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.
Highlights
Gastrointestinal stromal tumors (GISTs) are a type of mesenchymal tumor, and constitute the most common form of subepithelial tumor in the stomach [1, 2]
Functional and clinical studies in a variety of cancers have correlated the loss of long non-coding RNA (lncRNA) HOTAIR regulation with carcinogenesis and metastasis [6, 13,14,15,16]
We provide mechanistic evidence that epigenetic disruption of protocadherin 10 (PCDH10) by HOTAIR induces carcinogenesis and invasiveness, and upregulates the transcriptional factor p53, which is a direct target of PCDH10
Summary
Gastrointestinal stromal tumors (GISTs) are a type of mesenchymal tumor, and constitute the most common form of subepithelial tumor in the stomach [1, 2]. GIST cells present sporadic mutations in the c-KIT and PDGFRA genes, which encode the KIT and platelet-derived growth factor receptor alpha proteins, respectively. GISTs present an extremely heterogeneous clinical prognosis. Most GISTs are detected via screening endoscopy. Though they usually remain clinically silent, some progress to become malignant. The criteria for risk estimation depend largely on clinicopathologic factors, such as size and mitosis index, these cannot accurately predict the risk of malignancy
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