 prostate cancer, 5 and glioma. 6 It was confirmed that FOXA1 regulated the expression of lots of carcinogenesis-related genes, [25][26][27] including HSP72, 28 BCL2, 29 HOXB13, 30 UGT2B15, 31 UGT2B17.…”

“…As a transcriptional activator for liverspecific transcripts, FOXA1 plays a key role in proliferation, apoptosis and cell cycle. Many physiology and pathology studies on cancer reported that overexpression of FOXA1 was associated with poor prognosis of urothelial carcinoma, 3 colorectal cancer, 4 prostate cancer, 5 and glioma. 6 AGR2, also known as secreted cement gland protein XAG-2 homolog, is a suppressor of p53 via preventing DNA damage-induced phosphorylation of p53.…”

Knockdown of Forkhead box A1 suppresses the tumorigenesis and progression of human colon cancer cells through regulating the phosphatase and tensin homolog/Akt pathway

“…18 Together, these findings indicate the inhibitory effects of FOXA1 on colon cancer progression, consistent with results from previous studies in CRC. 12,13 A recent study has reported that FOXA1 methylation altered gene expression in estrogen receptor-negative breast cancer. 20 Only two studies 12,13 have reported the oncogenic role of FOXA1 in human CRC; however, the exact mechanism remains to be fully elucidated.…”

“…18 Together, these findings indicate the inhibitory effects of FOXA1 on colon cancer progression, consistent with results from previous studies in CRC. 12,13…”

“…However, only two studies have reported the role of FOXA1 in human colorectal cancer (CRC). 12,13 Therefore, we aimed to elucidate the potential biological function and the underlying mechanism of FOXA1 in human colon cancer.…”