Dataset Information

Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors.

ABSTRACT: HOTAIR, a long non-coding RNA (lncRNA), plays a crucial role in tumor initiation and metastasis by interacting with the PRC2 complex and the modulation of its target genes. The role of HOTAIR in gastrointestinal stromal tumors (GISTs) is remains unclear. Herein we investigate the mechanism of HOTAIR in the genesis and promotion of GISTs. The expression of HOTAIR was found to be higher in surgically resected high-risk GISTs than that in low- and intermediate-risk GISTs. Using GIST-T1 and GIST882 cells, we demonstrated that HOTAIR repressed apoptosis, was associated with cell cycle progression, and controlled the invasion and migration of GIST cells. Using a gene expression microarray and lists of HOTAIR-associated candidate genes, we suggested that protocadherin 10 (PCDH10) is a key molecule. PCDH10 expression was significantly decreased in GIST-T1 and GIST882 cells, possibly as a consequence of hypermethylation. We observed that HOTAIR induced PCDH10 methylation in a SUZ12-dependent manner. In this study, we found that the malignant character of GISTs was initiated and amplified by PCDH10 in a process regulated by HOTAIR. In summary, our findings imply that PCDH10 and HOTAIR may be useful markers of disease progression and therapeutic targets.

SUBMITTER: Lee NK

PROVIDER: S-EPMC5342742 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors.

Lee Na Keum NK Lee Jung Hwa JH Kim Won Kyu WK Yun Seongju S Youn Young Hoon YH Park Chan Hyuk CH Choi Yun Young YY Kim Hogeun H Lee Sang Kil SK

Oncotarget 20161101 46

HOTAIR, a long non-coding RNA (lncRNA), plays a crucial role in tumor initiation and metastasis by interacting with the PRC2 complex and the modulation of its target genes. The role of HOTAIR in gastrointestinal stromal tumors (GISTs) is remains unclear. Herein we investigate the mechanism of HOTAIR in the genesis and promotion of GISTs. The expression of HOTAIR was found to be higher in surgically resected high-risk GISTs than that in low- and intermediate-risk GISTs. Using GIST-T1 and GIST882 ...[more]

PMID: 27659532

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Project description:PurposeKIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GISTs) represent a heterogeneous subgroup of GISTs that lack KIT or PDGFRA mutations and possess distinct genetic alterations and primary resistance to imatinib. Succinate dehydrogenase (SDH)-deficient GISTs comprise the largest subpopulation of WT GISTs that are characterized by loss-of-function of SDH. O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA repair enzyme that has been identified as a predictor of positive treatment response to alkylating agents in a variety of cancers. The aim of this study was to evaluate the expression of MGMT and the prevalence of MGMT promoter methylation in GISTs and to determine the association between MGMT promoter methylation and clinicopathological characteristics and clinical outcomes.Patients and methodsA heterogeneous cohort of 137 primary GISTs that confirmed by immunohistochemistry and KIT/PDGFRA mutation analysis were retrospectively selected and analyzed for MGMT expression and MGMT promoter methylation using immunohistochemical staining and methylation-specific PCR (MSP). A concordance analysis between MGMT promoter methylation and clinicopathological characteristics and prognosis was also performed.ResultsA total of 44.5% (65/137) of GIST patients displayed loss of MGMT protein expression, and 10.9% (15/137) of these patients exhibited MGMT promoter methylation. However, no significant correlation was observed between the loss of MGMT protein expression and MGMT promoter methylation. WT GISTs possessing an epithelioid or mixed phenotype, particularly those that were SDH-deficient, displayed a markedly higher prevalence of MGMT promoter methylation compared to that in KIT/PDGFRA mutated GISTs. Moreover, MGMT promoter methylation was identified as a potential independent prognostic factor for OS and DFS in patients with GIST.ConclusionMGMT promoter methylation is particularly frequent in SDH-deficient GISTs and in WT GISTs possessing an epithelioid/mixed phenotype, and knowledge of this methylation status may offer a novel potential therapeutic option for WT GISTs.

Project description:BackgroundGastrointestinal stromal tumor (GIST) is a common tumor that originates from the alimentary system mesenchyme. Compared to typical gastrointestinal carcinomas, GISTs exhibit unique malignant behaviors. Bioinformatic tools and subsequent experiments were applied to investigate novel targets involved in GIST progression and imatinib resistance.MethodsDifferences in gene expression profiles between advanced and nonadvanced GISTs were comprehensively analyzed based on the Gene Expression Omnibus (GEO) dataset GSE136755. A protein-protein interaction (PPI) network was constructed to identify the potential target gene. Gene set enrichment analysis (GSEA) was used to elucidate relevant biological events related to the target gene based on the GSE47911 dataset. Subsequently, immunohistochemistry and Kaplan-Meier analysis were performed to validate the prognostic value of the target gene in GISTs. Overexpression of the target gene was conducted to analyze its function in the proliferation, apoptosis, and imatinib resistance of GIST/T1 cells.ResultsIn the current study, a total of 606 differentially expressed genes (DEGs) were screened based on the GSE136755 dataset, and the upregulated DEGs in advanced GISTs were mainly involved in cell division through functional annotations. The intersecting hub gene, Aurora kinase A (AURKA), was identified by degree and bottleneck algorithms. GSEA revealed that AURKA was involved in cell cycle-related biological processes. Analysis of the Oncomine and GEPIA databases revealed a pattern of elevated AURKA expression in most human malignances. Clinical assays demonstrated that AURKA could be an independent prognostic factor for GISTs. Additionally, overexpression of AURKA was experimentally demonstrated to promote cell proliferation, inhibit cell apoptosis, and enhance imatinib resistance in GIST/T1 cells.ConclusionsThese findings indicated that overexpression of AURKA promoted GIST progression and enhanced imatinib resistance, implying that AURKA is a potential therapeutic target for GISTs.

Project description:Gastrointestinal stromal tumors (GIST) are rare mesenchymal smooth muscle sarcomas that can arise anywhere within the gastrointestinal tract. Sporadic mutations within the tyrosine kinase receptors of the interstitial cells of Cajal have been identified as the key molecular step in GIST carcinogenesis. Although many patients are asymptomatic, the most common associated symptoms include: abdominal pain, dyspepsia, gastric outlet obstruction, and anorexia. Rarely, GIST can perforate causing life-threatening hemoperitoneum. Most are ultimately diagnosed on cross-sectional imaging studies (i.e., computed tomography and/or magnetic resonance imaging in combination with upper endoscopy. Endoscopic ultrasonographic localization of these tumors within the smooth muscle layer and acquisition of neoplastic spindle cells harboring mutations in the c-KIT gene is pathognomonic. Curative treatment requires a complete gross resection of the tumor. Both open and minimally invasive operations have been shown to reduce recurrence rates and improve long-term survival. While there is considerable debate over whether GIST can be benign neoplasms, we believe that all GIST have malignant potential, but vary in their propensity to recur after resection and metastasize to distant organ sites. Prognostic factors include location, size (i.e., > 5 cm), grade (> 5-10 mitoses per 50 high power fields and specific mutational events that are still being defined. Adjuvant therapy with tyrosine kinase inhibitors, such as imatinib mesylate, has been shown to reduce the risk of recurrence after one year of therapy. Treatment of locally-advanced or borderline resectable gastric GIST with neoadjuvant imatinib has been shown to induce regression in a minority of patients and stabilization in the majority of cases. This treatment strategy potentially reduces the need for more extensive surgical resections and increases the number of patients eligible for curative therapy. The modern surgical treatment of gastric GIST combines the novel use of targeted therapy and aggressive minimally invasive surgical procedures to provide effective treatment for this lethal, but rare gastrointestinal malignancy.

Dataset Information

Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors.

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Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors.

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