title: Promoter methylation attenuates SHP1 expression and function in patients with primary central nervous system lymphoma.
abstract: The Src homology region 2 domain-containing phosphatase-1 (SHP1) is a critical negative regulator involved in the JAK/STAT signaling pathway. The SHP1 gene has been proposed as a candidate tumor suppressor in solid and hematological malignancies and promoter methylation is an important biological process in controlling tumorigenesis. However, the detailed roles of SHP1 promoter methylation in the pathogenesis of primary central nervous system lymphoma (PCNSL) is largely unknown. In the present study, we evaluated the correlation between SHP1 expression and promoter methylation in patients with PCNSL. Thirty-three patients with PCNSL were included. We evaluated SHP1 protein expression levels by immunohistochemistry and the SHP1 promoter methylation profile by pyrosequencing analysis. For cases (n=8) with a good yield of total protein, SHP1 phosphorylation (pSHP1) and STAT3 protein expression levels were further analyzed by western blot analysis to uncover the molecular impact of SHP1 promoter methylation on downstream signaling pathways. In this study, a lower expression of SHP1 protein level was observed in 16/33 cases (48.5%) of PCNSL. SHP1 promoter methylation was predominant in 29/33 cases (87.9%) with a mean methylation level of 31.7±36.5%. The mean methylation level of the SHP1 promoter was significantly elevated in patients with a lower SHP1 protein expression, compared with those showing a higher SHP1 protein expression (50.3±38.9 vs. 14.2±24.0%, p=0.004). Further analysis showed that SHP1 protein expression was significantly decreased in patients with a higher SHP1 promoter methylation status (p=0.001), and such attenuation was correlated with a downregulation of pSHP1 (p=0.005) and an upregulation of STAT3 protein expression (p=0.020). Our data demonstrated that epigenetic alterations in the promoter region downregulated SHP1 expression in PCNSL patients. SHP1 promoter methylation was correlated with tyrosine phosphorylation and activation of transcription factor STAT3, which may contribute to the pathogenesis of PCNSL. Therapeutical regimens with epigenetic modifiers may be a potential option for patients with PCNSL.
authors.affiliation: Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Navy General Hospital, Beijing 100050, P.R. China.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Institute of Neurological Sciences, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Ji
authors.affiliation: Neuroimaging Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Shengjun
authors.initials: S
authors.lastname: Sun
authors.affiliation: Core Laboratory for Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Neurological Sciences, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Qu
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Department of Internal Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
authors.forename: Yuanbo
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6