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Deregulation of HIF1-alpha and hypoxia-regulated pathways in hepatocellular carcinoma and corresponding non-malignant liver tissue—influence of a modulated host stroma on the prognosis of HCC

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Abstract

Purpose

The aim of this study was to elucidate the role of HIF1A expression in hepatocellular carcinoma (HCC) and the corresponding non-malignant liver tissue and to correlate it with the clinical outcome of HCC patients after curative liver resection.

Methods

HIF1A expression was determined by quantitative RT-PCR in HCC and corresponding non-malignant liver tissue of 53 patients surgically treated for HCC. High-density gene expression analysis and pathway analysis was performed on a selected subset of patients with high and low HIF1A expression in the non-malignant liver tissue.

Results

HIF1A over-expression in the apparently non-malignant liver tissue was a predictor of tumor recurrence and survival. The estimated 1-year and 5-year disease-free survival was significantly better in patients with low HIF1A expression in the non-malignant liver tissue when compared to those patients with high HIF1 expression (88.9% vs. 67.9% and 61.0% vs. 22.6%, respectively, p = 0.008). Based on molecular pathway analysis utilizing high-density gene-expression profiling, HIF1A related molecular networks were identified that contained genes involved in cell migration, cell homing, and cell–cell interaction.

Conclusion

Our study identified a potential novel mechanism contributing to prognosis of HCC. The deregulation of HIF1A and its related pathways in the apparently non-malignant liver tissue provides for a modulated environment that potentially enhances or allows for HCC recurrence after curative resection.

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Acknowledgments

This work is funded by the German Research Foundation (DFG) (WE 2729/4-1 to F.W. as part of the clinical research group, KFO117) and by the Dr. Deichmann Foundation (AF 1-HCC to A.F.). We thank Joachim Fandrey and Andreas Paul for their helpful discussions and support. Special thanks goes to Jutta Hunke, Alexander Rácz, and Daniel Burdziak for their technical support.

Author information

Authors and Affiliations

  1. Department of General-, Visceral- and Transplantation Surgery, University Hospital Essen, Essen, Germany

    Frank Simon, Christian Praha, Christoph E. Broelsch, Andrea Frilling & Frank Weber

  2. Department of Pathology and Neuropathology, University Hospital Essen, Essen, Germany

    Hideo A. Baba

  3. Department of Physiology, University Hospital Essen, Essen, Germany

    Christian Praha

  4. Department of General-, Visceral- and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Maximilian Bockhorn & Frank Weber

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  1. Frank Simon
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Correspondence to Frank Weber.

Additional information

Authors Contributions

Study concept and design: Frank Weber, Maximilian Bockhorn, Chritoph E. Broelsch, Andrea Frilling

Acquisition of data: Frank Simon, Maximilian Bockhorn, Frank Weber, Christian Praha, Hideo A. Baba, Christoph E. Broelsch, Andrea Frilling

Analysis and interpretation of data: Frank Weber, Frank Simon, Maximilian Bockhorn, Christian Praha

Drafting of manuscript: Frank Weber, Frank Simon, Maximilian Bockhorn

Critical revision of manuscript: Frank Weber, Frank Simon, Maximilian Bockhorn, Christian Praha, Hideo A. Baba, Christoph E. Broelsch, Andrea Frilling

Frank Simon and Maximilian Bockhorn contributed equally to this work.

“Best of Abstracts—Chirurgisches Forum 2010, Deutsche Gesellschaft für Chirurgie”

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Supplemental figure 1

Unsupervised cluster analysis. Based on the selection criteria (1) 40% of data show at least 1.5-fold change from the median gene expression value in either direction; (2) probe sets with over 50% missing data were excluded, 1,697 genes were identified and used for further analysis. For the cluster distance measure average linkage method and 1-minus the correlation coefficient was used. After clustering, samples were labeled according to its class (i.e., high and low HIF1A expression). (JPEG 61 kb)

High resolution image file (TIF 24 KB)

Supplemental figure 2

HCC HIF1A expression was normalized to commercially available normal liver tissue and not to the corresponding non-malignant liver tissue. Kaplan–Meier representation of the overall survival of the two cohorts of HCC patients with high (dotted line) or low (solid line) HIF1A expression. Estimated mean overall free survival 42 months vs. 64 months (p = 0.018). The 1-year and 5-year overall survival was estimated in high and low HIF1A expressing tumors to 76.2%, 88.2% and 33.2%, 60.2%, respectively. (JPEG 75 kb)

High resolution image file (TIF 54 KB)

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Simon, F., Bockhorn, M., Praha, C. et al. Deregulation of HIF1-alpha and hypoxia-regulated pathways in hepatocellular carcinoma and corresponding non-malignant liver tissue—influence of a modulated host stroma on the prognosis of HCC. Langenbecks Arch Surg 395, 395–405 (2010). https://doi.org/10.1007/s00423-009-0590-9

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