Purpose: Gain-of-function mutations of KIT are pathognomonic in the majority of sporadic gastrointestinal stromal tumors (GISTs). Several micro-RNAs have been shown to be dysregulated in GISTs and impact KIT expression levels. Little is known, though, about KIT-independent targets of KIT-regulating mRNAs. We sought to investigate how miR-494 inhibits GIST proliferation and to identify novel target gene. Experimental Design: We used gene expression analyses to identify pathways and target genes affected by miR-494. The expressional relationship between Survivin and miR-494 was determined in 35 GIST tissues. Cell proliferation assay, FACS analysis, colony formation assay, and promoter assays were performed to clarify the roles of Survivin in GIST progression. Results: Gene expression microarray analysis revealed that miR-494 inhibited GISTs by affecting multiple genes in the cell cycle pathway. Survivin was a key target gene of miR-494. Analysis of the 35 GISTs revealed that there was an inverse correlation between Survivin and miR-494 expression (Pearson’s correlation coefficient, r = -0.418, P = 0.012). Downregulation of Survivin inhibited proliferation and colony formation, and resulted in cell cycle alteration. Induced Survivin overexpression relieved miR-494 mediated inhibition of GIST progression. Targeting PI3K effectively suppressed proliferation of GISTs with downregulation of Survivin. Survivin regulated KIT expression at the transcription level. Immunohistochemical analysis using 113 GIST tissues revealed that Survivin expression was significantly correlated with overall survival of GIST patients (P = 0.004). Conclusion: Our findings indicated that miR-494 synergistically suppressed GISTs by concomitantly targeting Survivin and KIT, with accompanying vertical blockade of the PI3K pathways.

Citation Format: Seongju Yun, Won Kyu Kim, Hoguen Kim. Identification of a novel regulator in GIST tumorigenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B088.