Pathogenesis of Multiple Lentigines in LEOPARD Syndrome with PTPN11 Gene Mutation

Motegi, Sei‐ichiro; Yokoyama, Yoko; Ogino, Sachiko; Yamada, Kazuya; Uchiyama, Akihiko; Perera, Buddhini; Takeuchi, Yûkô; Ohnishi, Hiroshi; Ishikawa, Osamu

doi:10.2340/00015555-2123

Cited by 24 publications

(19 citation statements)

References 20 publications

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“…This makes SHP-2 a bidirectional regulator for cytokines and growth-factors-mediated signal transduction. A previous study has shown [14] that abnormal expression of SHP-2 can promote the initiation, progression, and metastasis of breast cancer, gastric cancer, liver cancer, lung cancer, and other cancers. Therefore, there is great significance in prevention and treatment of glioma through studying the role and mechanism of SHP-2 in tumors.…”

Section: Discussionmentioning

confidence: 99%

SHP-2 Activating Mutation Promotes Malignant Biological Behaviors of Glioma Cells

et al. 2017

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BackgroundThis study investigated the mechanism underlying the activating mutation of SHP-2 in promoting malignant biological behaviors of glioma cells.Material/MethodsThe SHP-2 empty plasmid pcDNA3.1 and SHP-2 activating mutation plasmid pcDNA3.1 SHP-2 D61G mutant eukaryotic expression vectors were designed; stable SHP-2-expressing cells transfected with pcDNA3.1 SHP-2 D61G mutant were set as the mutation group; cells transfected with pcDNA3.1 were set as the empty vector group; and cells without transfection were set as the control group. The cell reproductive capacity in each group was measured by MTT method. The invasion ability of cells in vitro was detected by Transwell chamber assay, the cell apoptosis in each group was detected by Annexin-V/PE dual-staining method, and the clone formation ability of cells in vitro was detected by Tablet clone-forming assay. The activation of ERK1/2, ARK, and p38MAPK signal pathways in each group was determined by Western blot.ResultsAfter transfection, the expression of SHP-2 protein in the mutant group was significantly higher than that in the control group and empty vector group. The proliferation ability of transfected cells, the apoptosis rate, the invasion ability, and the expression levels of phosphorylated ERK1/2, AKT, and p38 in the mutation group was significantly higher than in the empty vector group and the control group (P<0.05). Moreover, the cell clone formation ability of the mutation group was obviously enhanced (P<0.05).ConclusionsThe activating mutation of SHP-2 can lead to malignant changes in biological behaviors of glioma cells, and the specific mechanism may be related to the activation of ERK1/2, AKT, and p38 signal pathway. SHP-2 protein may become a new target for anti-malignant transformation of glioma.

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Section: Discussionmentioning

confidence: 99%

SHP-2 Activating Mutation Promotes Malignant Biological Behaviors of Glioma Cells

et al. 2017

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“…Contrary to the gain-of-function changes resulting in excessive PTPN11 activity in NS (12), LS mutants are catalytically defective and exert a dominant negative effect (22), suggesting that mutation type and region are important in the underlying pathogenic mechanisms and differential diagnoses of NS and LS. A recent study has suggested that LS-associated mutations may increase melanin synthesis in melanocytes via the activation of Akt/mammalian target of rapamycin signaling, thus, resulting in a phenotype with multiple lentigines (23). …”

Section: The Rasopathies With Calmmentioning

confidence: 99%

Molecular screening strategies for NF1-like syndromes with café-au-lait macules

Zhang

Yao

2016

Molecular Medicine Reports

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Multiple café-au-lait macules (CALM) are usually associated with neurofibromatosis type 1 (NF1), one of the most common hereditary disorders. However, a group of genetic disorders presenting with CALM have mutations that are involved in human skin pigmentation regulation signaling pathways, including KIT ligand/KIT proto-oncogene receptor tyrosine kinase and Ras/mitogen-activated protein kinase. These disorders, which include Legius syndrome, Noonan syndrome with multiple lentigines or LEOPARD syndrome, and familial progressive hyperpigmentation) are difficult to distinguish from NF1 at early stages, using skin appearance alone. Furthermore, certain syndromes are clinically overlapping and molecular testing is a vital diagnostic method. The present review aims to provide an overview of these ‘NF1-like’ inherited diseases and recommend a cost-effective strategy for making a clear diagnosis among these diseases with an ambiguous borderline.

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“…PTPN11 mutations have been extensively investigated in the past years. Germline mutations in PTPN11 cause Noonan syndrome (9)(10)(11) and its clinically related Leopard syndrome (12), whereas somatic mutations of PTPN11 contribute to leukemogenesis (13)(14)(15)(16)(17), as well as in the development of specific solid tumors, including neuroblastoma (18,19), metachondromatosis (20,21), brain tumors (22)(23)(24), neurofibromatosis (25), optic nerve pilomyxoid astrocytoma (26), breast carcinoma (27,28), colorectal cancer (29,30) and Ewing sarcoma (31). However, oncogenic mutations of PTPN11 are rare in the majority of solid tumors including GC (32,33).…”

Section: Introductionmentioning

confidence: 99%

PTPN11 hypomethylation is associated with gastric cancer progression

Zhou

Pan

et al. 2020

Oncol Lett

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Protein tyrosine phosphatase non-receptor type 11 (PTPN11) encodes the tyrosine phosphatase SHP-2 that is overexpressed in gastric cancer (GC). In the present study, the association of PTPN11 methylation levels with the incidence of GC and its correlation with SHP-2 overexpression were investigated. The methylation levels of PTPN11 in tumor and adjacent normal tissues of 112 GC patients were assessed by quantitative methylation specific PCR (qMSP). The Cancer Genome Atlas (TCGA) public database was used to analyze the association between PTPN11 methylation and PTPN11 expression. Survival analyses were conducted in order to evaluate the prognostic value of PTPN11 methylation for GC. The results of the qMSP analysis indicated that the methylation levels of PTPN11 in GC tumor tissues were significantly decreased compared with those noted in the normal adjacent tissues (mean with standard deviation: 40.91±26.33 vs. 51.99±37.37, P=0.007). An inverse correlation between PTPN11 methylation levels and PTPN11 mRNA expression levels (P=4x10 -6 , r=-0.237) was noted. Subgroup analyses indicated that the association of PTPN11 hypomethylation with the incidence of GC was specific to male subjects (P= 0.015), heavy drinking patients (P=0.019), patients with poor tumor differentiation (P=0.010) and patients with tumor node and metastasis (TNM) stage III+IV (P=0.008). Kaplan-Meier analyses and log-rank test suggested that PTPN11 hypomethylation was not associated with GC patient overall survival (P=0.605) and recurrence (P=0.485), although it could predict the recurrence of GC patients up to and including 60 years (≤60, P=0.049). The results indicated that PTPN11 levels were hypomethylated in GC patients. TCGA data analysis suggested that PTPN11 hypomethylation could cause an upregulation in the transcription levels of PTPN11. Although, this may explain the pattern of SHP-2 overexpression in GC, additional studies are required to verify this hypothesis. The association of PTPN11 hypomethylation with GC incidence may be specific to male patients, heavy drinking patients, patients with poor tumor differentiation and patients with TNM stage of III+IV. PTPN11 hypomethylation can be considered a biomarker for the recurrence of GC patients with an age of 60 years or lower.

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Pathogenesis of Multiple Lentigines in LEOPARD Syndrome with PTPN11 Gene Mutation

Cited by 24 publications

References 20 publications

SHP-2 Activating Mutation Promotes Malignant Biological Behaviors of Glioma Cells

SHP-2 Activating Mutation Promotes Malignant Biological Behaviors of Glioma Cells

Molecular screening strategies for NF1-like syndromes with café-au-lait macules

PTPN11 hypomethylation is associated with gastric cancer progression

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