Estrogen receptor a (ERA) is a DNA-binding transcription factor that plays an important role in the regulation of cell growth. Previous studies indicated that the expression of ERa in cell lines and tumors derived from oral squamous cell carcinoma (OSCC). The aim of this study was to examine the activity and function of ERa in OSCC cells and the mechanism underlying ERa activation. Immunochemical analyses in benign (nZ11) and malignant (nZ21) lesions of the oral cavity showed that ERa immunoreactivity was observed in 43% (9/21) of malignant lesions, whereas none of benign lesions showed ERa immunoreactivity. The ERa expression was also found in three OSCC cell lines and its transcriptional activity was correlated with cell growth. Addition of estradiol stimulated cell growth, whereas treatment of tamoxifen or knockdown of ERa expression caused reduced cell growth. Interestingly, the expression and activity of focal adhesion kinase (FAK) were associated with the phosphorylation of ERa at serine 118 in OSCC cells. Elevated expression of FAK in the slow-growing SCC25 cells caused increases in ERa phosphorylation, transcriptional activity, and cell growth rate, whereas knockdown of FAK expression in the rapid-growing OECM-1 cells led to reduced ERa phosphorylation and activity and retarded cell growth. Inhibition of the activity of protein kinase B (AKT), but not ERK, abolished FAK-promoted ERa phosphorylation. These results suggest that OSCC cells expressed functional ERa, whose activity can be enhanced by FAK/AKT signaling, and this was critical for promoting cell growth. Thus, FAK and ERa can serve as the therapeutic targets for the treatment of OSCC.
Key Words" oral squamous cell carcinoma " estrogen receptor a " focal adhesion kinase
See page 240Fully 95% of Merkel cell carcinomas, a primary cutaneous neuroendocrine carcinoma, express cytokeratin-20 (CK20), which distinguishes them from morphologically similar entities such as metastatic small-cell lung carcinoma. Diagnosis of the 5% of Merkel cell carcinomas that are CK20-negative is more challenging. Harms et al found that CK20-negative Merkel cell carcinoma has important molecular similarities to CK20-positive Merkel cell carcinoma. Recurrent mutations were identified that were more prevalent in Merkel cell polyomavirus-negative tumors, including several tumor-suppressor genes previously implicated in Merkel cell carcinoma, such as APC, TET2, and BAP1. In addition, the authors identified activating mutations in the PI3K pathway in a subset of tumors. EZH2, an oncogenic histone methyltransferase not previously described in Merkel cell carcinoma, is now under investigation as a therapeutic target. Harms and colleagues also showed that Merkel cell polyomavirus-negative tumors display ultraviolet-signature mutation spectra.
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