Xiong Ying, Ma Yuanyuan

Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute

Objective:Acquiredresistance to standard chemotherapy causes treatment failure in patients with advanced non-small lung cancer (NSCLC). Cancer stem cells (CSCs) are a small subpopulation within cancer that is thought to be resistant toconventional therapy like chemotherapy. The Notch pathway is one of the most intensively studied putative therapeutic targets to CSCs insolid tumors. However, how Notch signal influence chemoresistance has notbeen elucidated. Method: Immunohistochemisry were used to evaluate the expression of Notch3 and stem-related markers. Specific siRNA was performed to knock-down Notch3 expression levels. Colony formation and sphere formation assays were used to detect clonogenicity of stem-like feature. Flow cytometry were done to test CSCs surface makers. Result: In our study, Notch3 expression was demonstrated to be upregualted in the patients with chemoresistance. The γ-secretase inhibition (GSI) to inhibit Notch signal orspecific knockdown of Notch3 could reduce drug resistanceability in lung cancer cells. In addition, suppression of Notch3 decreased stem-like property of lung cancer cells. Further results showed that CSCs markers of ALDH1A1 and CD44 were relatively more positivity in lung cancer cells with chemoresistance and these two surface markers were positive correlation with Notch3 expression in lung cancer specimens. Furthermore, the lung cancer cells with drug resistance were shown to be associated with activation of autophagy. Conclusion:Our findings suggest that Notch3 has considerable value as a chemoresistance marker and potential therapeutic target in NSCLC.

Key Words: Notch3  NSCLC  CSCs  chemoresistance