Chunxiang Cao¹, Zhi Xu², Haiyan Xia², Jianmin Bian², Wenbin Huang², Yixin Zhang³, Song He⁴, Nikki Lee⁵

¹Department of Oncology, Nanjing First Hospital, Nanjing Medical University, ²Nanjing Medical University, Nanjing First Hospital, ³Department of General Surgery, Nantong Tumor Hospital, ⁴Department of Pathology, Nantong Tumor Hospital, ⁵Department of Surgery, The University of Hong Kong

Objective:Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide and lacking effective medication. Protein phosphatase magnesium-dependent 1δ (PPM1D) is a potential oncogene and promising prognostic marker in a variety of solid tumors. We aimed to investigate the clinical and prognostic value of PPM1D in HCC. Method: Immunohistochemical staining was performed toexamine PPM1D expression in HCC tissue microarrays. The associations between PPM1D expression and individual clinicopathologic variables with overall survival were analyzed by SPSS. We used gain-of-function and loss-of-function experiments to explore the effects of PPM1D in HCC cells, and confirmed the results in tumor xenograft mouse model. Result: A retrospective cohort of 81 HCC patients who underwent hepatectomy were enrolled in this study. Our results showed that PPM1D was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P=0.044). Kaplan-Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor for HCC-specific overall survival (HR, 2.799; 95% CI, 1.346-5.818, P=0.006). Overexpressing PPM1D could promote cellular viability and invasion, while RNA interference–mediated knockdown of PPM1D could inhibit proliferation, cellular invasion and migration in HCC cell lines. In addition, we found that PPM1D small interfering RNA was able to decrease tumorigenicity of HCC cells in vivo. Conclusion: Our results suggest that PPM1D is a prognostic marker and attractive therapeutic target for this aggressive malignancy.

Key Words: PPM1D  hepatocellular carcinoma  prognosis