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BMC Cancer

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01-12-2021 | Choroidal Melanoma | Research

MMP1 and MMP9 are potential prognostic biomarkers and targets for uveal melanoma

Authors: Tianyu Wang, Yuanyuan Zhang, Jianhao Bai, Yawen Xue, Qing Peng

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

Uveal melanoma (UVM) is the leading cause of eye-related mortality worldwide. This study aimed to explore the expression and prognostic value of matrix metalloproteinases (MMPs) in UVM.

Methods

Gene expression levels were obtained from the Gene Expression Omnibus (GEO) and Oncomine databases. Functional and pathway enrichment analyses were performed using the Metascape database. GeneMANIA was then applied to construct a protein-protein interaction network and identify the hub genes. Moreover, overall survival (OS) and disease-free survival (DFS) analysis for the hub genes was performed using the UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) online tool. Furthermore, TRRUST was used to predict the targets of the MMPs.

Results

Our results revealed that the transcriptional levels of MMP1, MMP9, MMP10, MMP11, MMP13, MMP14, and MMP17 were upregulated in UVM tissues compared to normal tissues. A protein-protein interaction (PPI) network was constructed and the top 50 hub genes were identified. The functions of MMPs and their neighboring proteins are mainly associated with ECM-receptor interaction, proteoglycans in cancer, the IL-17 signaling pathway, and microRNAs in cancer. Among the MMPs, MMP1/2/9/11/14/15/16/17/24 played significant roles in the progression of UVM from stage 3 to stage 4. We also found that the expression of MMP1, MMP2, MMP9, and MMP16 positively correlated with OS and DFS in patients with UVM. Additionally, 18 transcription factors associated with nine MMPs were identified.

Conclusions

The results of this study may provide potential biomarkers and targets for UVM. However, further studies are required to confirm these results.

Krantz BA, Dave N, Komatsubara KM, Marr BP, Carvajal RD. Uveal melanoma: epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol (Auckland, N.Z.). 2017;11:279–89.CrossRef

Andreoli MT, Mieler WF, Leiderman YI. Epidemiological trends in uveal melanoma. Br J Ophthalmol. 2015;99(11):1550–3. https://doi.org/10.1136/bjophthalmol-2015-306810.CrossRefPubMed

Schank TE, Hassel JC. Immunotherapies for the treatment of Uveal melanoma-history and future. Cancers. 2019;11(8):1048. https://doi.org/10.3390/cancers11081048.CrossRefPubMedCentral

Singh AD, Bergman L, Seregard S. Uveal melanoma: epidemiologic aspects. Ophthalmol Clin N Am. 2005;18(1):75–84. https://doi.org/10.1016/j.ohc.2004.07.002.CrossRef

Derrien AC, Rodrigues M, Eeckhoutte A, Dayot S, Houy A, Mobuchon L, et al. Germline MBD4 mutations and predisposition to Uveal melanoma. J Natl Cancer Inst. 2021;113(1):80–7. https://doi.org/10.1093/jnci/djaa047.CrossRefPubMed

Katopodis P, Khalifa MS, Anikin V. Molecular characteristics of uveal melanoma and intraocular tumors. Oncol Lett. 2021;21(1):9. https://doi.org/10.3892/ol.2020.12270.CrossRefPubMed

Mondal S, Adhikari N, Banerjee S, Amin SA, Jha T. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: a minireview. Eur J Med Chem. 2020;194:112260. https://doi.org/10.1016/j.ejmech.2020.112260.CrossRefPubMed

Churg A, Wang R, Wang X, Onnervik PO, Thim K, Wright JL. Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax. 2007;62(8):706–13. https://doi.org/10.1136/thx.2006.068353.CrossRefPubMedPubMedCentral

Roscilli G, Cappelletti M, De Vitis C, Ciliberto G, Di Napoli A, Ruco L, et al. Circulating MMP11 and specific antibody immune response in breast and prostate cancer patients. J Transl Med. 2014;12(1):54. https://doi.org/10.1186/1479-5876-12-54.CrossRefPubMedPubMedCentral

10.

Wang JF, Gong YQ, He YH, Ying WW, Li XS, Zhou XF, et al. High expression of MMP14 is associated with progression and poor short-term prognosis in muscle-invasive bladder cancer. Eur Rev Med Pharmacol Sci. 2020;24(12):6605–15. https://doi.org/10.26355/eurrev_202006_21646.CrossRefPubMed

11.

Xu DM, Han PH, Chen L, Li TT, Yang XH, Guo R. Knockdown of MMP16 inhibits cell proliferation and invasion in chordoma in vitro. J Biol Regul Homeost Agents. 2020;34(6):2263–70. https://doi.org/10.23812/20-559-L.CrossRefPubMed

12.

Zhao S, Yu M. Identification of MMP1 as a potential prognostic biomarker and correlating with immune infiltrates in cervical squamous cell carcinoma. DNA Cell Biol. 2020;39(2):255–72. https://doi.org/10.1089/dna.2019.5129.CrossRefPubMed

13.

Eiro N, Cid S, Fernandez B, Fraile M, Cernea A, Sanchez R, et al. MMP11 expression in intratumoral inflammatory cells in breast cancer. Histopathology. 2019;75(6):916–30. https://doi.org/10.1111/his.13956.CrossRefPubMed

14.

Host L, Paye A, Detry B, Blacher S, Munaut C, Foidart JM, et al. The proteolytic activity of MT4-MMP is required for its pro-angiogenic and pro-metastatic promoting effects. Int J Cancer. 2012;131(7):1537–48. https://doi.org/10.1002/ijc.27436.CrossRefPubMed

15.

Mohammad MA, Ismael NR, Shaarawy SM, El-Merzabani MM. Prognostic value of membrane type 1 and 2 matrix metalloproteinase expression and gelatinase a activity in bladder cancer. Int J Biol Markers. 2010;25(2):69–74. https://doi.org/10.1177/172460081002500202.CrossRefPubMed

16.

Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML. Matrix metalloproteinase-9: many shades of function in cardiovascular disease. Physiology (Bethesda). 2013;28(6):391–403. https://doi.org/10.1152/physiol.00029.2013.CrossRef

17.

Rappaport N, Twik M, Plaschkes I, Nudel R, Iny Stein T, Levitt J, et al. MalaCards: an amalgamated human disease compendium with diverse clinical and genetic annotation and structured search. Nucleic Acids Res. 2017;45(D1):D877–D87. https://doi.org/10.1093/nar/gkw1012.CrossRefPubMed

18.

Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007;9(2):166–80. https://doi.org/10.1593/neo.07112.CrossRefPubMedPubMedCentral

19.

Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6. https://doi.org/10.1016/S1476-5586(04)80047-2.CrossRefPubMedPubMedCentral

20.

Tomczak K, Czerwinska P, Wiznerowicz M. The Cancer genome atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn). 2015;19(1A):A68–77. https://doi.org/10.5114/wo.2014.47136.CrossRef

21.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4. https://doi.org/10.1158/2159-8290.CD-12-0095.CrossRefPubMed

22.

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523. https://doi.org/10.1038/s41467-019-09234-6.CrossRefPubMedPubMedCentral

23.

Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010;38(Web Server issue):W214–20.CrossRefPubMedPubMedCentral

24.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–W102. https://doi.org/10.1093/nar/gkx247.CrossRefPubMedPubMedCentral

25.

Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649–58. https://doi.org/10.1016/j.neo.2017.05.002.CrossRefPubMedPubMedCentral

26.

Han H, Cho JW, Lee S, Yun A, Kim H, Bae D, et al. TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res. 2018;46(D1):D380–D6. https://doi.org/10.1093/nar/gkx1013.CrossRefPubMed

27.

Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509–W14. https://doi.org/10.1093/nar/gkaa407.CrossRefPubMedPubMedCentral

28.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77(21):e108–e10. https://doi.org/10.1158/0008-5472.CAN-17-0307.CrossRefPubMedPubMedCentral

29.

Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016;17(1):174. https://doi.org/10.1186/s13059-016-1028-7.CrossRefPubMedPubMedCentral

30.

Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14(1):7. https://doi.org/10.1186/1471-2105-14-7.CrossRefPubMedPubMedCentral

31.

Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782–95. https://doi.org/10.1016/j.immuni.2013.10.003.CrossRefPubMed

32.

Ostridge K, Williams N, Kim V, Bennett M, Harden S, Welch L, et al. Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD. Thorax. 2016;71(2):126–32. https://doi.org/10.1136/thoraxjnl-2015-207428.CrossRefPubMed

33.

Wang C, Mao C, Lai Y, Cai Z, Chen W. MMP1 3’UTR facilitates the proliferation and migration of human oral squamous cell carcinoma by sponging miR-188-5p to up-regulate SOX4 and CDK4. Mol Cell Biochem. 2021;476(2):785–96. https://doi.org/10.1007/s11010-020-03944-y.CrossRefPubMed

34.

de Vos I, Wong ASW, Welting TJM, Coull BJ, van Steensel MAM. Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling. Am J Med Genet Part A. 2019;179(8):1652–64. https://doi.org/10.1002/ajmg.a.61264.CrossRefPubMed

35.

Li C, Deng L, Shen H, Meng Q, Qian A, Sang H, et al. O-6-methylguanine-DNA methyltransferase inhibits gastric carcinoma cell migration and invasion by Downregulation of matrix metalloproteinase 2. Anti Cancer Agents Med Chem. 2016;16(9):1125–32. https://doi.org/10.2174/1871520615666150914114455.CrossRef

36.

Liu C. Pathological and prognostic significance of matrix metalloproteinase-2 expression in ovarian cancer: a meta-analysis. Clin Exp Med. 2016;16(3):375–82. https://doi.org/10.1007/s10238-015-0369-y.CrossRefPubMed

37.

Ren F, Tang R, Zhang X, Madushi WM, Luo D, Dang Y, et al. Overexpression of MMP family members functions as prognostic biomarker for breast Cancer patients: a systematic review and Meta-analysis. PLoS One. 2015;10(8):e0135544. https://doi.org/10.1371/journal.pone.0135544.CrossRefPubMedPubMedCentral

38.

Bi MC, Hose N, Xu CL, Zhang C, Sassoon J, Song E. Nonlethal levels of Zeaxanthin inhibit cell migration, invasion, and secretion of MMP-2 via NF-kappaB pathway in cultured human Uveal melanoma cells. J Ophthalmol. 2016;2016:8734309–8. https://doi.org/10.1155/2016/8734309.CrossRefPubMedPubMedCentral

39.

Chiranjeevi P, Spurthi KM, Rani NS, Kumar GR, Aiyengar TM, Saraswati M, et al. Gelatinase B (−1562C/T) polymorphism in tumor progression and invasion of breast cancer. Tumour Biol. 2014;35(2):1351–6. https://doi.org/10.1007/s13277-013-1181-5.CrossRefPubMed

40.

Tokito A, Jougasaki M. Matrix Metalloproteinases in non-neoplastic disorders. Int J Mol Sci. 2016;17(7):1178. https://doi.org/10.3390/ijms17071178.CrossRefPubMedCentral

41.

Vandooren J, Knoops S, Aldinucci Buzzo JL, Boon L, Martens E, Opdenakker G, et al. Differential inhibition of activity, activation and gene expression of MMP-9 in THP-1 cells by azithromycin and minocycline versus bortezomib: a comparative study. PLoS One. 2017;12(4):e0174853. https://doi.org/10.1371/journal.pone.0174853.CrossRefPubMedPubMedCentral

42.

Liu Y, Gao M, An J, Wang X, Jia Y, Xu J, et al. Dysregulation of MiR-30a-3p/gastrin enhances tumor growth and invasion throughSTAT3/MMP11 pathway in gastric Cancer. Onco Targets Ther. 2020;13:8475–93. https://doi.org/10.2147/OTT.S235022.CrossRefPubMedPubMedCentral

43.

Chen GL, Wang SC, Huang WC, Chang WS, Tsai CW, Li HT, et al. The association of MMP-11 promoter polymorphisms with susceptibility to lung Cancer in Taiwan. Anticancer Res. 2019;39(10):5375–80. https://doi.org/10.21873/anticanres.13731.CrossRefPubMed

44.

Fu J, Khaybullin R, Zhang Y, Xia A, Qi X. Gene expression profiling leads to discovery of correlation of matrix metalloproteinase 11 and heparanase 2 in breast cancer progression. BMC Cancer. 2015;15(1):473. https://doi.org/10.1186/s12885-015-1410-y.CrossRefPubMedPubMedCentral

45.

Han J, Choi YL, Kim H, Choi JY, Lee SK, Lee JE, et al. MMP11 and CD2 as novel prognostic factors in hormone receptor-negative, HER2-positive breast cancer. Breast Cancer Res Treat. 2017;164(1):41–56. https://doi.org/10.1007/s10549-017-4234-4.CrossRefPubMedPubMedCentral

46.

Claesson-Welsh L. How the matrix metalloproteinase MMP14 contributes to the progression of colorectal cancer. J Clin Invest. 2020;130(3):1093–5. https://doi.org/10.1172/JCI135239.CrossRefPubMedPubMedCentral

47.

Ager EI, Kozin SV, Kirkpatrick ND, Seano G, Kodack DP, Askoxylakis V, et al. Blockade of MMP14 activity in murine breast carcinomas: implications for macrophages, vessels, and radiotherapy. J Natl Cancer Inst. 2015;107(4):djv017.CrossRefPubMedPubMedCentral

48.

Zheng L, Li D, Xiang X, Tong L, Qi M, Pu J, et al. Methyl jasmonate abolishes the migration, invasion and angiogenesis of gastric cancer cells through down-regulation of matrix metalloproteinase 14. BMC Cancer. 2013;13(1):74. https://doi.org/10.1186/1471-2407-13-74.CrossRefPubMedPubMedCentral

49.

Wang Y, Zhang L, Wei N, Sun Y, Pan W, Chen Y. Silencing LINC00482 inhibits tumor-associated inflammation and angiogenesis through down-regulation of MMP-15 via FOXA1 in bladder cancer. Aging. 2020;13(2):2264–78. https://doi.org/10.18632/aging.202247.CrossRefPubMedPubMedCentral

50.

Kudelski J, Mlynarczyk G, Darewicz B, Bruczko-Goralewska M, Romanowicz L. Dominative role of MMP-14 over MMP-15 in human urinary bladder carcinoma on the basis of its enhanced specific activity. Medicine. 2020;99(7):e19224. https://doi.org/10.1097/MD.0000000000019224.CrossRefPubMedPubMedCentral

51.

Zheng W, Li ZY, Zhao DL, Li XL, Liu R. microRNA-26a directly targeting MMP14 and MMP16 inhibits the Cancer cell proliferation, migration and invasion in cutaneous squamous cell carcinoma. Cancer Manag Res. 2020;12:7087–95. https://doi.org/10.2147/CMAR.S265775.CrossRefPubMedPubMedCentral

52.

Morton SE, O'Hare KJM, Maha JLK, Nicolson MP, Machado L, Topless R, et al. Testing the validity of Taxonic Schizotypy using genetic and environmental risk variables. Schizophr Bull. 2017;43(3):633–43. https://doi.org/10.1093/schbul/sbw108.CrossRefPubMed

53.

Xu Y, Wang Y, Liu H, Shi Q, Zhu D, Amos CI, et al. Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival. Mol Carcinog. 2018;57(1):22–31. https://doi.org/10.1002/mc.22716.CrossRefPubMed

54.

Nimri L, Barak H, Graeve L, Schwartz B. Restoration of caveolin-1 expression suppresses growth, membrane-type-4 metalloproteinase expression and metastasis-associated activities in colon cancer cells. Mol Carcinog. 2013;52(11):859–70. https://doi.org/10.1002/mc.21927.CrossRefPubMed

55.

Huang CH, Yang WH, Chang SY, Tai SK, Tzeng CH, Kao JY, et al. Regulation of membrane-type 4 matrix metalloproteinase by SLUG contributes to hypoxia-mediated metastasis. Neoplasia. 2009;11(12):1371–82. https://doi.org/10.1593/neo.91326.CrossRefPubMedPubMedCentral

Title: MMP1 and MMP9 are potential prognostic biomarkers and targets for uveal melanoma
Authors: Tianyu Wang
Yuanyuan Zhang
Jianhao Bai
Yawen Xue
Qing Peng
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Choroidal Melanoma
Biomarkers
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08788-3

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