Background: Hepatocellular carcinoma (HCC) is an aggressive form of liver cancer with particularly poor survival rates for patients. Targeted molecular therapies are lacking, and current treatment is generally limited to surgical resection or liver transplantation. Overexpression and aberrant signaling of the ErbB family of receptors has been implicated in HCC, but the mechanisms underlying ErbB overexpression are unclear. In this study, we investigated the potential role of neuregulin receptor degradation protein-1 (Nrdp1), a regulator of ErbB3 protein stability, in HCC progression.
Methods: We compared the expression of Nrdp1 in various HCC cell lines and in 8 pairs of tumor and peritumor tissue samples using Western blot analysis. Changes in the degree of proliferation were determined before and after small interfering RNA (siRNA)-induced knockdown of Nrdp1 using a cell counting Kit-8 (ccK-8) assay and cell-cycle analysis. The correlation between Nrdp1 expression and prognosis was determined in specimens of 89 HCC patients.
Results: Nrdp1 expression is significantly reduced in HCC tissues compared with adjacent healthy tissues. Higher Nrdp1 expression corresponds to lower maximal tumor size (χ ², P <0.05), lower histological grade (χ ², P <0.05), and higher survival rates by Kaplan–Meier estimate (P <0.05). Higher Nrdp1 expression also corresponds to reduced expression of Ki-67, a marker of cell proliferation (Spearman, r²=0.734; P <0.05). Nrdp1 accumulates in serum-starved HepG2 cancer cells and progressively decreases in expression after re-feeding. Furthermore, depletion of Nrdp1 in healthy L02 cells by siRNA results in enhanced cell proliferation and a greater proportion of cells in S phase.
Conclusions: Our findings suggest an inhibitory role for Nrdp1 in HCC tumorigenesis, and we propose that Nrdp1 may serve as a prognostic biomarker for HCC and as a potential therapeutic target for the treatment of HCC.
Keywords: neuregulin receptor, ErbB3 protein stability, HCC therapeutic target, ErbB, Nrdp1 depletion