Thymosin 관4 expression correlates with lymph node metastasis through hypoxia inducible factor-관 induction in breast cancer.

다국어 초록 (Multilingual Abstract)

<P>Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1관 and HIF-2관, are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin 관4 (T관4) 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-관 with T관4 and the intracellular functional roles of T관4 on HIF-관 activation. We examined HIF-1관, HIF-2관 and T관4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1관 and HIF-2관 strongly correlates with T관4 expression (P??.0001) and overexpression of T관4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular T관4 protein, which then affects HIF-관 activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular T관4 and HIF-관 activities were reduced by interference of T관4 expression using T관4 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 T관4 is strongly associated with HIF-1관 and HIF-2관 expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-관activation and induction of VEGF-A. Ultimately, these results highlight T관4 as a potentially therapeutic target in malignant cancers.</P>