Downregulation of lncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation.

Jingyi Yan,Changyuan Hu,Wei Chen,Feng Zhou,Didi Chen,Xiaolei Chen,Qiantong Dong,Xuecheng Sun

doi:10.1590/1414-431x20198399

Abstract

Imatinib is the first line of therapy for patients with metastatic or gastrointestinal stromal tumors (GIST). However, drug resistance limits the long-term effect of imatinib. Long non-coding RNAs (lncRNAs) are emerging as key players in regulating drug resistance in cancer. In this study, we investigated the association between lncRNA CCDC26 and IGF-1R in GIST and their involvement in drug resistance. Considering the key role of lncRNAs in drug resistance in cancer, we hypothesized that IGF-1R is regulated by lncRNAs. The expression of a series of reported drug resistance-related lncRNAs, including CCDC26, ARF, H19, NBR2, NEAT1, and HOTAIR, in GIST cells treated with imatinib H19 was examined at various time-points by qRT-PCR. Based on our results and published literature, CCDC26, a strongly down-regulated lncRNA following imatinib treatment, was chosen as our research target. GIST cells with high expression of CCDC26 were sensitive to imatinib treatment while knockdown of CCDC26 significantly increased the resistance to imatinib. Furthermore, we found that CCDC26 interacted with c-KIT by RNA pull down, and that CCDC26 knockdown up-regulated the expression of IGF-1R. Moreover, IGF-1R inhibition reversed CCDC26 knockdown-mediated imatinib resistance in GIST. These results indicated that treatments targeting CCDC26-IGF-1R axis would be useful in increasing sensitivity to imatinib in GIST.

Highlights

Imatinib is the only approved first-line drug for gastrointestinal stromal tumor (GIST) patients, especially for patients with advanced or metastatic tumors [1,2]
These results indicated that overexpression of IGF-1R, which was observed in imatinib-treated cells, was responsible for the development of imatinib resistance in GIST cells
We explored the role and mechanism of Long non-coding RNAs (lncRNAs) CCDC26 in imatinib resistance in GIST cells and demonstrated for the first time that CCDC26 enhanced imatinib sensitivity by downregulating IGF-1R expression

Summary

Introduction

Imatinib is the only approved first-line drug for gastrointestinal stromal tumor (GIST) patients, especially for patients with advanced or metastatic tumors [1,2]. Imatinib has significantly improved the prognosis of end-stage patients. Disease control ranges from 70 to 85%, median progression-free survival is 29 months, and median overall survival is 57 months [3,4,5]. GIST patients treated with imatinib are confronted with primary and secondary drug resistance. The drug resistance limits the long-term curative effect of imatinib [6,7,8]. The underlying molecular mechanisms of imatinib resistance in GIST have not been fully elucidated

Methods

Results

Conclusion