Epigenetic mechanisms and therapeutic targets of chemotherapy resistance in epithelial ovarian cancer

Figures & data

Table I. Summary of studies investigating single gene methylation in relation to EOC chemotherapy resistance.

Author	Year	Gene name	Locus methylation in relation to drug resistance	Tissue source	Histological type	Chemotherapy response definition	Experimental model
Strathdee et al. (42)	1999	hMLH1	Hypermethylation	Cell lines (A2780 and resistant clones)	NA	NA	MSP
Gifford et al. (44)	2004	hMLH1	Hypermethylation	Plasma	Heterogeneous	South Western Oncology Group Solid Tumour Response Criteria or CA125	Fluorescent MSP
Strathdee et al. (5)	2005	MCJ	Hypermethylation	Tumour tissue	Heterogeneous	RECIST	Bisulphite sequencing
Teodoridis et al. (46)	2005	At least one of BRCA1, GSTp1, MGMT	Hypermethylation	Tumour tissue	Heterogeneous	South Western Oncology Group Solid Tumour Response Criteria or CA125	MSP
Watanabe et al. (43)	2007	hMLH1	Hypermethylation	Tumour tissue	Heterogeneous, paired samples	WHO criteria	MSP
Staub et al. (86)	2007	Hsulf-1	Hypermethylation	Cell line (OV207, SKOV3)	NA	NA	Bisulphite sequencing
Nicholson et al. (87)	2009	ASS1	Hypermethylation	Cell line (A2780, A2780 CisR), tumour tissue	Heterogeneous (80% serous)	RECIST	MSP
Su et al. (88)	2009	SFRP5	Hypermethylation	Tumour tissue	Heterogeneous	CT and CA125	MSP
Bram et al. (89)	2009	ABCG2	Hypomethylation	Cell line (IGROV1, IGROV1/T8)	NA	NA	COBRA
Chaudhry et al. (47)	2009	BRCA1	Hypomethylation	Tumour tissue	Heterogeneous (86% serous)	CT and CA125	MSP
Dai et al. (56)	2011	DVL1, NFATC3	Hypermethylation	Tumour tissue	Heterogeneous	RECIST	DMH array
Iramaneerat et al. (90)	2011	HERV-K	Hypomethylation	Tumour tissue	Clear cell	Not specified	COBRA
Syed et al. (91)	2011	Plk2	Hypermethylation	Cell line (SKOV3, A2780, and resistant clones)	NA	NA	MSP and bisulphite sequencing
Wang et al. (48)	2012	TGFBI	Hypermethylation	Cell line (SKOV3, A2780, and resistant clones)	NA	NA	MSP and bisulphite sequencing
Coley et al. (49)	2012	p57kip2	Hypermethylation	Cell line (PEO1 and resistant clones)	NA	NA	MSP and pyrosequencing
Ali et al. (92)	2013	RGS10-1	Hypermethylation	Cell line (A2780 and resistant clone)	NA	NA	Bisulphite sequencing

Table II. Summary of validated miRNA associated with EOC chemotherapy resistance.

Author	Year	MicroRNA ID	Regulation in resistant models	Gene target	Platform	Initial identifying tissue	Validation in tumour	Functional in vitro / in vivo validation
Yang et al. (93)	2008	mir-214	up	PTEN	RT-PCR	cell lines	✓	✓
Yang et al. (64)	2008	let-7i	down		Customized array	tumour tissue	✓	✓
		34 miRNA differentially expressed
Li et al. (94)	2010	miR-27a	up	HIPK2	RT-PCR	cell lines	✗	✓
Ye et al. (95)	2010	miR-376c	up	ALK7	RT-PCR	cell lines	✓	✓
Bagnoli et al. (65)	2011	chrXq27.3 cluster	up		miRNA BeadChip Array (Illumina)	tumour tissue	✓	✓
Kong et al. (96)	2011	miR-125b	up	Bak1	RT-PCR	cell lines	✗	✓
Mateescu et al. (97)	2011	MiR-141	down	p38alpha	RTPCR	cell lines	✗	validation study
		miR-200a	down	p38alpha
Boyerinas et al. (98)	2012	let-7	down		RTPCR	cell lines	✗	validation study
Cheng et al. (99)	2012	miR-199a	up		RT-PCR	cell line	✗	validation study
Cittelly et al. (100)	2012	miR-200c	down		RT-PCR	cell line	✗	validation study
Fu et al. (101)	2012	miR-93	up	PTEN	Customized microarray	cell line	✓	✓
Yang et al. (102)	2012	miR-130b	down	CSF-1	RT-PCR	cell lines	✗	✓
Yang et al. (103)	2012	miR-130a	up	MDR1	miRCURY LNA Array (Exiqon)	cell line		✓
		89 miRNA differentially expressed					✗
Ziliak et al. (104)	2012	miR-193b	up	CRIM1	miRURY LNA Array (Exiqon)	cell lines	✗	✓
		miR-320a
Cai et al. (105)	2013	Let-7e	down	EZH2, CCND1	RT-PCR	cell lines	✗	✓
Huh et al. (106)	2013	mir-106a	up	caspase-7, BCL10	miRNA-V1 BeadChips (Illumina)	cell line	✓	✓
		mir-591	down	ZEB1				✓
		10 miRNA differentially expressed
Li et al. (107)	2013	miR-320a	up	RAB34	Exiqon microarray, RT-PCR	cell line	✓	✗
		miR-22	up
		mir-129-5p	up
		miR-9	down
		miR-155	down
		miR-640	down
van Jaarsveld et al. (108)	2013	miR-141	up	KEAP1	LNA-based capture probe set (Exiqon)	cell line	✗	✓
		miR-200c	up
		27 miRNA differentially expressed
Prislei et al. (109)	2013	mir-200c	down	TUBB3	RT-PCR	cell line	✗	✓
Rao et al. (110)	2013	mir-106a	down	Mcl-1	RT-PCR	cell lines	✗	✓
Vecchione et al. (63)	2013	mir-484	down	VEGFB and VEGFR2	TaqMan microRNA assay	tumour tissue	✓	✓
		mir-642	down
		mir-217	down
Zhang et al. (111)	2013	miR-130a	down	XIAP	RT-PCR	cell line	✗	✓
Xiang et al. (112)	2013	miR-152	down	DNMT1	RT-PCR	cell line	✗	✓
		miR-185	down	DNMT1
Yu et al. (113)	2014	mir-29a/b/c	down	COL1A1	RT-PCR	cell line	✗	✓
Chan et al. (114)	2014	miR-21	up	PDCD4, c-IAP2	Exiqon microarray, RT-PCR	cell line	✓(TCGA)	✓
Chen et al. (115)	2014	miR- 367	down	Multiple	Customized array, RT-PCR	cell line	✗	✓
		miR- 30a-5p	up
Li et al. (116)	2014	miR-128	down	ABCC5, Bmi-1	RT-PCR	cell line	✗	✓
Li et al. (117)	2014	miR-106a	up	PDCD4	RT-PCR	cell line	✗	✓
Zhu et al. (118)	2014	miR-145	down	Sp1, Cdk6	RT-PCR	tumour tissue	✓	✓
Zong et al. (119)	2014	miR-130b	up	MDR1	RT-PCR	cell line	✗	✓

Table III. Summary of four independent studies associating miRNA expression and chemotherapy response in clinical material.

Study	miRNA ID	Expression in relation to resistance	FDR correction
Yang et al. 2008	let-7i	up	0.67
	mif-216	down	0.67
	mir-106b	up	0.69
	mir-123	down	0.67
	mir-126	down	0.67
	mir-129	down	0.67
	mir-140	down	0.67
	mir-146	down	0.67
	mir-148	down	0.67
	mir-152	down	0.67
	mir-181c	down	0.67
	mir-196a	down	0.67
	mir-198	down	0.67
	mir-1b-1	down	0.67
	mir-203	up	0.67
	mir-214	down	0.67
	mir-22	down	0.67
	mir-223	down	0.67
	mir-29a	down	0.67
	mir-320	down	0.67
	mir-320	down	0.67
	mir-321	up	0.67
	mir-365	down	0.67
	mir-370	down	0.67
	mir-452	down	0.67
	mir-453	up	0.67
	mir-491	up	0.67
	mir-507	up	0.67
	mir-509	up	0.67
	mir-513	up	0.67
	mir-514	up	0.67
	mir-519e	down	0.67
	mir-520e	down	0.67
	mir-521	down	0.67
Eitan et al. 2009	let-7g	up	> 0.3
	mir-23a	up	0.3
	mir-27a	up	0.3
	mir-30c	up	> 0.3
	mir-378	down	0.3
	mir-625	down	> 0.3
	mirr-199a-3p	up	> 0.3
Vecchione at al. 2013	mir-181a	down	Not corrected
	mir-19a	up	Not corrected
	mir-217	down	Not corrected
	mir-302d	down	Not corrected
	mir-483-5q	down	Not corrected
	mir-484	down	Not corrected
	mir-491	down	Not corrected
	mir-592	up	Not corrected
	mir-642	down	Not corrected
	mir-653	down	Not corrected
	mir-671-3p	down	Not corrected
	mir-744	down	Not corrected
Bagnoli et al. 2011	HS-138	down	< 0.1
	HS-141	down	< 0.1
	let-7f-1	up	< 0.1
	mir-139-5p	up	< 0.1
	mir-15b	up	< 0.1
	mir-188-5p	down	< 0.1
	mir-191	down	< 0.1
	mir-202	down	< 0.1
	mir-202	down	< 0.1
	mir-22	up	< 0.1
	mir-27b	up	< 0.1
	mir-299-5p	up	< 0.1
	mir-30c-2	up	< 0.1
	mir-32	down	< 0.1
	mir-339-3p	down	< 0.1
	mir-411	up	< 0.1
	mir-454	up	< 0.1
	mir-485-3p	up	< 0.1
	mir-493	up	< 0.1
	mir-494	up	< 0.1
	mir-506	down	< 0.1
	mir-507	down	< 0.1
	mir-508-3p	down	< 0.1
	mir-509-3-5p	down	< 0.1
	mir-509-3p	down	< 0.1
	mir-509-5p	down	< 0.1
	mir-513a-3p	down	< 0.1
	mir-513a-5p	down	< 0.1
	mir-513b	down	< 0.1
	mir-514	down	< 0.1
	mir-656	up	< 0.1
	solexa-499–2217	up	< 0.1

Bold text = significant in training and test set.

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