Role of non-coding RNAs in pathogenesis of gastrointestinal stromal tumors

Table 1 Chromosomal loss of 14q and miRNA expression studies

Ref.	Samples	miRNAs studied	Results
Choi et al[38], 2010	20 GISTs (15 gastric, 5 intestinal)	73	38 miRNAs encoded at 14q region
Haller et al[40], 2010	12 GISTs for microarray analysis and then 49 GISTs for qRT-PCR analysis	miR-370; miR-134	Downregulated in GISTs with 14q loss
Kelly et al[39], 2013	73 GISTs 47 adult and 18 pediatric	667	74 downregulated miRNAs in GISTs with 14q loss

GISTs: Gastrointestinal stromal tumors.

Table 2 Non-coding RNAs as potential prognostic biomarkers of gastrointestinal stromal tumors

Ref.	Compared groups	ncRNAs studied	Results and potential prognostic biomarkers
Subramanian et al[41], 2008	8 GISTs compared to 19 mesenchymal tumors	84 miRNAs	16 upregulated miRNAs: miRNA-10, miRNA-22, miRNA-29a, miRNA-29b, miRNA-29c, miRNA-30a-5p, miRNA-30e-5 miRNA-30c, miRNA-30d miRNA-99b miRNA-125a miRNA-140, miRNA-143, miRNA-145 miRNA-368 ABI-13268 let-7b, miRNA-1; 10 downregulated miRNAs: miRNA-1 miR-92 miRNA-133a, miRNA-133b miRNA-200b miRNA-221, miRNA-222 miRNA-368, miRNA-376a ABI-13232
Haller et al[40], 2010	4 gastric PDGFRAmut, 4 gastric KITmut and 4 intestinal KITmut. 49 GISTs further analyzed by qRT-PCR	734 miRNAs	Downregulated miRNA-221 and miR-222 in in KIT-mutant GIST compared with KIT/PDGFRA wild type GIST
Koelz et al[42], 2011	54 GISTs compared to healthy blood samples	miRNAs-22/-222	Depressed miRNA-221 and 222 in kit positive tumor samples, whereas Kit-negative GISTs exhibited a completely inverse expression pattern
Niinuma et al[43], 2012	56 GISTs	939 miRNAs	Association of miR-196a and HOTAIR with high risk tumors, metastasis, and overall survival
Yamamoto et al[44], 2013	4 low grade vs 4 intermediate vs 11 high grade GISTs	904 miRNAs	Downregulation of miR-133b in high grade tumors and correlation with Fachin-1 overexpression
Gits et al[45], 2013	50 GISTs compared to 10 gastrointestinal leiomyosarcomas	725 miRNAs	Downregulated miR-17-92 and miRNAs 221/222 in tumor samples
Gyvyte et al[46], 2017	15 GISTs compared to 15 samples of adjacent tissue	1672 miRNAs	15 downregulated and 4 upregulated miRNAs; miRNA-215-5p negative correlation with the grade; miRNA-509-3p association with epithelioid and mixed subtypes
Gyvyte et al[48], 2018	15 gastric GISTs vs 15 adjacent tissue through next generation seq and then validation analysis of 22 more GISTs	7250 lincRNAs	6 upregulated lincRNAs, 3 downregulated lincRNAs; Strong correlation between expression of lincRNA H19 with both ETV1 and miR-455-3p
Hu et al[49], 2018	79 GISTs vs 79 paracancerous normal tissues	LncRNA AOC4P	Increased in GIST vs normal tissue, Higher expression in high risk vs low/medium risk. AOC4P regulate EMT thus increase the metastatic ability of the tumor
Yan et al[51], 2019	3 primary GISTs (A) vs 3 GISTs secondarily resistance to IM (B) vs 3 normal gastric tissue (C)	63,542 lncRNAs 27,134 miRNAs	2250 deregulated lncRNAs on group B vs group A; 2209 deregulated lncRNAs on group C vs group A; 922 deregulated lncRNAs on group C vs group B
Badalamenti et al[50], 2019	40 GISTs (25 localized disease vs 15 advanced disease)	H19, MALAT1	H19 and MALAT1 higher expression levels in advanced disease samples
Kosela-Paterczyk et al[48], 2020	31 high grade GISTs treated with IM, 16 high grade OS, 26 high grade SS, 8 high grade ES, 30 healthy controls	156 dysregulated miRNAs in sarcomas vs control group	10 microRNAs were commonly deregulated in SS, OS and GISTs; 99, 42, 36 and 24 differentiated controls from GISTs, ES, SS and OS, respectively

GISTs: Gastrointestinal stromal tumors; OS: Osteosarcoma; SS: Synovial sarcoma; ES: Ewing sarcoma.

Table 3 Studies about the role of non-coding RNAs expression profile and imatinib resistance

Ref.	Compared groups and samples	NcRNAs studied	Results
Akçakaya et al[52], 2014	7 IM resistant vs 10 IM sensitive (profiling analysis) 10 IM resistant vs 14 IM sensitive (validation analysis)	903 miRNAs in profiling analysis (microarray) 10 miRs for validation analysis (RT-PCR)	27 overexpressed miRNAs and 17 underexpressed miRNAs in IM resistant group compared to IM sensitive. Mir-125a-5p as a key modulator to IM resistance
Huang et al[53], 2018	28 tumor samples (all patients received neoadjuvant IM)	miRNA-125a-5p RNU6B	Phosphorylation of FAK is regulated by PTPB18 and miR-125a-5p. Pfak plays crucial role in IM resistance
Fan et al[54], 2015	IM sensitive GIST cells (GIST882) vs IM resistance cell line (GIST430)	miRNA-218	MiR-218 is down-regulated in IM-resistant GIST430 cells; MiR-218 over-expression may improve the IM sensitivity through PI3K/AKT signaling pathway
Lee et al[55], 2016	9 low vs 1 intermediate vs 7 high risk tumors.	HOTAIR	HOTAIR higher expression in high risk GISTs. HOTAIR also found to regulate promoter methylation of PCDH10 through in vitro investigation of high-risk GIST cell lines
Bure et al[56], 2018	67 primary GIST samples subdivided according the tumor grade and the cell line.	HOTAIR	HOTAIR higher expression in high risk GISTs. Distinct methylation patterns through upregulation of HOTAIR during the different stages of carcinogenesis
Yan et al[51], 2019	3 primary GISTs (A) vs 3 GISTs secondarily resistance to IM (B) vs 3 normal gastric tissue (C)	63542 lncRNAs 27134 miRNAs	They found lnc-DNAJC6-2 to be associated with the HIF-1 pathway
Yan et al[58], 2019	IM sensitive cell lines (GIST-882) vs IM resistance cell lines (GIST-T1)	LncRNA CCDC26	LncRNA CCDC26 regulate IM resistance and interact with IGF-1R

GISTs: Gastrointestinal stromal tumors; IM: Imatinib.