LASP1 induces colorectal cancer proliferation and invasiveness through Hippo signaling and Nanog mediated EMT.

The role of LIM and SH3 protein 1 (LASP1) in colorectal cancer (CRC) has been described in multiple studies, however, the underlying molecular mechanisms remained inclusive. In the present study, we performed immunohistochemistry (IHC) staining for LASP1 and found that LASP1 expression was higher in CRC tissue of advanced stage. Over-expressed (OE) LASP1 promoted proliferation, tumorigenesis and migration of CRC cell lines SW480 and SW620. Using the TCGA database, we identified Yes-associated protein (YAP1) was positively correlated with LASP1 expression in CRC patients. Introducing a novel YAP1 inhibitor CA3, we found that CA3 treatment inhibited LAPS1 OE SW480 and SW620 cells proliferation, colony number formation, invasion and migration. Further mechanistic experiments showed that Nanog, a stem cell marker, was up-regulated in LASP1 OE cells but suppressed by CA3 treatment. Chromatin immunoprecipitation (CHIP) and luciferase reporter assay revealed that YAP1 can directly target the promoter region of Nanog and enhance its activity. LASP1 accelerated CRC migration through targeting YAP1-mediated vimentin and E-cadherin expression. Finally, by developing murine CRC model, we found the primary tumor size was almost abolished and the survival rate was greatly improved by chemotherapy and CA3 combined treatment compared with negative control or chemotherapy treated alone. Collectively, our findings demonstrated that LASP1 could induce CRC tumor cells proliferation and migration through activating hippo signaling pathway component YAP1 and further enhancing Nanog expression. AJTR