PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection

Background: Under hypoxia, tumour cells undergo genetic and adaptive changes that allow their survival. Previously, we reported that high expression of hypoxia-inducible factor (HIF)-1 was a significant predictive factor for recurrence in hepatocellular carcinoma (HCC). Hypoxia also stimulates expression of procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) genes via the HIF-1 pathway. Aims: The aim was to evaluate the relationship between hypoxia stress and expression of PLOD genes in HCC in vitro and to identify a new prognostic marker in HCC patients. Methods: The PLOD2 expression was assessed under hypoxia in hepatoma cell lines and characterized in 139 HCC samples following hepatic resection using microarray experiments, quantitative RT-PCR and immunohistochemistry. Prognostic factors in HCC patients were assessed using univariate and multivariate analyses. Results: The PLOD2 expression was induced under the hypoxia in vitro. Disease-free survival in the high PLOD2 expression group of HCC patients was significantly shorter when compared with the low-expression group (P = 0.002). In a subset of HCCs, we found that the PLOD2 expression of microarray was correlated with data of quantitative RT-PCR and immunohistochemistry. Of clinicopathological factors, PLOD2 expression was significantly correlated with tumour size (P = 0.022) and macroscopic intrahepatic metastasis (P = 0.049). In univariate analysis, six prognostic factors (tumour multiplicity, macroscopic intrahepatic metastasis, histological grade, microscopic portal invasion, microscopic intrahepatic metastasis and PLOD2 expression) were significant for disease-free survival. PLOD2 expression was identified as a significant, independent factor of poor prognosis (P = 0.013). Conclusions: PLOD2 is a potential novel prognostic factor for HCC patients following surgery.