Syndecan-2 modulates the YAP pathway in epithelial-to-mesenchymal transition-related migration, invasion, and drug resistance in colorectal cancer

Abstract

Epithelial-to-mesenchymal transition (EMT) is associated with an invasive phenotype in colorectal cancer (CRC). Here, we examined the roles of YES-associated protein (YAP) and syndecan-2 (SDC2) in EMT-related progression, invasion, metastasis, and drug resistance in CRC. The expression levels of YAP and SDC2 in CRC patient tumor tissue were quantified by PCR and western blotting. EMT-associated characteristics were assessed using Transwell assays and immunohistochemistry. Co-immunoprecipitation, glutathione S-transferase pull-down, and luciferase reporter assays were used to assess interactions between YAP and SDC2. YAP was found to be highly expressed in tumor tissue from 13/16 CRC patients, while SDC2 was highly expressed in the tumor tissue of 12/16 CRC patients. Overexpression of YAP in colon cancer cells led to increased cell viability, invasion, migration, and oxaliplatin resistance demonstrating that YAP plays a role in EMT. In addition, overexpression of YAP led to decreased expression of the large tumor suppressor kinase 1 (LATS1) and mammalian sterile 20-like kinases (MST1/2). Decreased LATS1 expression was associated with increased levels of cell proliferation. Knockdown of YAP by shRNA interference led to decreased cell invasion, migration, and drug resistance in colon cancer cells and reduced tumorigenesis in a mouse xenograft model. Finally, we established that YAP interacted with SDC2, and demonstrated that SDC2 mediated the YAP pathway through the EMT-related factors BMP4, CTGF and FOXM1.

Keywords

• YAP
• SDC2
• Colorectal cancer
• Metastasis
• Drug resistance