title: The expression of HIF-1α in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome.
abstract: The purpose of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) protein expression in hepatocellular carcinoma (HCC), and responses of abdominal metastatic lymph nodes (LNs) from HCC patients treated with external beam radiotherapy (EBRT). HIF-1α immunohistochemical staining was performed on tissue microarrays (TMAs) of primary HCC specimens from 69 HCC patients with abdominal LN metastases. All patients received abdominal metastatic LN EBRT at the Department of Radiation Oncology at Zhongshan Hospital. A receiver-operating characteristic (ROC)-based approach and logistical regression analysis were used to determine the predictive value of HIF-1α expression in primary tumors with HCC metastatic LN EBRT response. Kaplan-Meier curves and log-rank tests were used to analyze patient survival. Cox proportional hazards regression model was used to analyze independent prognostic factors. HIF-1α expression was correlated with blood hemoglobin (Hb: r = -0.280, P = 0.020), response of abdominal metastatic LNs to EBRT (r = 0.286, P = 0.017), locoregional recurrence (r = 0.278, P = 0.021), and cancer-specific deaths (r = 0.298, P = 0.013). HIF-1α expression was predictive of EBRT response of metastatic LNs [area under the curve (AUC): 0.646; 95% confidence interval (CI): 0.499-0.793; P = 0.047], locoregional recurrence (AUC: 0.657; 95% CI: 0.509-0.805; P = 0.049) and cancer-specific deaths (AUC: 0.671; 95% CI: 0.531-0.812; P = 0.035). Patients with tumors exhibiting high HIF-1α expression had significantly poorer overall survival (OS) than those with low tumor expression of HIF-1α (P = 0.016). Multivariate analysis showed that Hb (P = 0.035), vascular invasion (P = 0.026), Child-Pugh score (P < 0.001), intrahepatic tumor control (P < 0.001), and HIF-1α (P = 0.020) were independent prognosis factors for OS of HCC patients after receiving abdominal metastatic LN EBRT. HIF-1α expression in primary HCCs was associated with EBRT response of abdominal metastatic LNs and poor prognosis.
authors.affiliation: Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China.
authors.forename: Zuo-Lin
authors.initials: ZL
authors.lastname: Xiang
authors.forename: Zhao-Chong
authors.initials: ZC
authors.lastname: Zeng
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
authors.forename: Jian
authors.initials: J
authors.lastname: He
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Zeng
authors.forename: Joe Y
authors.initials: JY
authors.lastname: Chang
mesh_terms: D019540:Area Under Curve; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000532:radiotherapy / Q000556:secondary*; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D056726:Genetic Association Studies; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D016015:Logistic Models; D008207:Lymphatic Metastasis; D046228:Microarray Analysis; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D016016:Proportional Hazards Models; D012372:ROC Curve
chemical_list: C497442:HIF1A protein, human; D006454:Hemoglobins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit