PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors

Abstract

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 PTPµ (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.

Cellular and clinical impact of Protein Phosphatase Enzyme epigenetic silencing in multiple cancer tissues

“…Of the 160 PPEIP genes, 88 (55%) were considered "rare" (observed in <1% of all cancer cases) and 41 (26%) as "recurrent" (identified in >5% of cancer samples) (Supplementary data S5). Many recurrent genes were known tumor suppressors with previously described cancer-related promoter hypermethylation anomalies (PTPN13, DUSP5, (Stebbing et al, 2014) PPP1R14A (Li et al, 2017, PPP1R3C (Takane et al, 2014), PTPRM (Barazeghi et al, 2019) and IGFBP3 (Kawasaki et al, 2007;Torng et al, 2009;Ye et al, 2016) validating the robustness of our approach. We also detected several PPEIP genes with previously undescribed recurrent methylation changes (Figure .…”

“…2D). INPP5B (Inositol Polyphosphate-5-Phosphatase) is an anti-apoptotic protein with a proliferative role in different cancer types (H et al, 2013; J et al, 2009) and epimutations were observed in 130 individuals in all 5 tissues (Figure 2D). Proline-serine-threonine phosphatase interacting protein 2 or PSTPIP2 promoter hyper-methylation was observed in 37 cases in all 5 tissues examined (Figure.…”

High expression of PTPRM predicts poor prognosis and promotes tumor growth and lymph node metastasis in cervical cancer

“…Similar to our study, Wang Y et al and Gebbink M.F et al demonstrated that PTPRM plays oncogenic role in lung cancer 14 , 26 . However, some studies indicated that PTPRM was negatively correlated with the progression of colorectal adenoma-carcinoma, small intestinal neuroendocrine tumors and breast cancer 11 – 13 . To our knowledge, there has been few functional studies of PTPRM in cancer cells to date, and published literature on PTPRM mostly came from the bioinformatic analysis aspects lacking of experiments verification.…”

“…Protein tyrosine phosphatase receptor type M (PTPRM) is a member of the PTP family and was reported as a tumor-associated factor which was mutated in many kinds of cancers. It has been reported that increased expression of PTPRM was negatively correlated with the progression of colorectal adenoma-carcinoma, small intestinal neuroendocrine tumors and breast cancer 11 – 13 , while the single-nucleotide polymorphisms of the PTPRM suggested it could play an oncogenic role in lung cancer 14 . However, the role and precise mechanism of PTPRM in CCa remains unknown, warranting further exploration.…”

Whole-Genome Resequencing to Study Brucellosis Susceptibility in Sheep

“…In esophageal cancer, PARD3 overexpression promotes cell apoptosis, inhibits cell proliferation, and inhibits cell migration and invasion, whereas PARD3 silencing promotes cell proliferation and increases migration and invasion ( Wang et al, 2017 ). PTPRM overexpression in small intestinal neuroendocrine tumor cell lines reduced cell growth and proliferation and induced apoptosis ( Barazeghi et al, 2019 ). Neuroligins are cell differentiation molecules located on the postsynaptic side of the synapse, which interact with their presynaptic partners neurexins to maintain trans-synaptic connection ( Südhof, 2008 ).…”