J Cancer 2021; 12(3):827-839. doi:10.7150/jca.46749

Research Paper

Hypoxia Inducible Factor-1alpha (HIF-1A) plays different roles in Gallbladder Cancer and Normal Gallbladder Tissues

Youliang Wu1, Delong Meng2, Yexiang You1, Ruochuan Sun1, Min Fu1, Qiang Yan1, Shangxin Zhang1, Zheng Fang1, Junjun Bao1, Yongxiang Li1✉

1. Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China.
2. Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA.

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Wu Y, Meng D, You Y, Sun R, Fu M, Yan Q, Zhang S, Fang Z, Bao J, Li Y. Hypoxia Inducible Factor-1alpha (HIF-1A) plays different roles in Gallbladder Cancer and Normal Gallbladder Tissues. J Cancer 2021; 12(3):827-839. doi:10.7150/jca.46749. Available from https://www.jcancer.org/v12p0827.htm

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Purpose: Hypoxia-inducible factor-1alpha (HIF-1A) is a transcription factor that plays an “angiogenic switch” role especially under hypoxia microenvironment in solid tumor. However, the functions and clinical significance of HIF-1A in gallbladder cancer (GBC) are still controversial, and it has not been studied in normal gallbladder tissues. In this study, we sought to clarify the role of sub-cellular localization of HIF-1A expression in GBC and normal gallbladder tissues.

Methods: The expressions of HIF-1A and CD34 in 127 GBC and 47 normal gallbladder tissues were evaluated by immunohistochemistry. Cox's proportional hazards model analysis and Kaplan-Meier method analysis were used to assess the correlations between these factors and clinicopathological features and prognosis.

Results: HIF-1A was expressed in both cytoplasm and nucleus of GBC and normal control tissues, and was significantly correlated with microvessel density (MVD). GBC tissues with positive nuclear HIF-1A expression had higher MVD compared to that with positive cytoplasmic HIF-1A expression; however, in normal gallbladder tissues, samples with positive cytoplasmic HIF-1A had higher MVD compared to that with positive nuclear HIF-1A expression. Moreover, GBC with nuclear HIF-1A expression tended to be more poorly differentiated and had larger tumor size compared to that with cytoplasm HIF-1A expression. Furthermore, GBC patients with nuclear HIF-1A positive were significantly correlated with worse overall survival (OS) compared with cytoplasmic HIF-1A positive. Multivariate Cox regression analysis identified lymph node metastasis and nuclear HIF-1A expression to be independent prognostic parameter in GBC.

Conclusions: Our findings provide evidence for the first time that HIF-1A is expressed in normal gallbladder tissues. Nuclear HIF-1A and cytoplasm HIF-1A plays different roles in GBC and normal gallbladder tissues.

Keywords: gallbladder cancer, normal gallbladder tissue, HIF-1A, MVD, prognosis bio-marker