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PLOD 2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection
Author(s) -
Noda Takehiro,
Yamamoto Hirofumi,
Takemasa Ichiro,
Yamada Daisaku,
Uemura Mamoru,
Wada Hiroshi,
Kobayashi Shogo,
Marubashi Shigeru,
Eguchi Hidetoshi,
Tanemura Masahiro,
Umeshita Koji,
Doki Yuichro,
Mori Masaki,
Nagano Hiroaki
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2011.02619.x
Subject(s) - immunohistochemistry , hepatocellular carcinoma , hypoxia (environmental) , univariate analysis , pathology , cancer research , biology , hccs , hypoxia inducible factors , metastasis , medicine , oncology , multivariate analysis , gene , cancer , chemistry , organic chemistry , oxygen , biochemistry
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 PLOD 2 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 PLOD 2 expression was induced under the hypoxia in vitro . Disease‐free survival in the high PLOD 2 expression group of HCC patients was significantly shorter when compared with the low‐expression group ( P = 0.002). In a subset of HCC s, we found that the PLOD 2 expression of microarray was correlated with data of quantitative RT‐PCR and immunohistochemistry. Of clinicopathological factors, PLOD 2 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 PLOD 2 expression) were significant for disease‐free survival. PLOD 2 expression was identified as a significant, independent factor of poor prognosis ( P = 0.013). Conclusions PLOD 2 is a potential novel prognostic factor for HCC patients following surgery.