LncRNA-HOTAIR activates autophagy and promotes the imatinib resistance of gastrointestinal stromal tumor cells through a mechanism involving the miR-130a/ATG2B pathway

Jinyan Zhang,Xuemei Lu,Xianning Zhang,Shufen Zhang,Yuexiao Tang,Xiaorui Luan,Wei Chen,Ke Chen,Jiayan Mao,Liqiang Hu,Xiaoxiao Zheng

doi:10.1038/s41419-021-03650-7

Abstract

Gastrointestinal stromal tumors (GISTs) are common neoplasms of the gastrointestinal tract that can be treated successfully using C-kit target therapy and surgery; however, imatinib chemoresistance is a major barrier to success in therapy. The present study aimed to discover alternative pathways in imatinib-resistant GISTs. Long noncoding RNAs (lncRNAs) are newly discovered regulators of chemoresistance. Previously, we showed that the lncRNA HOTAIR was upregulated in recurrent GISTs. In this study, we analyzed differentially expressed lncRNAs after imatinib treatment and found that HOTAIR displayed the largest increase. The distribution of HOTAIR in GISTs was shifted from nucleus to cytoplasm after imatinib treatments. The expression of HOTAIR was validated as related to drug sensitivity through Cell Counting Kit-8 assays. Moreover, HOTAIR was associated strongly with cell autophagy and regulated drug sensitivity via autophagy. Mechanistically, HOTAIR correlated negatively with miRNA-130a in GISTs. The downregulation of miRNA-130a reversed HOTAIR-small interfering RNA-induced suppression of autophagy and imatinib sensitivity. We identified autophagy-related protein 2 homolog B (ATG2B) as a downstream target of miR-130a and HOTAIR. ATG2B downregulation reversed the effect of pEX-3-HOTAIR/miR-130a inhibitor on imatinib sensitivity. Finally, HOTAIR was shown to influence the autophagy and imatinib sensitivity of GIST cells in mouse tumor models. Our results suggested that HOTAIR targets the ATG2B inhibitor miR-130a to upregulate the level of cell autophagy so that promotes the imatinib resistance in GISTs.

Highlights

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract whose incidence is increasing[1]
There is no Long noncoding RNAs (lncRNAs) expression database for GISTs, the research significance of HOTAIR was confirmed by the overall survival curves obtained from the GEPIA database regarding the high expression of HOTAIR in several types of gastrointestinal tumors, including stomach adenocarcinoma, colon adenocarcinoma, esophageal carcinoma, rectal adenocarcinoma (Fig. 1C)
Cell Counting kit-8 (CCK-8) assays indicated that the upregulation of HOTAIR remarkably decreased the cytotoxicity of imatinib to GIST-T1 and GIST-882 cells, whereas the downregulation of HOTAIR had the opposite effects (Fig. 1E, F)

Summary

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract whose incidence is increasing[1]. GISTs are frequently driven by activating mutations in the receptor tyrosine kinase encoding genes KIT (KIT proto-oncogene, receptor tyrosine kinase) or PDGFRA (platelet -derived growth factor receptor alpha)[2]. These mutations result in constitutive activation of KIT or PDGFRA-mediated ligandindependent activation and signaling[3,4]. GISTs are most commonly found in the stomach (60%), small intestine, jejunum, and ileum (30%), but they occur in the Official journal of the Cell Death Differentiation Association. Imatinib is a small-molecule inhibitor of tyrosine kinase signaling enzymes, such as Abelson tyrosine-protein kinase. About 12–14% of patients are resistant to imatinib and 40% will develop resistance[10]

Methods

Results

Conclusion