PCNP promotes hepatocellular carcinoma progression by upregulating UHRF2 to activate ErbB3/Ras/Raf pathway

The PEST-containing nuclear protein (PCNP) has been reported to play paradoxical roles in tumorigenesis. While PCNP functions as a tumor suppressor in neuroblastoma and lung adenocarcinoma, it has been identified as a tumor promoter in ovarian cancer. However, the underlying mechanisms driving these contrasting effects remain unclear. Gene Expression Profiling Interactive Analysis (GEPIA) was employed to analyze relevance of PCNP expression with prognosis in HCC. To evaluate the role of PCNP in hepatocellular carcinoma (HCC), we analyzed the expression of PCNP in 87 HCC tissues and 80 adjacent normal tissues. Correlation between PCNP and ubiquitin-like with PHD and ring finger domains 2 (UHRF2) was transcriptionally detected, and then their effects on malignant behaviors, including proliferation, invasion, tumor formation in vitro and in vivo were evaluated. According to tissues array results, it is found that PCNP was significantly upregulated in HCC tissues, which was further confirmed in HCC cell lines by western blotting. Importantly, both the cytoplasmic and nuclear PCNP fractions were correlated with pathological grade, T staging, clinical staging and recurrence, and patients with a high level of PCNP had lower overall survival and disease-free survival and a higher recurrence rate than those with a low PCNP level, indicating that PCNP might be an independent prognostic factor for HCC patients. Functional investigations revealed that PCNP knockdown inhibited malignant behaviors, including proliferation, invasion, colony formation and tumor formation, in vitro and in vivo. Pearson correlation analysis indicated a positive association between PCNP and UHRF2, with evidence that PCNP transcriptionally upregulates UHRF2. Furthermore, ectopic overexpression of PCNP activated the ErbB3/Ras/Raf1 signaling pathway through upregulation of UHRF2. Our findings suggest that PCNP promotes HCC progression by activating the ErbB3/Ras/Raf signaling pathway through upregulation of UHRF2. Consequently, PCNP holds potential as both a diagnostic biomarker and a therapeutic target for hepatocellular carcinoma.