PinX1 suppresses tumorigenesis by negatively regulating telomerase/telomeres in colorectal carcinoma cells and is a promising molecular marker for patient prognosis

Dong Qian,1 Jingjing Cheng,1 Xiaofeng Ding,1 Xiuli Chen,1 Xi Chen,1 Yong Guan,1 Bin Zhang,2 Jiefu Wang,3 Puchun Er,1 Minghan Qiu,1 Xianliang Zeng,1 Yihang Guo,1 Huanhuan Wang,1 Lujun Zhao,1 Dan Xie,4 Zhiyong Yuan,1 Ping Wang,1 Qingsong Pang1 1Department of Radiotherapy, 2Department of Lung Cancer, 3Department of Colorectal Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 4State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China Abstract: PinX1 plays positive and negative roles in the maintenance of telomerase and telomeres, as well as in tumorigenesis. The aim of the present study was to investigate the expression and clinical significance of PinX1 in colorectal carcinoma (CRC) and to determine the effect of PinX1 on CRC cell proliferation and apoptosis. A total of 86 CRC patients treated with radical resection and 5-fluorouracil-based adjuvant chemotherapy were enrolled in this study. The expression dynamics of PinX1 was detected by immunohistochemistry in the CRC patients and 25 normal colonic mucosa controls. PinX1 expression was significantly reduced in tumor tissues as compared to normal tissues, and the rate of PinX1 protein low/negative expression in CRC and normal tissues was 60% (52/86) and 24% (6/25), respectively (P=0.037). In addition, PinX1 downregulation was significantly associated with short overall survival (P=0.016) and disease-free survival (P=0.042) in CRC patients. Cox proportional hazards model further revealed that PinX1 expression was an independent factor in predicting overall survival and disease-free survival for CRC patients. Furthermore, we demonstrated that ectopic overexpression of PinX1 in CRC cells inhibited their proliferation, promoted apoptosis, repressed telomerase activity, and induced telomere shortening. These findings suggest that PinX1 may be a prognostic biomarker for CRC patients’ survival and that it inhibits cell proliferation and promotes apoptosis by repressing telomerase activity and inducing telomere shortening. Targeting PinX1 may therefore provide a novel therapeutic strategy for CRC patients. Keywords: colorectal carcinoma, PinX1, cell proliferation, apoptosis, telomerase, telomere, prognostic biomarker