PPM1D is a prognostic marker and therapeutic target in colorectal cancer

Abstract

Protein phosphatase, Mg²⁺/Mn²⁺ dependent, 1D (PPM1D) has been associated with carcinogenesis. The present study investigated PPM1D expression as a potential biomarker in colorectal cancer (CRC). PPM1D expression was assessed using immunohistochemistry in 368 patients with CRC. The correlation between PPM1D expression, clinicopathological features and prognosis was analyzed. PPM1D small interfering (si)RNA-induced PPM1D silencing was performed in CRC cell lines to assess the effect of PPM1D on tumor cell proliferation and invasion in vitro. A total of 68.48% (252/368) of the CRC samples displayed high PPM1D expression. By contrast, only 9.24% (34/368) of the matched non-cancerous tissue samples exhibited high PPM1D expression. High PPM1D expression was correlated with node metastasis (P=0.0024), distant metastasis (P<0.001) and TNM stage (P=0.0016). Kaplan-Meier survival analysis revealed that patients with low PPM1D expression had significantly longer survival than those with high PPM1D expression (P=0.012). Moreover, multivariate analyses demonstrated that high PPM1D expression was an independent prognostic factor for overall survival (hazard ratio = 0.24; 95% confidence interval, 0.13-0.86; P=0.004). Furthermore, PPM1D gene silencing was found to significantly reduce the proliferation and invasion of CRC cells in vitro. These findings suggest a role for PPM1D as a prognostic marker and potential therapeutic target in CRC.

Keywords: PPM1D; biomarker; colorectal cancer; prognosis.

Figure 1

Immunohistochemical nuclear staining of PPM1D in colorectal cancer. Colorectal cancer samples were classified as having (A and B) low or (C and D) high PPM1D expression. Magnification: A and C, ×100; B and D, ×400. PPM1D, protein phosphatase, Mg²⁺/Mn²⁺ dependent, 1D.

Figure 2

Kaplan-Meier curves showing PPM1D expression and overall survival in patients with CRC. (A) Patients with high PPM1D expression levels had poorer overall survival compared with patients with low PPM1D expression. Data are representative of 368 CRC tissues (P<0.001). (B) Patients with high PPM1D expression in metastatic lymph nodes had poorer overall survival than patients with low metastatic lymph node PPM1D levels. Data are representative of 74 metastatic lymph node tissues (P=0.009). PPM1D, protein phosphatase, Mg²⁺/Mn²⁺ dependent, 1D; CRC, colorectal cancer.

Figure 3

PPM1D siRNA significantly reduces proliferation and invasion in colorectal cancer cells. (A) PPM1D expression in HCT-116, RKO and COLO-320 cells detected using western blot analysis. (B) siRNA-induced PPM1D silencing confirmed using quantitative polymerase chain reaction and western blot analyses. (C) PPM1D siRNA inhibited the proliferation of RKO and COLO-320 cells. (D) PPM1D siRNA inhibited invasion by RKO and COLO-320 cells. Data are presented as the mean ± standard deviation of three independent experiments. ^*P<0.05 for the difference between the two groups.