Correlation of hypoxia inducible factor-1α with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer

Hypoxia inducible factor (HIF)-1α is a transcription factor that regulates the transcription of genes associated with cell proliferation and vascular development. In various cancer tissues, HIF-1α is associated with clinicopathological factors, such as the tumor size, histological grade, and lymph node status. Although HIF-1α plays a critical role in tumor growth by inducing vascular endothelial growth factor (VEGF), it is unclarified whether HIF-1α affects lymphatic metastasis. The purpose of this study is to clarify the correlation of HIF-1α protein expression with lymph node metastasis in esophageal squamous cell carcinoma (ESCC). The expressions of HIF-1α and VEGF-C, which is one of the main lymphangiogenic factors, were examined in five ESCC cell lines and 48 surgical specimens of ESCC. HIF-1α and VEGF-C mRNAs were expressed in all the five ESCC cell lines as determined by RT-PCR analysis. Immunohistochemically, 34 of the 48 patients (70.8%) were positive for HIF-1α and 29 patients (60.4%) were positive for VEGF-C. Clinicopathologically, HIF-1α expression correlated with lymphatic invasion and VEGF-C expression (P = 0.003 and P = 0.01, respectively). Furthermore, HIF-1α expression tended to correlate with lymph node metastasis (P = 0.09). These findings suggest that HIF-1α plays a role in lymphatic invasion and lymph node metastasis through the induction of VEGF-C in ESCC.