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

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. In th...

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Published in:	Diabetes (New York, N.Y.) Vol. 71; no. 3; pp. 497 - 510
Main Authors:	Garranzo-Asensio, María, Solís-Fernández, Guillermo, Montero-Calle, Ana, García-Martínez, José Manuel, Fiuza, Maria Carmen, Pallares, Pilar, Palacios-Garcia, Nuria, García-Jiménez, Custodia, Guzman-Aranguez, Ana, Barderas, Rodrigo
Format:	Journal Article
Language:	English
Published:	United States American Diabetes Association 01-03-2022
Subjects:	Adult Animals Autoantibodies Autoantibodies - blood Biomarkers - blood Cell Line, Tumor Chronic illnesses Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - diagnosis Colorectal Neoplasms - immunology Colorectal Neoplasms - mortality Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - immunology Female Humans Insulin Invasiveness Kinases Liver Neoplasms - secondary Male Medical diagnosis Mesenchyme Metastases Mice Mice, Nude Middle Aged Neoplasm Transplantation Phosphatase Protein phosphatase Protein-tyrosine kinase receptors Protein-tyrosine-phosphatase Receptor-Like Protein Tyrosine Phosphatases, Class 8 - immunology Receptor-Like Protein Tyrosine Phosphatases, Class 8 - physiology Risk Factors Signal transduction Therapeutic applications Therapeutic targets Tumors
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Summary:	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. In this study, we explore the value of autoantibodies against receptor-type tyrosine-protein phosphatase-like N (PTPRN; full-length or selected domains) as diagnostic markers using a cohort of individuals with type 2 diabetes (T2D), CRC, or both diseases or healthy individuals. We show that PTPRN autoantibody levels in plasma discriminated between patients with T2D with and without CRC. Consistently, high PTPRN expression correlated with decreased survival of patients with CRC. 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 patients with T2D at high risk of developing CRC. Consistent with the critical role played by tyrosine kinases in diabetes and tumor biology, we provide evidence that tyrosine phosphatases such as PTPRN may hold potential as therapeutic targets in patients with CRC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0012-1797 1939-327X
DOI:	10.2337/db20-1206