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Aurora-A activation, correlated with hypoxia-inducible factor-1?, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma.

ABSTRACT: Previously, we and others showed that hypoxia-inducible factor-1? (HIF-1?) and transcriptionally upregulated Aurora-A were required for disease progression in several tumors. Here, we address the clinicopathologic value of Aurora-A and HIF-1? in locally advanced nasopharyngeal carcinoma (NPC). Aurora-A and HIF-1? expression was semiquantitatively evaluated by immunohistochemistry staining in 144 cases from a randomized controlled trial. Of these patients, 69 received neoadjuvant chemotherapy plus concurrent chemoradiotherapy, and acted as the training set, and 75 cases treated with neoadjuvant chemotherapy plus radiotherapy were used as the testing set to validate the prognostic effect of Aurora-A and HIF-1?. We found that Aurora-A and HIF-1? were highly expressed in NPC, but were deficient in normal adjacent epithelia. In the testing set, Aurora-A overexpression predicted a shortened 5-year overall survival (59.1% vs 82.5%, P = 0.024), progression-free survival (44.8% vs 79.8%, P = 0.004), and distant metastasis-free survival (43.0% vs 17.3%, P = 0.016). Multivariate regression analysis confirmed that Aurora-A was indeed an independent prognostic factor for death, recurrence, and distant metastasis both in the testing set and overall patients. Moreover, a positive correlation between Aurora-A and HIF-1? was detected (P = 0.037). Importantly, although HIF-1? did not show any prognostic effect for patient outcome, the subset with Aurora-A and HIF-1? co-overexpression had the poorest overall, progression-free, and distant metastasis-free survival (all P < 0.05). Our results confirmed that Aurora-A was an independent prognostic factor for NPC. Aurora-A combined with HIF-1? refined the risk definition of the patient subset, thus potentially directing locally advanced NPC patients for more selective therapy.

SUBMITTER: Wan XB

PROVIDER: S-EPMC7659277 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Aurora-A activation, correlated with hypoxia-inducible factor-1α, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma.

Wan Xiang-Bo XB Fan Xin-Juan XJ Huang Pei-Yu PY Dong Dong D Zhang Yan Y Chen Ming-Yuan MY Xiang Jin J Xu Jie J Liu Li L Zhou Wei-Hua WH Lv Yan-Chun YC Wu Xiang-Yuan XY Hong Ming-Huang MH Liu Quentin Q

Cancer science 20120705 8

Previously, we and others showed that hypoxia-inducible factor-1α (HIF-1α) and transcriptionally upregulated Aurora-A were required for disease progression in several tumors. Here, we address the clinicopathologic value of Aurora-A and HIF-1α in locally advanced nasopharyngeal carcinoma (NPC). Aurora-A and HIF-1α expression was semiquantitatively evaluated by immunohistochemistry staining in 144 cases from a randomized controlled trial. Of these patients, 69 received neoadjuvant chemotherapy plu ...[more]

PMID: 22587416

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Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets.

Dataset Information

Aurora-A activation, correlated with hypoxia-inducible factor-1?, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma.

Publications

Aurora-A activation, correlated with hypoxia-inducible factor-1α, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma.

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