Predictive Value of CD44 in Muscle-Invasive Bladder Cancer and Its Relationship with IL-6 Signaling
CD44, a cancer stem cell surface marker, is associated with treatment resistance and prognosis in some cancers. In the present study, we examined the predictive value of CD44 in muscle-invasive bladder cancer (MIBC).
We retrospectively analyzed the clinical outcomes of 105 MIBC patients and correlated these outcomes with the expression of CD44. Furthermore, the bladder cancer cell lines HT1197 and MB49 were selected for cellular and animal experiments to investigate the correlation between CD44 and tumor aggressiveness.
Analysis of clinical specimens indicated that CD44 staining was significantly associated with a higher clinical stage, higher locoregional failure rate, and lower disease-specific survival rate for MIBC patients. Using cellular experiments and orthotopic tumor models, we showed that CD44+ bladder cancer cells had a higher invasion ability and augmented epithelial-mesenchymal transition (EMT) compared with CD44 cells. There was a significant correlation between interleukin (IL)-6 and CD44 levels noted by in vitro testing, and clinical samples. Blockade of IL-6 attenuated the expression of CD44, cancer stem-cell-like properties, and aggressive tumor behavior in vitro and in vivo. The related changes included the attenuated STAT3 activation and EMT, and decreased programmed death ligand 1-mediated T-cell suppression.
Our findings suggest that CD44 expression is positively associated with tumor aggressiveness in bladder cancer, and activated IL-6 signaling provides a suitable microenvironment for the induction of CD44 expression.
This work was support by Chang Gung Memorial Hospital, Taiwan (Grant Number OMRPG6C0011 and CMRPG6D0323, to M-F Chen), and the National Science Council, Taiwan (Grant Number NMRPG2E6031, to C-T Wu).
Conflicts of interest
Chun-Te Wu, Wei-Yu Lin, Wen-Cheng Chen, and Miao-Fen Chen confirm they have no conflicts of interest.
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