Silencing DVL3 defeats MTX resistance and attenuates stemness via Notch Signaling Pathway in colorectal cancer.

Chemoresistance and recurrence of colorectal cancer are mainly caused by the existence of cancer stem-like cells. Dishevelled-3 (DVL3) is a common member of both Wnt/β-catenin pathway and the Notch signaling pathway, which were involved in cancer progression, chemoresistance and even maintenance of stem cell-like properties. However, the underlying biological function of DVL3 still remains unclear. In this study, we proposed DVL3 was simultaneously involved in Methotrexate (MTX) resistance and Colorectal cancer (CRC) stemness by bioinformatic analysis. We also demonstrated DVL3 knockdown sensitized CRC cells to MTX and inhibited their stem cell-like properties by functional experiments. As for the mechanism, DVL3 silencing attenuated the activated Notch signaling by down-regulating Notch intracellular domain (NICD) as well as its downstream targets. Additionally, we demonstrated that CRC cancer tissues had greater DVL3 expression than adjacent non-cancer tissues and patients' overall survival was closely associated with DVL3 according to the data in our clinical center. Accordingly, our data suggest that DVL3 is a key regulator in CRC stemness and chemoresistance and targeting DVL3 could be a potential strategy for CRC therapy.

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.