Hypoxia inducible factor-α expression correlates with thymosin β4 overexpression related to lymph node metastasis in breast cancer (165.5)

Abstract

Abstract Two hypoxia inducible factors (HIFs), HIF-1α and HIF-2α, are induced by hypoxia, and high expression of these proteins is correlated with angiogenesis and distant metastasis. Thymosin β4 (Tβ4) is frequently highly expressed in cancer, and this over-expression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-α with Tβ4 and the intracellular functional roles of Tβ4 on HIF-α activation. We showed that high expression levels of HIF-1α and HIF-2α strongly correlated with Tβ4 expression (P<0.0001), and over-expression of Tβ4 correlated significantly with lymph node metastasis (P<0.05) in patients with breast cancer. Additionally, we demonstrated that hypoxia up-regulates intracellular Tβ4 protein, which then affects HIF-α activity, which is a key in regulating vascular epidermal growth factor (VEGF) expression. We confirmed that hypoxia-induced intracellular Tβ4 and HIF-α activity were reduced by inhibiting Tβ4 expression using Tβ4 shRNA lentivirus. VEGF-A was also down regulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that over-expression of Tβ4 is strongly associated with HIF-1α and HIF-2α expression and is also clinicopathologically involved in lymph node metastatic potential of breast cancer through the modulation of HIF-α activation and induction of VEGF-A. Ultimately, these results highlight Tβ4 as a potentially therapeutic target in malignant cancers.