Overexpression of hypoxia inducible factor-1 alpha is an independent risk factor for recurrence after curative resection of colorectal liver metastases.

Abstract

Hypoxia inducible factor-1α (HIF-1α) is a major regulator of tumorigenesis in hypoxic conditions and therefore represents a potential therapeutic target in colorectal cancer (CRC). Clinical significance of HIF-1α expression in liver metastases has not been elucidated. Therefore, this study aimed to clarify the clinical significance of HIF-1α expression in colorectal liver metastasis (CRLM). We retrospectively analyzed 64 patients who underwent curative resection of CRLM from 2000 to 2008. We evaluated HIF-1α expression by immunohistochemical staining and analyzed its association with several clinicopathological characteristics, including vascular endothelial growth factor (VEGF) expression. We analyzed the mutation status of genes involved in CRC (p53, KRAS, BRAF, and PIK3CA). Finally, we compared HIF-1α expression between the primary tumor and the corresponding liver metastases. We found a significant positive correlation between HIF-1α expression in liver metastases and PIK3CA mutation status (p = 0.019). A significant correlation was also observed between the expressions of HIF-1α and VEGF in liver metastases and primary tumors (p = 0.015, 0.024, respectively). High HIF-1α expression in liver metastases was an independent risk factor for recurrence (p = 0.031). Our results suggest a possible induction of HIF-1α expression by mutant PIK3CA. The expressions of HIF-1α and VEGF in liver metastases significantly correlated with those in the corresponding primary tumor. Overexpression of HIF-1α was an independent risk factor for recurrence after curative resection of CRLM, suggesting that HIF-1α represents an important candidate for the treatment of CRLM in a subset of patients with high HIF-1α expression.