RP11-616M22.7 recapitulates imatinib resistance in gastrointestinal stromal tumor

Abstract

Emerging evidence has shown that long non-coding RNAs (lncRNAs) play crucial roles in human cancers. However, systematic characterization of lncRNAs and their roles in gastrointestinal stromal tumor (GIST) therapy have been lacking. We performed high-throughput RNA sequencing (RNA-seq) of 20 GIST and paired adjacent normal samples. We characterized the transcriptional landscape and dysregulation of lncRNAs in GIST. We identified 866 upregulated and 1,268 downregulated lncRNAs in GIST samples, the majority of which were GIST-specific over other cancer types. Most hallmarks were found to be dysregulated in GIST samples, and lncRNAs were highly associated with cancer-related hallmarks. RP11-616M22.7 was identified to increase in imatinib-resistant samples compared to those in non-resistant samples. Further analysis revealed that RP11-616M22.7 was closely associated with the Hippo signaling pathway. By treating GIST cells with different doses of imatinib, we verified that RP11-616M22.7 knockdown promotes the sensitivity of tumor cells, whereas RP11-616M22.7 overexpression induces resistance to imatinib. We further confirmed reducing of resistance to imatinib by knocking down RP11-616M22.7 in vivo. Additionally, RP11-616M22.7 was observed to interact with RASSF1 protein.Our study revealed that deficiency of RP11-616M22.7 was able to reduce resistance of the GIST cell response to imatinib treatment both in vitro and in vivo.

Noncoding RNAs in Drug Resistance of Gastrointestinal Stromal Tumor

“…Moreover, expression levels of miRNA-518e-5p in the serum were positively correlated with imatinib resistance in GISTs ( Kou et al, 2018 ). The lncRNA HOTAIR and RP11-616M22.7 were also proved to increase the resistance of imatinib in GISTs ( Shao et al, 2021 ; Zhang et al, 2021 ). NcRNAs might promote drug resistance which could be applied as therapy targets against drug resistance in GISTs.…”

“…In GISTs, KIT was also targeted directly by miRNA-218 and miRNA-148b-3p, which acted as tumor suppressors and sensitized GIST cells to imatinib therapy ( Fan et al, 2014 ; Wang Y. et al, 2018 ). Moreover, through collaborating with c-KIT, knocking down lncRNA CCDC26 and overexpressing lncRNA RP11-616M22.7 increased the resistance of GIST cells to imatinib ( Cao K. et al, 2018 ; Shao et al, 2021 ). The microarrays which screened tumour-specific circRNA profiles of GIST, identified a GIST-specific circRNA-miRNA-mRNA regulatory network related to KIT, which showed the potentials of circRNAs in the drug resistance of GIST by targeting KIT ( Jia et al, 2019 ).…”

“…STAT3 was also found to be downregulated by miRNA-148b-3p in GISTs, thus reducing the imatinib resistance of GIST cells ( Wang Y. et al, 2018 ). Gene set enrichment analysis (GSEA) also identified JAK-STAT3 signaling pathway as one of the interfered signaling pathways of lncRNA RP11-616M22.7, which was increased in the imatinib-resistant GIST samples ( Shao et al, 2021 ).…”

“…NcRNAs targeting the Hippo pathway also involved in the malignant transformation of GISTs ( Yin et al, 2021 ). In the drug resistance of GISTs, lncRNA RP11-616M22.7 promoted GIST resistance to imatinib by interacting with the Ras association domain family protein1 isoform A (RASSF1A), which is an important upstream regulator of the Hippo pathway ( Shao et al, 2021 ). And through specifically binding to RASSF1A thus inhibiting its function, lncRNA RP11-616M22.7 decreased the expression of mammalian STE20-like kinase (MST)-1, MST2, large tumor suppressor kinase (LATS)-1, and LATS2, and increased the expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), thus promoting the cell proliferation and inhibiting the apoptosis under imatinib treatment ( Shao et al, 2021 ).…”

“…And lncRNA-DNAJC6-2 probably played a part in the secondary imatinib-resistant GISTs by targeting the translational factors, including TBP, TAF1, NRF1, MAX, STAT3 and E2F6, which regulate the translation process of mRNA ( Yan et al, 2019a ). LncRNA RP11-616M22.7 was also found to regulate the imatinib resistance of GISTs through the Hippo pathway ( Shao et al, 2021 ). These researches showed that lncRNA, as a noncoding RNA, is closely related to drug resistance in GISTs, which might be applied as novel therapeutic strategies against GISTs.…”