<scp>PLOD</scp>2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection

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