Matrix metalloproteinases and their inhibitors in the gastrointestinal cancers: current knowledge and clinical potential

Figures & data

Table 1 Expression of MMPs and TIMPs in gastrointestinal cancers

MMPs/TIMPs	Sample type	Method of analysis	Correlation
Esophageal squamous cell carcinoma
MMP-1	Tissue^Citation21,Citation22,Citation104	IHC;^Citation21,Citation22 M^Citation22,Citation104	Regional lymph node;^Citation21 TNM stage;^Citation21 poor survival^Citation21,Citation22
MMP-2	Tissue;^Citation17 serum^Citation29	IHC;^Citation17 ELISA^Citation29	Tumor invasion depth;^Citation17 tumor-node-metastasis stages;^Citation17 lymph node metastasis^Citation17
MMP-3	Serum;^Citation5 tissue^Citation19,Citation104	Z;^Citation19 qRT-PCR;^Citation19 M^Citation104	Poor survival^Citation5
MMP-7
MMP-9	Serum;^Citation5,Citation18 tissue^Citation17,Citation23,Citation104	ELISA;^518 IHC;^Citation17,Citation23 M^Citation104	Differentiation;^Citation23 lymph node metastasis;^Citation23 poor survival^Citation5,Citation23
MMP-10	Tissue^Citation19,Citation20,Citation104	Z;^Citation18 qRT-PCR;^Citation19,Citation20 IHC;^Citation19,Citation20	M^Citation104 Lymph node metastasis;^Citation20 TNM stage;^Citation20 poor survival^Citation20
MMP-11	Tissue^Citation104	M^Citation104
MMP-12	Tissue^Citation104	M^Citation104
MMP-13	Serum;^Citation24 tissue^Citation26,Citation104	IHC;^Citation26 ELISA;^Citation24 M^Citation104	Lymph node metastasis;^Citation26 poor survival^Citation24
MMP-14	Tissue^Citation87	IHC^Citation87	Depth of wall invasion;^Citation87 lymph node metastasis;^Citation87 tumor stage;^Citation87 survival;^Citation87 recurrence^Citation87
MMP-15	Tissue^Citation27	IHC^Citation27	Tumor size^Citation27
TIMP-2	Serum^Citation29	ELISA^Citation29
TIMP-3	Tissue^Citation25	IHC^Citation25
TIMP-4	Tissue^Citation25	IHC^Citation25
Gastric cancer
MMP-1	Tissue;^Citation31 serum^Citation38	RT-PCR;^Citation31 IHC;^Citation31 ELISA^Citation38	Tumor size;^Citation38 depth of wall invasion;^Citation38 lymph node metastasis;^Citation31,Citation38 liver metastasis;^Citation38 advanced stage^Citation38
MMP-2	Tissue;^Citation33 serum^Citation39	qRT-PCR;^Citation33 ELISA^Citation39	Advanced-stage^Citation33
MMP-3	Tissue;^Citation30 serum^Citation3	IHC;^Citation30 ELISA^Citation3	Invasion;^Citation30 lymph node invasion;^Citation3 metastasis;^Citation30 advanced- stage;^Citation30 poor survival^Citation3
MMP-7	Peritoneal lavage fluid;^Citation34 tissue;^Citation35 serum^Citation3	qRT-PCR;^Citation34 IHC;^Citation35 ELISA^Citation3	Lymph node invasion;^Citation3 poor survival;^Citation3 recurrence^Citation34
MMP-12	Tissue^Citation32	IHC^Citation32	Tumor invasion;^Citation32 lymph node metastasis;^Citation32 distant metastasis;^Citation32 TNM stage;^Citation32 poor survival^Citation32
MMP-21	Tissue^Citation36	IHC^Citation36	Invasion;^Citation36 metastasis;^Citation36 poor survival^Citation36
MMP-24	Tissue^Citation33	qRT-PCR^Citation33	Advanced stage^Citation33
MMP-25	Tissue^Citation33	qRT-PCR^Citation33	Advanced stage^Citation33
MMP-14	Tissue^Citation33,Citation37	IHC;^Citation37 wB^Citation33	Advanced stage;^Citation33 tumor size;^Citation37 increased recurrence risk;^Citation37 poor survival^Citation37
TIMP-1	Serum^Citation38	ELISA^Citation38	Tumor size;^Citation38 depth of wall invasion;^Citation38 lymph node metastasis;^Citation38 liver metastasis;^Citation38 advanced stage^Citation38
TIMP-2	Serum^Citation39	ELISA^Citation39	Depth of wall invasion^Citation39
TIMP-3	Tissue^Citation30,Citation33	IHC;^Citation30 wB^Citation33	Advanced stage;^Citation30,Citation33 invasion;^Citation30 metastasis^Citation30
Colorectal cancer
MMP-1	Tissue^Citation44	IHC^Citation44	Poor survival^Citation44
MMP-2	Tissue^Citation43,Citation44,Citation105	Z;^Citation105 ELISA^Citation43	Cancer presence;^Citation105 poor survival^Citation43
MMP-7	Tissue^Citation106	IHC^Citation106	Poor prognosis^Citation106
MMP-8	Serum^Citation45	TR-IFMA^Citation45	Tumor stage;^Citation45 distant metastases^Citation45
MMP-9	Tissue^Citation43,Citation44,Citation107	IHC;^Citation107 ELISA^Citation43	Recurrence;^Citation107 poor survival^Citation43
MMP-13	Tissue^Citation41	qRT-PCR^Citation41	Liver metastasis^Citation41
MMP-21	Tissue^Citation42	IHC^Citation42	Poor prognosis^Citation42
MMP-14	Tissue^Citation40	qRT-PCR^Citation40	Survival^Citation40
TIMP-1	Tissue;^Citation108 serum^Citation46	IHC;^Citation108 ELISA^Citation46	Poor prognosis;^Citation108 tumor stage; survival^Citation46
Hepatocellular carcinoma
MMP-1	Tissue^Citation49	IHC^Citation49	Recurrence;^Citation49 poorer survival^Citation49
MMP-2	Tissue^Citation47	IHC^Citation47	Lymph node metastasis^Citation47
MMP-8	Serum^Citation51	TR-IFMA^Citation51	Survival^Citation51
MMP-9	Tissue;^Citation48 serum^Citation51	IHC;^Citation48 ELISA^Citation51	Recurrence;^Citation48 survival^Citation48,Citation51
MMP-12	Tissue^Citation51	qRT-PCR^Citation51	Recurrence;^Citation51 survival^Citation51
TIMP-1	Serum^Citation51	ELISA^Citation51	Survival^Citation51
Pancreatic cancer
MMP-2	Tissue^Citation109	Z^Citation109
MMP-9	Tissue^Citation109	Z^Citation109	High tumor grades^Citation109
TIMP-1	Serum^Citation52	ELISA^Citation52	Early stage^Citation52

Abbreviations: ELISA, enzyme-linked immunosorbent assay; IHC, immunohistochemistry; M, microarray; MMP, matrix metalloproteinase; RT-PCR, reverse transcription polymerase chain reaction; q, quantitative; TIMP, tissue inhibitor of metalloproteinase; TR-IFMA: time-resolved immunofluorometric assay; WB, Western blot; Z, zymogram.

Table 2 SNPs of MMPs and TIMPs in gastrointestinal cancers

Gene	SNP (rs number)	Cancer type	Ethnicity	Comments
MMP-1	−422T>A (rs475007)	GC	Indian^Citation61	T carrier showed significant risk for regional lymph node metastasis
	−519A>G (rs1144393)	GC	Indian^Citation61	G carrier displayed poor cellular differentiation attributing to a higher risk of cancer progression
	−1607 IG>2G (rs11292517)	CRC	Iranian^Citation59	2G/2G genotype with invasion risk of CRC
MMP-2	−1306C>T (rs243865)	ESCC	Chinese^Citation63	C/C genotype correlated with increased risk of ESCC
		CRC	Netherlander^Citation64	T/T genotype was associated with poor survival
	−1575G>A (rs243866)	CRC	Taiwanese^Citation67	A/A genotype had a 6.32-fold higher risk of developing distant metastasis
MMP-3	−1612 5A>6A (rs35068180)	HCC	Japanese^Citation69	5A carriers had a significantly poorer prognosis
MMP-7	−181A>G (rs11568818)	ESCC	Indian^Citation72	G/G genotype carries a higher risk of ESCC
		GC	Indian^Citation73	G/G genotype was associated with a more than two-fold increased risk of GC
		GC	Japanese^Citation70	G carrier associated with an increased risk for Helicobacter pylori-related noncardial GC
		CRC	Pole^Citation71	G/G had an increased risk of CRC, higher lymph node involvement, and advanced tumor infiltration
MMP-9	P574R (rs2250889)	ESCC	Chinese^Citation79	G/G genotype was associated with a significantly increased risk of ESCC
		GC	Chinese^Citation80	P/P associated with lymph node metastasis
	R279Q (rs17576)	GC	Chinese^Citation80	R/R associated with lymph node metastasis
		CRC	Chinese^Citation60	R/R associated with an increased risk of CRC
	−1562C>T (rs34016235)	CRC	Korean^Citation82	C/C associated with higher risk of CRC
MMP-12	−82A>G (rs2276109)	CRC	Swedish^Citation85	A/A genotype is connected with a higher risk of disseminated CRC
MMP-14	6767G>A (rs1042704)	HCC	Taiwanese^Citation86	G/G genotypes had higher risk of HCC
	7096T>C (rs2236307)	HCC	Taiwanese^Citation86	T/T genotypes had higher risk of HCC
TIMP-2	303C>T (rs2277698)	GC	German^Citation65	C/C genotype associated with higher lymph node metastasis and more distant metastasis
		CRC	Korean^Citation82	C/C associated with higher risk of CRC
	−418G>C (rs8179090)	CRC	Korean^Citation82	G/G associated with higher risk of CRC and metastasis

Abbreviations: CRC, colorectal cancer; ESCC, esophageal squamous cell carcinoma; GS, gastric cancer; HCC, hepatocellular carcinoma; MMP, matrix metalloproteinase; PC, pancreatic cancer; rs, reference single nucleotide polymorphism cluster identification; SNP, single nucleotide polymorphism; TIMP, tissue inhibitor of metalloproteinase.

Table 3 MMPs and TIMPs are targeted directly or indirectly by miRNAs in gastrointestinal cancers

MMPs/TIMPs	miRNAs	Cancer type	Target
MMP-2	miR-29a	CRC^Citation93	Target KLF4, and then indirectly downregulate its downstream MMP-2
	miR-29b	CRC;^Citation44	Target MMP-2 directly
		HCC^Citation45
	miR-139	CRC^Citation94	Target IGF-IR, and then indirectly downregulate its downstream MMP-2 via IGF-IR/MEK/ERK signaling
MMP-7	miR-148a	GC^Citation89	Target MMP-7 directly
MMP-9	miR-145	GC^Citation90	Target N-cadherin, and then indirectly downregulate its downstream MMP-9
	miR-491	HCC^Citation97	Target MMP-9 directly
MMP-11	miR-125a	HCC^Citation99	Target MMP-11 directly
	let-7c	CRC^Citation95	Target MMP-11 directly
MMP-14	miR-133a	ESCC^Citation87	Target MMP-14 directly
	let-7	PC^Citation102	Target MMP-14 indirectly
TIMP-2	miR-106a	GC;^Citation53PC^Citation54	Target TIMP-2 directly
TIMP-3	miR-21	ESCC^Citation88	Target TIMP-3 directly
	miR-181b,	HCC^Citation101	Target TIMP-3 directly
	miR-181d,	HCC^Citation100	Target TIMP-3 directly
	miR-211,
	miR-222

Abbreviations: CRC, colorectal cancer; ESCC, esophageal squamous cell carcinoma; GS, gastric cancer; HCC, hepatocellular carcinoma; miRNA, microRNA; MMP, matrix metalloproteinase; PC, pancreatic cancer; TIMP, tissue inhibitor of metalloproteinase.

Peng HH, Zhang X, Cao PG. MMP-1/PAR-1 signal transduction axis and its prognostic impact in esophageal squamous cell carcinoma. Braz J Med Biol Res. 2012;45(1):86–92.

 Web of Science ®Google Scholar

Tao YS, Ma XY, Chai DM, et al. Overexpression of MMP-1 and VEGF-C is associated with a less favorable prognosis in esophageal squamous cell carcinoma. Onkologie. 2012;35(11):651–656.

 Google Scholar

Kashyap MK, Marimuthu A, Kishore CJ, et al. Genomewide mRNA profiling of esophageal squamous cell carcinoma for identification of cancer biomarkers. Cancer Biol Ther. 2009;8(1):36–46.

 PubMed Web of Science ®Google Scholar

Li Y, Ma J, Guo Q, et al. Overexpression of MMP-2 and MMP-9 in esophageal squamous cell carcinoma. Dis Esophagus. 2009;22(8):664–667.

 PubMed Web of Science ®Google Scholar

Groblewska M, Mroczko B, Kozlowski M, Niklinski J, Laudanski J, Szmitkowski M. Serum matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in esophageal cancer patients. Folia Histochem Cytobiol. 2012;50(4):590–598.

 Web of Science ®Google Scholar

Wang WL, Chang WL, Yeh YC, et al. Concomitantly elevated serum matrix metalloproteinases 3 and 9 can predict survival of synchronous squamous cell carcinoma of the upper aero-digestive tract. Mol Carcinog. 2013;52(6):438–445.

 Web of Science ®Google Scholar

Mukherjee S, Roth MJ, Dawsey SM, Yan W, et al. Increased matrix metalloproteinase activation in esophageal squamous cell carcinoma. J Transl Med. 2010;8:91.

 Web of Science ®Google Scholar

Lukaszewicz-Zajac M, Mroczko B, Kozlowski M, Niklinski J, Laudanski J, Szmitkowski M. Elevated levels of serum metalloproteinase 9 in patients with esophageal squamous cell carcinoma. Pol Arch Med Wewn. 2009;119(9):558–563.

 Web of Science ®Google Scholar

Li Y, Guo H, Dong D, Wu H, Li E. Expression and prognostic relevance of cyclophilin A and matrix metalloproteinase 9 in esophageal squamous cell carcinoma. Diagn Pathol. 2013;8:207.

 Web of Science ®Google Scholar

Liu H, Qin YR, Bi J, Guo A, Fu L, Guan XY. Overexpression of matrix metalloproteinase 10 is associated with poor survival in patients with early stage of esophageal squamous cell carcinoma. Dis Esophagus. 2012;25(7):656–663.

 Web of Science ®Google Scholar

Jiao XL, Chen D, Wang JG, Zhang KJ. Clinical significance of serum matrix metalloproteinase-13 levels in patients with esophageal squamous cell carcinoma (ESCC). Eur Rev Med Pharmacol Sci. 2014;18(4):509–515.

 Web of Science ®Google Scholar

Ye Q, Yan Z, Liao X, et al. MUC1 induces metastasis in esophageal squamous cell carcinoma by upregulating matrix metalloproteinase 13. Lab Invest. 2011;91(5):778–787.

 Web of Science ®Google Scholar

Akanuma N, Hoshino I, Akutsu Y, et al. MicroRNA-133a regulates the mRNAs of two invadopodia-related proteins, FSCN1 and MMP14, in esophageal cancer. Br J Cancer. 2014;110(1):189–198.

 PubMed Web of Science ®Google Scholar

Chen L, Di D, Luo G, et al. Immunochemical staining of MT2-MMP correlates positively to angiogenesis of human esophageal cancer. Anticancer Res. 2010;30(10):4363–4368.

 Web of Science ®Google Scholar

Maurer J, Schopp M, Thurau K, Haier J, Kohler G, Hummel R. Immunohistochemical analysis on potential new molecular targets for esophageal cancer. Dis Esophagus. 2014;27(1):93–100.

 Web of Science ®Google Scholar

Cai QW, Li J, Li XQ, Wang JQ, Huang Y. Expression of STAT3, MMP-1 and TIMP-1 in gastric cancer and correlation with pathological features. Mol Med Rep. 2012;5(6):1438–1442.

 Web of Science ®Google Scholar

Kemik O, Kemik AS, Sumer A, et al. Levels of matrix metalloproteinase-1 and tissue inhibitors of metalloproteinase-1 in gastric cancer. World J Gastroenterol. 2011;17(16):2109–2112.

 Web of Science ®Google Scholar

de la Pena S, Sampieri CL, Ochoa-Lara M, Leon-Cordoba K, Remes-Troche JM. Expression of the matrix metalloproteases 2, (14), 24, and 25 and tissue inhibitor 3 as potential molecular markers in advanced human gastric cancer. Dis Markers. 2014;2014:285906.

 Google Scholar

Mroczko B, Lukaszewicz-Zajac M, Gryko M, Kedra B, Szmitkowski M. Clinical significance of serum levels of matrix metalloproteinase 2 (MMP-2) and its tissue inhibitor (TIMP-2) in gastric cancer. Folia Histochem Cytobiol. 2011;49(1):125–131.

 Web of Science ®Google Scholar

Liu HQ, Song S, Wang JH, Zhang SL. Expression of MMP-3 and TIMP-3 in gastric cancer tissue and its clinical significance. Oncol Lett. 2011;2(6):1319–1322.

 Web of Science ®Google Scholar

Yeh YC, Sheu BS, Cheng HC, Wang YL, Yang HB, Wu JJ. Elevated serum matrix metalloproteinase-3 and -7 in H. pylori-related gastric cancer can be biomarkers correlating with a poor survival. Dig Dis Sci. 2010;55(6):1649–1657.

 PubMed Web of Science ®Google Scholar

Li Z, Zhang D, Zhang H, et al. Prediction of peritoneal recurrence by the mRNA level of CEA and MMP-7 in peritoneal lavage of gastric cancer patients. Tumour Biol. 2014;35(4):3463–3470.

 Google Scholar

Chung WC, Jung SH, Lee KM, et al. The detection of Helicobacter pylori cag pathogenicity islands (PAIs) and expression of matrix metalloproteinase-7 (MMP-7) in gastric epithelial dysplasia and intramucosal cancer. Gastric Cancer. 2010;13(3):162–169.

 Web of Science ®Google Scholar

Zheng J, Chu D, Wang D, et al. Matrix metalloproteinase-12 is associated with overall survival in Chinese patients with gastric cancer. J Surg Oncol. 2013;107(7):746–751.

 PubMed Web of Science ®Google Scholar

Wu T, Li Y, Lu J, et al. Increased MMP-21 expression is associated with poor overall survival of patients with gastric cancer. Med Oncol. 2013;30(1):323.

 Web of Science ®Google Scholar

Peng CW, Wang LW, Fang M, Yang GF, Li Y, Pang DW. Combined features based on MT1-MMP expression, CD11b + immunocytes density and LNR predict clinical outcomes of gastric cancer. J Transl Med. 2013;11:153.

 Web of Science ®Google Scholar

Langenskiold M, Ivarsson ML, Holmdahl L, Falk P, Kabjorn-Gustafsson C, Angenete E. Intestinal mucosal MMP-1 – a prognostic factor in colon cancer. Scand J Gastroenterol. 2013;48(5):563–569.

 Web of Science ®Google Scholar

Langers AM, Verspaget HW, Hawinkels LJ, et al. MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients. Br J Cancer. 2012;106(9):1495–1498.

 Web of Science ®Google Scholar

Murnane MJ, Cai J, Shuja S, McAneny D, Klepeis V, Willett JB. Active MMP-2 effectively identifies the presence of colorectal cancer. Int J Cancer. 2009;125(12):2893–2902.

 PubMed Web of Science ®Google Scholar

Koskensalo S, Louhimo J, Nordling S, Hagstrom J, Haglund C. MMP-7 as a prognostic marker in colorectal cancer. Tumour Biol. 2011;32(2):259–264.

 PubMedGoogle Scholar

Vayrynen JP, Vornanen J, Tervahartiala T, et al. Serum MMP-8 levels increase in colorectal cancer and correlate with disease course and inflammatory properties of primary tumors. Int J Cancer. 2012;131(4):E463–E474.

 Web of Science ®Google Scholar

Bendardaf R, Buhmeida A, Hilska M, et al. MMP-9 (gelatinase B) expression is associated with disease-free survival and disease-specific survival in colorectal cancer patients. Cancer Invest. 2010;28(1):38–43.

 PubMed Web of Science ®Google Scholar

Yamada T, Oshima T, Yoshihara K, et al. Overexpression of MMP-13 gene in colorectal cancer with liver metastasis. Anticancer Res. 2010;30(7):2693–2699.

 Web of Science ®Google Scholar

Wu T, Li Y, Liu X, et al. Identification of high-risk stage II and stage III colorectal cancer by analysis of MMP-21 expression. J Surg Oncol. 2011;104(7):787–791.

 Web of Science ®Google Scholar

Kanazawa A, Oshima T, Yoshihara K, et al. Relation of MT1-MMP gene expression to outcomes in colorectal cancer. J Surg Oncol. 2010;102(6):571–575.

 Web of Science ®Google Scholar

Jensen SA, Vainer B, Bartels A, Brunner N, Sorensen JB. Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells – associations with histopathology and patients outcome. Eur J Cancer. 2010;46(18):3233–3242.

 Web of Science ®Google Scholar

Mroczko B, Groblewska M, Okulczyk B, Kedra B, Szmitkowski M. The diagnostic value of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) determination in the sera of colorectal adenoma and cancer patients. Int J Colorectal Dis. 2010;25(10):1177–1184.

 PubMed Web of Science ®Google Scholar

Liao M, Tong P, Zhao J, et al. Prognostic value of matrix metalloproteinase-1/proteinase-activated receptor-1 signaling axis in hepatocellular carcinoma. Pathol Oncol Res. 2012;18(2):397–403.

 Web of Science ®Google Scholar

Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zeng HY, Gao DM. Gene expression profiling of fixed tissues identified hypoxia-inducible factor-1α, VEGF, and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma. Clin Cancer Res. 2011;17(16):5463–5472.

 Web of Science ®Google Scholar

Lempinen M, Lyytinen I, Nordin A, et al. Prognostic value of serum MMP-8, -9 and TIMP-1 in patients with hepatocellular carcinoma. Ann Med. 2013;45(7):482–487.

 PubMed Web of Science ®Google Scholar

Chen R, Cui J, Xu C, et al. The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection. Ann Surg Oncol. 2012;19(Suppl 3):S375–S384.

 PubMedGoogle Scholar

Durlik M, Gardian K. Metalloproteinase 2 and 9 activity in the development of pancreatic cancer. Pol Przegl Chir. 2012;84(8):377–382.

 Google Scholar

Poruk KE, Firpo MA, Scaife CL, et al. Serum osteopontin and tissue inhibitor of metalloproteinase 1 as diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. Pancreas. 2013;42(2):193–197.

 PubMed Web of Science ®Google Scholar

Dey S, Ghosh N, Saha D, Kesh K, Gupta A, Swarnakar S. Matrix metalloproteinase-1 (MMP-1) promoter polymorphisms are well linked with lower stomach tumor formation in eastern Indian population. PLoS One. 2014;9(2):e88040.

 Web of Science ®Google Scholar

Kouhkan F, Motovali-Bashi M, Hojati Z. The influence of interstitial collagenase-1 genotype polymorphism on colorectal cancer risk in Iranian population. Cancer Invest. 2008;26(8):836–842.

 PubMed Web of Science ®Google Scholar

Li Y, Sun DL, Duan YN, et al. Association of functional polymorphisms in MMPs genes with gastric cardia adenocarcinoma and esophageal squamous cell carcinoma in high incidence region of North China. Mol Biol Rep. 2010;37(1):197–205.

 Web of Science ®Google Scholar

Langers AM, Sier CF, Hawinkels LJ, et al. MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not. Br J Cancer. 2008;98(11):1820–1823.

 Web of Science ®Google Scholar

Ting WC, Chen LM, Pao JB, et al. Genetic polymorphisms of matrix metalloproteinases and clinical outcomes in colorectal cancer patients. Int J Med Sci. 2013;10(8):1022–1027.

 PubMed Web of Science ®Google Scholar

Okamoto K, Ishida C, Ikebuchi Y, et al. The genotypes of IL-1 beta and MMP-3 are associated with the prognosis of HCV-related hepatocellular carcinoma. Intern Med. 2010;49(10):887–895.

 PubMed Web of Science ®Google Scholar

Malik MA, Sharma KL, Zargar SA, Mittal B. Association of matrix metalloproteinase-7 (−181A>G) polymorphism with risk of esophageal squamous cell carcinoma in Kashmir Valley. Saudi J Gastroenterol. 2011;17(5):301–306.

 PubMed Web of Science ®Google Scholar

Malik MA, Zargar SA, Mittal B. Role of the metalloproteinase-7 (181A>G) polymorphism in gastric cancer susceptibility: a case control study in Kashmir valley. Asian Pac J Cancer Prev. 2011;12(1):73–76.

 Google Scholar

Sugimoto M, Furuta T, Kodaira C, et al. Polymorphisms of matrix metalloproteinase-7 and chymase are associated with susceptibility to and progression of gastric cancer in Japan. J Gastroenterol. 2008;43(10):751–761.

 Web of Science ®Google Scholar

Dziki L, Przybylowska K, Majsterek I, Trzcinski R, Mik M, Sygut A. A/G polymorphism of the MMP-7 gene promoter region in colorectal cancer. Pol Przegl Chir. 2011;83(11):622–626.

 Google Scholar

Wu J, Zhang L, Luo H, Zhu Z, Zhang C, Hou Y. Association of matrix metalloproteinases-9 gene polymorphisms with genetic susceptibility to esophageal squamous cell carcinoma. DNA Cell Biol. 2008;27(10):553–557.

 Web of Science ®Google Scholar

Tang Y, Zhu J, Chen L, Chen L, Zhang S, Lin J. Associations of matrix metalloproteinase-9 protein polymorphisms with lymph node metastasis but not invasion of gastric cancer. Clin Cancer Res. 2008;14(9):2870–2877.

 Web of Science ®Google Scholar

Fang WL, Liang WB, He H, et al. Association of matrix metalloproteinases 1, 7, and 9 gene polymorphisms with genetic susceptibility to colorectal carcinoma in a Han Chinese population. DNA Cell Biol. 2010;29(11):657–661.

 Web of Science ®Google Scholar

Park KS, Kim SJ, Kim KH, Kim JC. Clinical characteristics of TIMP2, MMP2, and MMP9 gene polymorphisms in colorectal cancer. J Gastroenterol Hepatol. 2011;26(2):391–397.

 PubMed Web of Science ®Google Scholar

Van Nguyen S, Skarstedt M, Lofgren S,. Gene polymorphism of matrix metalloproteinase-12 and -13 and association with colorectal cancer in Swedish patients. Anticancer Res. 2013;33(8):3247–3250.

 PubMed Web of Science ®Google Scholar

Chen TY, Li YC, Liu YF, et al. Role of MMP14 gene polymorphisms in susceptibility and pathological development to hepatocellular carcinoma. Ann Surg Oncol. 2011;18(8):2348–2356.

 Web of Science ®Google Scholar

Alakus H, Afriani N, Warnecke-Eberz U, et al. Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer. World J Surg. 2010;34(12):2853–2859.

 PubMed Web of Science ®Google Scholar

Tang W, Zhu Y, Gao J, et al. MicroRNA-29a promotes colorectal cancer metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4. Br J Cancer. 2014;110(2):450–458.

 PubMed Web of Science ®Google Scholar

Shen K, Liang Q, Xu K, et al. MiR-139 inhibits invasion and metastasis of colorectal cancer by targeting the type I insulin-like growth factor receptor. Biochem Pharmacol. 2012;84(3):320–330.

 PubMed Web of Science ®Google Scholar

Sakamoto N, Naito Y, Oue N, et al. MicroRNA-148a is downregulated in gastric cancer, targets MMP7, and indicates tumor invasiveness and poor prognosis. Cancer Sci. 2014;105(2):236–243.

 PubMed Web of Science ®Google Scholar

Gao P, Xing AY, Zhou GY, et al. The molecular mechanism of microRNA-145 to suppress invasion-metastasis cascade in gastric cancer. Oncogene. 2013;32(4):491–501.

 PubMed Web of Science ®Google Scholar

Zhou Y, Li Y, Ye J, et al. MicroRNA-491 is involved in metastasis of hepatocellular carcinoma by inhibitions of matrix metalloproteinase and epithelial to mesenchymal transition. Liver Int. 2013;33(8):1271–1280.

 Web of Science ®Google Scholar

Bi Q, Tang S, Xia L, et al. Ectopic expression of MiR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting MMP11 and VEGF. PLoS One. 2012;7(6):e40169.

 PubMed Web of Science ®Google Scholar

Han HB, Gu J, Zuo HJ, et al. Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer. J Pathol. 2012;226(3):544–555.

 PubMed Web of Science ®Google Scholar

Dangi-Garimella S, Strouch MJ, Grippo PJ, Bentrem DJ, Munshi HG. Collagen regulation of let-7 in pancreatic cancer involves TGF-β1-mediated membrane type 1-matrix metalloproteinase expression. Oncogene. 2011;30(8):1002–1008.

 Web of Science ®Google Scholar

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–233.

 PubMed Web of Science ®Google Scholar

Shukla GC, Singh J, Barik S. MicroRNAs: processing, maturation, target recognition, and regulatory functions. Mol Cell Pharmacol. 2011;3(3):83–92.

 PubMedGoogle Scholar

Wang N, Zhang CQ, He JH, et al. MiR-21 down-regulation suppresses cell growth, invasion and induces cell apoptosis by targeting FASL, TIMP3, and RECK genes in esophageal carcinoma. Dig Dis Sci. 2013;58(7):1863–1870.

 PubMed Web of Science ®Google Scholar

Wang B, Hsu SH, Majumder S, et al. TGFβ-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene. 2010;29(12):1787–1797.

 Web of Science ®Google Scholar

Garofalo M, Di Leva G, Romano G, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009;16(6):498–509.

 PubMed Web of Science ®Google Scholar