Imatinib Regulates miR-483-3p and Mitochondrial Respiratory Complexes in Gastrointestinal Stromal Tumors

Abstract

Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that miR-483-3p was one of the most downregulated miRNAs in imatinib-treated tumors compared to untreated tumors. Using an extended series of GIST samples, we further validated the downregulation of miR-483-3p in imatinib-treated GIST samples by RT-qPCR. Using both gain- and loss-of-function experiments, we showed that miR-483-3p could regulate mitochondrial respiratory Complex II expression, suggesting its role in OXPHOS regulation. Functionally, miR-483-3p overexpression could rescue imatinib-induced cell death. These findings provide the molecular link for imatinib-induced OXPHOS expression and the biological role of miR-483-3p in regulating cell viability upon imatinib treatment.

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors

“…A recent study demonstrated that IM specifically increases the expression of the complex II (SDHB) protein in oxidative phosphorylation (OXPHOS) proteins by downregulating miR-483-3p (Figure 1A). This study demonstrated the molecular mechanism of increased OXPHOS protein expression induced by IM and confirmed the biological role of miR-483-3p in regulating energy metabolism after IM treatment (20).This review will focus on the discussion and summary of research on the mechanisms of secondary resistance to IM conducted in the last 5 years from the aspects of abnormal gene mutation, energy metabolism, non-coding RNA, and key proteins.…”

Noncoding RNAs in Drug Resistance of Gastrointestinal Stromal Tumor

“…Moreover, the roles of microRNAs in regulating OXPHOS towards imatinib resistance of GISTs were recently explored. Huang et al found that miRNA-483-3p, whose expression was downregulated in imatinib-treated GIST samples, could inhibit the protein expression of mitochondrial respiratory Complex II, thus increasing the cell death induced by imatinib in GIST cells ( Huang et al, 2021 ). OXPHOS played a pivotal role in the drug resistance of GIST and the detailed mechanisms between cell metabolism and ncRNAs in the drug resistance need further investigation.…”

“…Moreover, reducing influence of miRNA-218 on imatinib resistance was proved by Fan et al ( Fan et al, 2014 ; 2015 ). There were also other miRNAs, such as miRNA-483-3p ( Huang et al, 2021 ), miRNA-518e-5p ( Kou et al, 2018 ), miRNA-518a-5p ( Shi Y. et al, 2016 ), miRNA-148b-3p ( Wang Y. et al, 2018 ), miRNA-17-92 ( Gits et al, 2013 ), miRNA-21 ( Cao et al, 2016 ), miRNA-23b ( Cao J. et al, 2018 ), miRNA-30a ( Zheng et al, 2015 ), miRNA-320a ( Gao et al, 2014 ), miRNA-505 ( Cao J. et al, 2018 ), miRNA-92a-3p ( Amirnasr et al, 2019 ) and miRNA-99a-5p ( Amirnasr et al, 2019 ), being identified or demonstrated that they played important roles in the process of imatinib resistance in GISTs.…”

“…In addition, imatinib treatment was found to reduce the expression levels of miRNA-30a, which was found to inhibit the imatinib resistance of GIST cells by targeting Beclin-1, thus lessening the imatinib resistance related autophagy ( Chen et al, 2020 ). Moreover, ncRNAs like miRNA-483-3p, miRNA-21, miRNA-22-3p, miRNA-518a-5p, miRNA-320a, miRNA-218, and miRNA-148b-3p acted as negative regulators to enhance the drug sensitivity and played significant roles in the process of GIST drug resistance ( Gao et al, 2014 ; Shi Y. et al, 2016 ; Cao et al, 2016 ; Wang Y. et al, 2018 ; Xu et al, 2018 ; Huang et al, 2021 ). These drug resistance-inhibiting ncRNAs could be served as small molecular drugs against drug resistance in GISTs in the future.…”

“…A series of studies based on the microarray and qRT-PCR analysis identified the differential expression levels of miRNAs between imatinib treated GIST patients with and without secondary resistance and highlighted the functional role of miRNA-125a-5p on secondary imatinib resistance by regulating PTPN18 to affect the phosphorylation of FAK ( Akcakaya et al, 2014 ; Huang et al, 2018 ). MiRNA-483-3p inhibited the mitochondrial respiratory complexes to restrain the OXPHOS caused by imatinib resistance in GIST cells ( Huang et al, 2021 ). MiRNA-518 family members miRNA-518a-5p and miRNA-518e-5p were also proved to play an important part in the secondary imatinib resistance through targeting PIK3C2A and affecting the cellular response to imatinib in GISTs ( Shi Y. et al, 2016 ; Kou et al, 2018 ).…”