Mitotic Spindle Positioning (MISP) Facilitates Colorectal Cancer Progression by Forming a Complex with Opa Interacting Protein 5 (OIP5) and Activating the JAK2-STAT3 Signaling Pathway

Abstract

Patients with inflammatory bowel disease (IBD) who experience long-term chronic inflammation of the colon are at an increased risk of developing colorectal cancer (CRC). Mitotic spindle positioning (MISP), an actin-binding protein, plays a role in mitosis and spindle positioning. MISP is found on the apical membrane of the intestinal mucosa and helps stabilize and elongate microvilli, offering protection against colitis. This study explored the role of MISP in colorectal tumorigenesis using a database, human CRC cells, and a mouse model for colitis-induced colorectal tumors triggered by azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment. We found that MISP was highly expressed in colon cancer patient tissues and that reduced MISP expression inhibited cell proliferation. Notably, MISP-deficient mice showed reduced colon tumor formation in the AOM/DSS-induced colitis model. Furthermore, MISP was found to form a complex with Opa interacting protein 5 (OIP5) in the cytoplasm, influencing the expression of OIP5 in a unidirectional manner. We also observed that MISP increased the levels of phosphorylated STAT3 in the JAK2-STAT3 signaling pathway, which is linked to tumorigenesis. These findings indicate that MISP could be a risk factor for CRC, and targeting MISP might provide insights into the mechanisms of colitis-induced colorectal tumorigenesis.

MISP Is Overexpressed in Intestinal Metaplasia and Gastric Cancer

“…Concordantly, reducing MISP expression in pancreatic ductal adenocarcinoma cells results in inhibited cell proliferation [21]. Similarly, in human colorectal cancer (CRC) cell lines, the knockdown of MISP significantly diminishes the colony-forming ability, suggesting that MISP promotes CRC cell proliferation [25]. These findings parallel the outcomes of the present study, where decreased MISP expression correlates with reduced cell viability/proliferation in GC cells.…”

“…In a follow-up investigation led by the same researchers, it was revealed, in the same mouse model, a notable reduction in CRC development in the context of colitis. This discovery implies that MISP might contribute as a potential risk factor for CRC through its interaction with Opa Interacting Protein 5 (OIP5), forming a complex which triggers the activation of the JAK2-STAT3 (Janus kinase 2-Signal transducer and activator of transcription 3) signaling pathway [25].…”