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Tumor necrosis factor-α (TNF-α) is involved in epithelial-mesenchymal transition (EMT) and expression of CD44, a cancer stem cell marker, in several cancers. This study was performed to clarify the significance of TNF-α and CD44 in clear cell renal cell carcinomas (ccRCCs). Expression of TNF-α and CD44 was examined by immunohistochemistry in 120 ccRCCs. Involvement of TNF-α in EMT and induction of CD44 was analyzed by monitoring expression of EMT-related genes and CD44, and invasion in cultured ccRCC cell lines. TNF-α and CD44 were immunolocalized mainly to carcinoma cells of high-grade ccRCCs with positive correlations with primary tumor stage. A positive correlation was also obtained between TNF-α and CD44 expression, and co-upregulation of TNF-α and CD44 was associated with primary tumor stage, distant metastasis, and poor prognosis. TNF-α enhanced migration and invasion of ccRCC cells together with down-regulation of E-cadherin expression and up-regulation of matrix metalloproteinase 9 and CD44 expression. TNF-α also up-regulated the expression of TNF-α itself in ccRCC cells. Among the 25 ccRCC patients treated with sunitinib for metastatic disease, high CD44 expression was associated with poor treatment outcome. Importantly, residual carcinoma cells in the sunitinib-treated metastatic ccRCCs were strongly positive for CD44, and the CD44 expression was significantly higher in the tumors from the sunitinib-treated patients than in those from untreated ones. Our data show that TNF-α plays an important role in progression of ccRCCs by inducing EMT and CD44 expression, and suggest that CD44 induced by TNF-α may be involved in the resistance to the sunitinib treatment.
Mikami et al. (Thu,) studied this question.