Seroreactivity Against Tyrosine Phosphatase PTPRN Links Type 2 Diabetes and Colorectal Cancer and Identifies a Potential Diagnostic and Therapeutic Target

Abstract

Colorectal cancer (CRC) and diabetes are two of the most prevalent chronic diseases worldwide with dysregulated receptor tyrosine kinase signaling and strong co-occurrence correlation. Plasma autoantibodies represent a promising early diagnostic marker for both diseases before symptoms appear. We explore here the value of autoantibodies against receptor-type tyrosineprotein phosphatase-like N PTPRN (full-length or selected domains) as diagnostic markers using a cohort of type 2 diabetic (T2D), CRC, healthy individuals or patients with both diseases. We show that PTPRN autoantibody levels in plasma discriminated between T2D patients with and without CRC. Consistently, high PTPRN expression correlated with decreased survival of CRC patients. Mechanistically, PTPRN depletion significantly reduced invasiveness of CRC cells in vitro and liver homing and metastasis in vivo by means of a dysregulation of the epithelial-mesenchymal transition and a decrease of the insulin receptor signaling pathway. Therefore, PTPRN autoantibodies may represent a particularly helpful marker for the stratification of T2D patients at high risk of developing CRC. Consistent with the critical role played by tyrosine kinases in diabetes and tumor biology, we provide evidences that tyrosine phosphatases such as PTPRN may hold potential as therapeutic targets in CRC patients.