| Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide and remains one of the major causes of death and disease burden worldwide, while epigenetic disruption of tumor suppressor genes (TSGs) is a fundamental contributor to their pathogenesis, epigenetics research of CRC has been developed widely.Purpose:FOXD3 (forkhead box D3), as one important member of the Fox transcription factor family, has many biological functions, such as, maintenance of embryonic development and pluripotency in embryonic stem cells (ESC), regulation of formation, migration and differentiation in neural crest. However, little is known about the expression or function of FOXD3 in the pathogenesis of colorectal cancer. Thus we studied the epigenetic and genetic alterations of FOXD3 and its functions in the pathogenesis of colorectal cancer.Methods:FOXD3 methylation was evaluated by methylation-specific PCR and bisulfite genome sequencing. FOXD3 expression was determined by quantitative RT-PCR and immunohistochemistry. The effects of FOXD3 such as the growth and migration of tumor cells were tested in vitro and in vivo. The regulation mechanism of FOXD3 was verified by Western Blot.Results:FOXD3 was frequently silenced and methylated in colorectal cancer. FOXD3 was downregulated in colorectal cancer tissues compared with paired adjacent non-tumor tissues, furthermore, the downregulation of FOXD3 expression was more commonly seen in cases presenting with poor prognostic factors of colorectal cancer, leading to poorly histopathological grading, lymph node metastasis, late-stage and reduced survival time, indicating its potential as a tumor marker. Restoring FOXD3 expression inhibited tumor cell proliferation and migration, furthermore, ectopic FOXD3 expression enhanced apoptosis by activating endoplasmic reticulum stress pathway, etc.Conclusions:FOXD3 is down-regulated and frequently silenced by promoter methylation in colorectal cancer, it acts as a functional tumor suppressor, through inhibiting tumor cell proliferation and metastasis, inducing apoptosis. FOXD3 methylation may could serve as an epigenetic biomarker and FOXD3 may be of potential values as a novel therapeutic target for colorectal cancer. |
