The Hypoxia inducible factor 1α (HIF-1α) regulates the malignant progression of gastric cancer

N. Rohwer; M. Vieth; W. Kemmner; P. M. Schlag; M. Höcker; T. Cramer

doi:10.1055/s-2006-950910

Zeitschrift für Gastroenterologie, Table of Contents

The Hypoxia inducible factor 1α (HIF-1α) regulates the malignant progression of gastric cancer

N Rohwer ¹, M Vieth ², W Kemmner ³, PM Schlag ³, M Höcker ¹, T Cramer ⁴

¹Labor für Angiogenese und Metastasierung, Charité, Campus Virchow-Klinikum, Berlin, Germany
²Institut für Pathologie, Otto-von-Guericke Universtiät, Magdeburg, Germany
³Institut für Chirurgie und Chirurgische Onkologie, Robert-Rössle-Klinik, Max Delbrück Centrum für Molekulare Medizin, Charité, Campus Buch, Berlin, Germany
⁴Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum, Berlin, Germany

Abstract

Introduction: Hypoxia is a hallmark of solid tumor growth and a negative predictor of patient survival. Adaptation to hypoxia is mainly achieved by the transcription factor HIF-1α, which is upregulated in a diverse range of human and experimental tumors and their metastases. HIF-1α target genes have been implicated in the induction of invasion and metastasis. Gastric cancer represents the second largest cause of cancer-related deaths worldwide. It has been shown that HIF-1α contributes to experimental gastric cancer pathogenesis. However, the underlying molecular and cell biological mechanisms have not been fully elucidated.

Methods: Expression of HIF-1α was analyzed by immunohistochemistry in tissue microarrays of 45 human gastric cancer samples and corresponding healthy control tissues. The influence of functional inactivation of HIF-1α on proliferation, migration and invasion of gastric cancer cells was studied using AGS and MKN28 cells. Inactivation of HIF-1α was achieved by stable lentiviral transfer of short interfering RNAs (siRNA).

Results: 89% (40/45) of gastric cancer samples displayed expression of HIF-1α in >90% of neoplastic cells. In benign controls HIF-1α protein abundance never exceeded 20% of total epithelial cells and parietal cells were found to be the principle source of HIF-1α protein. Proliferation and survival of gastric cancer cells in vitro was not affected by inactivating HIF-1α. However, anchorage-independent growth, a hallmark of cancer cells, was reduced significantly by loss of HIF-1α. In addition, HIF-1α knock-down diminished the migratory and invasive potential of gastric cancer cells significantly. Addition of excess free ATP did not revert the reduced migration or invasion of HIF-1α-deficient gastric cancer cells indicating that the observed phenotype can not be explained by a defect in energy generation.

Conclusion: Our analysis of tumor samples shows that broad epithelial expression of HIF-1α is a frequent and prominent feature of human gastric adenocarcinomas. Moreover, this study implicates an important role for HIF-1α in progression of gastric cancer and demonstrates that inhibition of HIF-1α may be an innovative therapeutic intervention strategy for this cancer.