Ubiquitin-specific protease 8 is a novel prognostic marker in early-stage lung adenocarcinoma

Alterations of epidermal growth factor receptor (EGFR) expression frequently occur in early-stage lung adenocarcinoma. Ubiquitin-specific protease 8 (USP8) has been reported to stabilize EGFR protein at the plasma membrane through the recycling pathway. Here, we examined the correlation between USP8 expression and the expression or mutation status of EGFR, as well as the clinicopathological features of lung adenocarcinoma and patient outcome. Expression of EGFR and USP8 in surgically resected specimens of lung adenocarcinoma (82 cases) was examined by immunohistochemistry. Overexpression of EGFR was mutually correlated with that of USP8, and was also associated with clinicopathological features including pathological subtype, lymphatic permeation, and vascular invasion. Moreover, patients who had USP8-positive tumors had a significantly poorer outcome than those who were USP8-negative, not only overall but also patients who were EGFR-negative. Although EGFR was expressed in invasive adenocarcinoma but not in adenocarcinoma in situ (AIS), USP8 was overexpressed in not only invasive adenocarcinoma but also 38.1% of AIS cases. In vitro, USP8 regulated the expression and half-life of EGFR in immortalized AIS cells, and also cell proliferation. Our findings indicate that overexpression of USP8 in lung adenocarcinoma is an early event during the course of tumor progression, and is related to EGFR expression.