Grainyhead-like 2 Promotes Tumor Growth and is Associated with Poor Prognosis in Colorectal Cancer

J Cancer. 2015 Feb 15;6(4):342-50. doi: 10.7150/jca.10969. eCollection 2015.


GRHL2 was implicated in regulating cancer development. Our previous study demonstrated that knockdown GRHL2 in colorectal cancer (CRC) cells inhibited cell proliferation by targeting ZEB1. It is unclear whether GRHL2 expression may have diagnostic or prognostic value in colorectal carcinoma. Additionally, how GRHL2 is associated with the clinical features of colorectal carcinoma is not known. In current study, immunohistochemistry stains were performed to examine GRHL2 in 171 colorectal cancers and paired normal colon mucosa. The prognostic value of GRHL2 was investigated in a retrospective cohort study with a five-year follow-up. The effects of GRHL2 on cell growth in vitro and in vivo were explored by GRHL2 over-expressing in HT29 and SW620 CRC cells. Further, the regulation of cell cycle and proliferation proteins by GRHL2 were assessed by flow cytometry and western blot. We found that GRHL2 was over-expressed in CRC tissues, and played an important role in CRC tumorigenesis. GRHL2 expression positively correlated with tumor size and TNM stage. Kaplan-Meier analysis showed that GRHL2 was an independent prognostic factor for both overall survival and recurrence-free survival. Ectopic over-expression of GRHL2 in CRC cell line HT29 and SW620 induced an increase of cellular proliferation in vitro and promoting tumor growth in vivo. The acquisition of GRHL2 regulated cell cycle and modulates the expression of proliferation proteins p21, p27, cyclin A and cyclin D1. Together, our findings reveal GRHL2 can be used as a novel predictive biomarker and represent a potential therapeutic target against CRC.

Keywords: Cell cycle; Colorectal cancer; GRHL2; Prognosis; Proliferation.