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PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
2019 (English)In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 8, no 8, p. 1126-1135Article in journal (Refereed) Published
Abstract [en]

Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTP mu (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2'deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.

Place, publisher, year, edition, pages
BIOSCIENTIFICA LTD , 2019. Vol. 8, no 8, p. 1126-1135
Keywords [en]
DNA methylation, neuroendocrine tumors, epigenetic, SI-NETs, PTPRM
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-393899DOI: 10.1530/EC-19-0279ISI: 000483142900007PubMedID: 31349215OAI: oai:DiVA.org:uu-393899DiVA, id: diva2:1362314
Funder
Swedish Cancer SocietyErik, Karin och Gösta Selanders FoundationAvailable from: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-18Bibliographically approved

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