Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsatellite instability (MIN) is frequently observed in hereditary nonpolyposis colon cancer and in other sporadic cancers including gliomas. Abnormalities in at least one of five mismatch repair (MMR) genes are implicated in the development of cancers in hereditary nonpolyposis colon cancer and the associated MIN. Using a newly developed multiplex reverse transcription-PCR assay, we evaluated the expression of the five known human MMR genes (hMSH2, hMLH1, hPMS1, hPMS2, and GTBP) in human gliomas by measuring simultaneously the relative levels of the transcripts. The beta-actin gene was used as an internal control for RNA degradation and DNA contamination and as a reference for quantifying the levels of their transcripts. Of the 33 gliomas examined, 42% (14) had low expression of hMSH2 (at least 4-5-fold lower than normal mean), 21% (7) had low expression of hMLH1, and 18% (6) had low expression of hPMS1 compared with the expression in the lymphocytes from 13 normal individuals. Furthermore, six of the 33 (18%) tumor samples had decreased expression of more than one MMR gene. Two of these six patients with multiple gene abnormalities had second primary cancers, and an additional patient had multifocal gliomas. Further molecular analysis of available DNA samples indicated that one of five of those tumors with aberrant expression of MMR genes had MIN, as compared with none of five tumors with normal expression. These data suggest that reduced expression of MMR genes is frequent in human gliomas and that aberrant expression of more than one MMR gene may be associated with increased risk of second primary malignancies in glioma patients.
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PMID:Reduced expression of mismatch repair genes measured by multiplex reverse transcription-polymerase chain reaction in human gliomas. 913 6

MSH6 (mutS homolog 6), one of the five key mismatch repair (MMR) genes, was found to play an important role in conferring resistance to alkylating agents-temozolomide (TMZ) in malignant glioma. This study aims to investigate whether genetic variations in MSH6 gene are associated with the survival outcomes in patients with malignant glioma. Each exon of the MSH6 gene was sequenced, and single nucleotide polymorphism (SNP) analysis was performed using 74 tumor tissues from glioblastoma multiforme (GBM) patients. Among these patients, 54 patients received radiotherapy plus TMZ treatment; 20 patients had radiotherapy only. The promoter methylation of O6-methylguanine methyltransferase (MGMT) was measured by methylation-specific polymerase chain reaction. Literature mining and related data collection were done with NCBI and PubMed databases. Of the 74 GBM patients, 50% (n = 37) harbored MSH6 G268A polymorphism, and no significant rates of other SNP or gene mutation across MSH6 exons were detected. The median overall survival (OS) was 15.6 months for who harbored the SNP and 12.6 months for SNP-negative patients (log-rank test: p = .324). The median OS for the MGMT promoter methylation group (n = 25) and nonmethylation group (n = 29) of the 54 GBM patients treated with TMZ was 21.3 and 8.9 months, respectively, (p = .002). In conclusion, we identified a high frequency of MSH6 G268A polymorphism in MSH6 gene, which did not have a notable influence on survival for the malignant glioma patients with/without TMZ treatment.
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PMID:A high frequency of MSH6 G268A polymorphism and survival association in glioblastoma. 2305 44

Glioblastoma multiforme (GBM) has been considered the most aggressive glioma type. Temozolomide (TMZ) is the main first-line chemotherapeutic agent for GBM. Decreased mutS homolog 6 (MSH6) expression is clinically recognized as one of the principal reasons for GBM resistance to TMZ. However, the specific functions of MSH6 in GBM, in addition to its role in mismatch repair, remain unknown. Methods: Bioinformatics were employed to analyze MSH6 mRNA and protein levels in GBM clinical samples and to predict the potential cancer-promoting functions and mechanisms of MSH6. MSH6 levels were silenced or overexpressed in GBM cells to assess its functional effects in vitro and in vivo. Western blot, qRT-PCR, and immunofluorescence assays were used to explore the relevant molecular mechanisms. Cu2(OH)PO4@PAA nanoparticles were fabricated through a hydrothermal method. Their MRI and photothermal effects as well as their effect on restraining the MSH6-CXCR4-TGFB1 feedback loop were investigated in vitro and in vivo. Results: We demonstrated that MSH6 is an overexpressed oncogene in human GBM tissues. MSH6, CXCR4 and TGFB1 formed a triangular MSH6-CXCR4-TGFB1 feedback loop that accelerated gliomagenesis, proliferation (G1 phase), migration and invasion (epithelial-to-mesenchymal transition; EMT), stemness, angiogenesis and antiapoptotic effects by regulating the p-STAT3/Slug and p-Smad2/3/ZEB2 signaling pathways in GBM. In addition, the MSH6-CXCR4-TGFB1 feedback loop was a vital marker of GBM, making it a promising therapeutic target. Notably, photothermal therapy (PTT) mediated by Cu2(OH)PO4@PAA + near infrared (NIR) irradiation showed outstanding therapeutic effects, which might be associated with a repressed MSH6-CXCR4-TGFB1 feedback loop and its downstream factors in GBM. Simultaneously, the prominent MR imaging (T1WI) ability of Cu2(OH)PO4@PAA could provide visual guidance for PTT. Conclusions: Our findings indicate that the oncogenic MSH6-CXCR4-TGFB1 feedback loop is a novel therapeutic target for GBM and that PTT is associated with the inhibition of the MSH6-CXCR4-TGFB1 loop.
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PMID:Oncogenic MSH6-CXCR4-TGFB1 Feedback Loop: A Novel Therapeutic Target of Photothermal Therapy in Glioblastoma Multiforme. 3086 43