Thymosin beta 4 expression correlates with lymph node metastasis through hypoxia inducible factor-alpha induction in breast cancer

초록

Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1 alpha and HIF-2 alpha, are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin beta 4 (T beta 4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-alpha with T beta 4 and the intracellular functional roles of T beta 4 on HIF-alpha activation. We examined HIF-1 alpha, HIF-2a and T beta 4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1 alpha and HIF-2 alpha strongly correlates with T beta 4 expression (P <= 0.0001) and overexpression of T beta 4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular T beta 4 protein, which then affects HIF-alpha activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular T beta 4 and HIF-alpha activities were reduced by interference of T beta 4 expression using T beta 4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also down-regulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of T beta 4 is strongly associated with HIF-1 alpha and HIF-2 alpha expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-alpha activation and induction of VEGF-A. Ultimately, these results highlight T beta 4 as a potentially therapeutic target in malignant cancers.

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