AccScience Publishing / TD / Volume 3 / Issue 1 / DOI: 10.36922/td.1973

Matrix metalloproteinase-1 as a potential biomarker for early gastric cancer detection and its effect on gastric cancer cell proliferation and migration

Ke Yi1† Yan Hu1† Xiaoli Zhu2† Qing Li2*
Show Less
1 Central Laboratory, The First People’s Hospital of Taicang, Soochow Medical College of Soochow University, Taicang Affiliated Hospital of Soochow University, Suzhou, China
2 Department of Gastroenterology, The First People’s Hospital of Taicang, Soochow Medical College of Soochow University, Taicang Affiliated Hospital of Soochow University, Suzhou, China
Tumor Discovery 2024, 3(1), 1973
Submitted: 28 September 2023 | Accepted: 12 January 2024 | Published: 26 March 2024
© 2024 by the Author (s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

The present study aimed to investigate the association between matrix metalloproteinase-1 (MMP-1) and early gastric cancer (EGC), while also evaluating the effect of MMP-1 on gastric cancer cell proliferation and migration. Transcriptome RNA sequencing and database analysis were conducted to assess the relationship between MMP-1 expression and EGC. Differences in MMP-1 expression between clinical EGC samples and paracancerous tissues were detected using fluorescence quantitative polymerase chain reaction (PCR). In N87 gastric cancer cells, changes in proliferation- and migration-related indicator expression were determined. Gene sequencing revealed differential expression of MMP-1 in early and advanced gastric cancers. Furthermore, enhanced MMP-1 expression was observed in early and advanced gastric cancer tissues, exhibiting a positive correlation with the malignant phenotype in gastric cancer cell lines. Fluorescence quantitative PCR revealed considerably higher MMP-1 expression in EGC tissues than in paracancerous tissues. CCK8 and EdU assays demonstrated a significant increase in N87 cell proliferation on MMP-1 upregulation and a decrease on its downregulation. The scratch assay results demonstrated a corresponding enhancement in N87 cell migratory capacity with MMP-1 upregulation, which was attenuated on its downregulation. Western blot experiments revealed a decrease in the expression of the epithelial-mesenchymal transition-related protein E-cadherin after MMP-1 upregulation, while vimentin expression significantly increased. Conversely, the downregulation of MMP-1 led to opposite outcomes. Overall, MMP-1 emerges as a potential biomarker for EGC diagnosis and plays a crucial role in the regulation of N87 gastric cancer cell proliferation and migration.

Gastric cancer
Early diagnosis
This study was supported by the guiding projects of the Suzhou Science and Technology Bureau (SYSD2019036), the Taicang Science and Technology Bureau (TC2019JCYL18), and the Taicang Science and Technology Bureau (TC2018JCYL20).

1. Rahman R, Asombang AW, Ibdah JA. Characteristics of gastric cancer in Asia. World J Gastroenterol. 2014;20(16):4483-4490. doi: 10.3748/wjg.v20.i16.4483


2. Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric cancer: Epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci. 2020;21(11):4012. doi: 10.3390/ijms21114012


3. Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet. 2016;388(10060):2654-2664. doi: 10.1016/s0140-6736(16)30354-3


4. Yang MD, Lin KC, Lu MC, et al. Contribution of matrix metalloproteinases-1 genotypes to gastric cancer susceptibility in Taiwan. BioMedicine (Taipei). 2017;7(2):10. doi: 10.1051/bmdcn/2017070203


5. Cui N, Hu M, Khalil RA. Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci. 2017;147:1-73. doi: 10.1016/bs.pmbts.2017.02.005


6. Tsai CW, Chang WS, Gong CL, et al. Contribution of matrix metallopeptidase-1 genotypes, smoking, alcohol drinking and areca chewing to nasopharyngeal Carcinoma susceptibility. Anticancer Res. 2016;36(7):3335-3340.


7. 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):255-272. doi: 10.1089/dna.2019.5129


8. Peng Q, Xu Y. Association between promoter polymorphisms of matrix metalloproteinase-1 and risk of gastric cancer. Onco Targets Ther. 2015;8:2519-2526. doi: 10.2147/ott.S83004


9. Scheau C, Badarau IA, Costache R, et al. The role of matrix metalloproteinases in the epithelial-mesenchymal transition of hepatocellular carcinoma. Anal Cell Pathol (Amst). 2019;2019:9423907. doi: 10.1155/2019/9423907


10. Wang X, Khalil RA. Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol. 2018;81:241-330. doi: 10.1016/bs.apha.2017.08.002


11. Moracho N, Learte AIR, Muñoz-Sáez E, et al. Emerging roles of MT-MMPs in embryonic development. Dev Dyn. 2022;251(2):240-275. doi: 10.1002/dvdy.398


12. Kassiri Z, Khokha R. Myocardial extra-cellular matrix and its regulation by metalloproteinases and their inhibitors. Thromb Haemost. 2005;93(2):212-219. doi: 10.1160/th04-08-0522


13. Craig VJ, Zhang L, Hagood JS, Owen CA. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2015;53(5): 585-600. doi: 10.1165/rcmb.2015-0020TR


14. Grillet B, Pereira RVS, Van Damme J, Abu El-Asrar A, Proost P, Opdenakker G. Matrix metalloproteinases in arthritis: Towards precision medicine. Nat Rev Rheumatol. 2023;19(6):363-377. doi: 10.1038/s41584-023-00966-w


15. Nissinen L, Kähäri VM. Matrix metalloproteinases in inflammation. Biochim Biophys Acta. 2014;1840(8):2571-2580. doi: 10.1016/j.bbagen.2014.03.007


16. Xie J, Zhou X, Wang R, et al. Identification of potential diagnostic biomarkers in MMPs for pancreatic carcinoma. Medicine (Baltimore). 2021;100(23):e26135. doi: 10.1097/md.0000000000026135


17. Lopez-Navarro ER, Gutierrez J. Metalloproteinases and their inhibitors in neurological disease. Naunyn Schmiedebergs Arch Pharmacol. 2022;395(1):27-38. doi: 10.1007/s00210-021-02188-x


18. Bassiouni W, Ali MAM, Schulz R. Multifunctional intracellular matrix metalloproteinases: Implications in disease. FEBS J. 2021;288(24):7162-7182. doi: 10.1111/febs.15701


19. Kapoor C, Vaidya S, Wadhwan V, Hitesh, Kaur G, Pathak A. Seesaw of matrix metalloproteinases (MMPs). J Cancer Res Ther. 2016;12(1):28-35. doi: 10.4103/0973-1482.157337


20. Jiang H, Li H. Prognostic values of tumoral MMP2 and MMP9 overexpression in breast cancer: A systematic review and meta-analysis. BMC Cancer. 2021;21(1):149. doi: 10.1186/s12885-021-07860-2


21. Shakery T, Safari F. Downregulation of PINKBAR/pAKT and MMP2/MMP9 expression in MDA-MB-231 breast cancer cells as potential targets in cancer therapy by hAMSCs secretome. Cells Tissues Organs. 2023;212(2):155-163. doi: 10.1159/000520370


22. Wang X, Wang B, Xie J, Hou D, Zhang H, Huang H. Melatonin inhibits epithelialtomesenchymal transition in gastric cancer cells via attenuation of IL1β/NFκB/MMP2/ MMP9 signaling. Int J Mol Med. 2018;42(4):2221-2228. doi: 10.3892/ijmm.2018.3788


23. Rani V, Yadav D, Atale N. Matrixmetalloproteinase inhibitors: Promising therapeutic targets against cancer. Curr Pharm Des. 2021;27(45):4557-4567. doi: 10.2174/1381612827666210830103059


24. Yang C, Gong A. Integrated bioinformatics analysis for differentially expressed genes and signaling pathways identification in gastric cancer. Int J Med Sci. 2021;18(3):792-800. doi: 10.7150/ijms.47339


25. Xu J, Changyong E, Yao Y, Ren S, Wang G, Jin H. Matrix metalloproteinase expression and molecular interaction network analysis in gastric cancer. Oncol Lett. 2016;12(4):2403-2408. doi: 10.3892/ol.2016.5013


26. 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. doi: 10.3892/mmr.2012.849


27. Chen YJ, Liang L, Li J, et al. IRF-2 inhibits gastric cancer invasion and migration by down-regulating MMP-1. Dig Dis Sci. 2020;65(1):168-177. doi: 10.1007/s10620-019-05739-8


28. Liu M, Hu Y, Zhang MF, et al. MMP1 promotes tumor growth and metastasis in esophageal squamous cell

carcinoma. Cancer Lett. 2016;377(1):97-104. doi: 10.1016/j.canlet.2016.04.034


29. 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 Bioll Res. 2012;45(1):86-92. doi: 10.1590/s0100-879x2011007500152


30. Zhou J, Xu M, Tan J, Zhou L, Dong F, Huang T. MMP1 acts as a potential regulator of tumor progression and dedifferentiation in papillary thyroid cancer. Front Oncol. 2022;12:1030590. doi: 10.3389/fonc.2022.1030590


31. Shen Q, Polom K, Williams C, et al. A targeted proteomics approach reveals a serum protein signature as diagnostic biomarker for resectable gastric cancer. EBioMedicine. 2019;44:322-333. doi: 10.1016/j.ebiom.2019.05.044


32. Wang K, Zheng J, Yu J, et al. Knockdown of MMP1 inhibits the progression of colorectal cancer by suppressing the PI3K/Akt/cmyc signaling pathway and EMT. Oncol Rep. 2020;43(4):1103-1112. doi: 10.3892/or.2020.7490


33. Kumar P, Sebastian A, Verma K, et al. mRNA expression analysis of E-cadherin, VEGF, and MMPs in gastric cancer: A pilot study. Indian J Surg Oncol. 2021;12(Suppl 1):85-92. doi: 10.1007/s13193-020-01096-5


34. Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol. 2018;24(26):2818-2832. doi: 10.3748/wjg.v24.i26.2818


35. Sun Y, Jin J, Jing H, et al. ITIH4 is a novel serum biomarker for early gastric cancer diagnosis. Clin Chim Acta. 2021;523:365-373. doi: 10.1016/j.cca.2021.10.022


36. Wu D, Zhang P, Ma J, et al. Serum biomarker panels for the diagnosis of gastric cancer. Cancer Med. 2019;8(4):1576-1583. doi: 10.1002/cam4.2055


37. Guo X, Peng Y, Song Q, et al. A liquid biopsy signature for the early detection of gastric cancer in patients. Gastroenterology. 2023;165(2):402-413.e13. doi: 10.1053/j.gastro.2023.02.044


38. Zheng L, Wu C, Xi P, et al. The survival and the long-term trends of patients with gastric cancer in Shanghai, China. BMC Cancer. 2014;14:300. doi: 10.1186/1471-2407-14-300


39. Yang J, Bo L, Han T, Ding D, Nie M, Yin K. Pathway-and clinical-factor-based risk model predicts the prognosis of patients with gastric cancer. Mol Med Rep. 2018;17(5):6345-6356. doi: 10.3892/mmr.2018.8722


40. Chrom P, Stec R, Szczylik C. Second-line treatment of advanced gastric cancer: Current options and future perspectives. Anticancer Res. 2015;35(9):4575-4583.


41. Wang X, Deng J, Liang H. Well differentiated carcinoma with a poor prognosis: A retrospective analysis of papillary gastric adenocarcinoma. Surg Today. 2021;51(8):1387-1396. doi: 10.1007/s00595-021-02289-3


42. Digklia A, Wagner AD. Advanced gastric cancer: Current treatment landscape and future perspectives. World J Gastroenterol. 2016;22(8):2403-2414. doi: 10.3748/wjg.v22.i8.2403


43. Wei R, Du X, Wang J, et al. Risk and prognosis of subsequent primary gastric cancer. Oncol Res Treat. 2022;45(4):186-196. doi: 10.1159/000521846


44. Chang JY, Shim KN, Tae CH, et al. Comparison of clinical outcomes after endoscopic submucosal dissection and surgery in the treatment of early gastric cancer: A single-institute study. Medicine (Baltimore). 2017;96(30):e7210. doi: 10.1097/md.0000000000007210


45. Kumar S, Katona BW, Long JM, et al. Endoscopic ultrasound has limited utility in diagnosis of gastric cancer in carriers of CDH1 mutations. Clin Gastroenterol Hepatol. 2020;18(2):505-508.e1. doi: 10.1016/j.cgh.2019.04.064


46. Wang F, Hu D, Lou X, et al. BNIP3 and DAPK1 methylation in peripheral blood leucocytes are noninvasive biomarkers for gastric cancer. Gene. 2024;898:148109. doi: 10.1016/j.gene.2023.148109


47. Hu D, Lou X, Meng N, et al. Peripheral blood-based DNA methylation of long non-coding RNA H19 and metastasis-associated lung adenocarcinoma transcript 1 promoters are potential non-invasive biomarkers for gastric cancer detection. Cancer Control. 2021;28:10732748211043667. doi: 10.1177/10732748211043667


48. Fan H, Li X, Li ZW, et al. Urine proteomic signatures predicting the progression from premalignancy to malignant gastric cancer. EBioMedicine. 2022;86:104340. doi: 10.1016/j.ebiom.2022.104340


49. Kao HW, Pan CY, Lai CH, et al. Urine miR-21-5p as a potential non-invasive biomarker for gastric cancer. Oncotarget. 2017;8(34):56389-56397. doi: 10.18632/oncotarget.16916


50. Hoshino I. The usefulness of microRNA in urine and saliva as a biomarker of gastroenterological cancer. Int J Clin Oncol. 2021;26(8):1431-1440. doi: 10.1007/s10147-021-01911-1


51. Miyamoto S, Watanabe Y, Oikawa R, et al. Analysis of helicobacter pylori genotypes in clinical gastric wash samples. Tumour Biol. 2016;37(8):10123-10132. doi: 10.1007/s13277-016-4886-4


52. Chae HD, Kim IH. Prognostic significance of CEA expression by RT-PCR in peritoneal wash from patients with gastric cancer: Result of a 5-year follow-up after curative resection. Scand J Gastroenterol. 2016;51(8):956-960. doi: 10.3109/00365521.2016.1172339


53. Zhou X, Liu J, Meng A, et al. Gastric juice piR-1245: A promising prognostic biomarker for gastric cancer. J Clin Lab Anal. 2020;34(4):e23131. doi: 10.1002/jcla.23131


54. Pan Y, Zheng Y, Yang J, et al. A new biomarker for the early diagnosis of gastric cancer: Gastric juice-and serum-derived SNCG. Future Oncol. 2022;18(28):3179-3190. doi: 10.2217/fon-2022-0253


55. Lopes C, Chaves J, Ortigão R, Dinis-Ribeiro M, Pereira C. Gastric cancer detection by non-blood-based liquid biopsies: A systematic review looking into the last decade of research. United European Gastroenterol J. 2023;11(1):114-130. doi: 10.1002/ueg2.12328


56. Enríquez-Sánchez LB, Gallegos-Portillo LG, Camarillo- Cisneros J, et al. Cost-benefit of serum pepsinogen screening for gastric adenocarcinoma in the Mexican population. Rev Gastroenterol Mexico (Eng Ed). 2022;87(3):285-291. doi: 10.1016/j.rgmxen.2021.11.002


57. Machii R, Takahashi H. Japanese cancer screening programs during the COVID-19 pandemic: Changes in participation between 2017-2020. Cancer Epidemiol. 2023;82:102313. doi: 10.1016/j.canep.2022.102313


58. Cesaretti M, Bian AZL. In vivo medical imaging technologies: New possibility in diagnosis of gastric cancer. Minerva Chir. 2016;71(4):270-277.


59. Zhu SL, Dong J, Zhang C, Huang YB, Pan W. Application of machine learning in the diagnosis of gastric cancer based on noninvasive characteristics. PLoS One. 2020;15(12):e0244869. doi: 10.1371/journal.pone.0244869


60. Thapa S, Fischbach LA, Delongchamp R, Faramawi MF, Orloff MS. Using machine learning to predict progression in the gastric precancerous process in a population from a developing country who underwent a gastroscopy for dyspeptic symptoms. Gastroenterol Res Pract. 2019;2019:8321942. doi: 10.1155/2019/8321942


61. Leja M, Linē A. Early detection of gastric cancer beyond endoscopy-new methods. Best Pract Res Clin Gastroenterol. 2021;50-51:101731. doi: 10.1016/j.bpg.2021.101731


62. Qian Z, Wang J. Application of computed tomography imaging in diagnosis of endocrine nerve of gastric cancer and nursing intervention effect. World Neurosurg. 2021;149:341-351. doi: 10.1016/j.wneu.2020.10.005


63. Rezaei Z, Ranjbaran J, Safarpour H, et al. Identification of early diagnostic biomarkers via WGCNA in gastric cancer. Biomed Pharmacother. 2022;145:112477. doi: 10.1016/j.biopha.2021.112477


64. Numakura S, Uozaki H. Low MLL2 protein expression is associated with fibrosis in early stage gastric cancer. In Vivo. 2021;35(1):603-609. doi: 10.21873/invivo.12297


65. Guan X. Cancer metastases: Challenges and opportunities. Acta Pharm Sin B. 2015;5(5):402-418. doi: 10.1016/j.apsb.2015.07.005


66. Fu BM. Tumor metastasis in the microcirculation. Adv Exp Med Biol. 2018;1097:201-218. doi: 10.1007/978-3-319-96445-4_11


67. Guo S, Huang J, Li G, Chen W, Li Z, Lei J. The role of extracellular vesicles in circulating tumor cell-mediated distant metastasis. Mol Cancer. 2023;22(1):193. doi: 10.1186/s12943-023-01909-5


68. Burr R, Gilles C, Thompson EW, Maheswaran S. Epithelial-mesenchymal plasticity in circulating tumor cells, the precursors of metastasis. Adv Exp Med Biol. 2020;1220:11-34. doi: 10.1007/978-3-030-35805-1_2


69. Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019;29(3):212-226. doi: 10.1016/j.tcb.2018.12.001


70. Fiori ME, Di Franco S, Villanova L, Bianca P, Stassi G, De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol Cancer. 2019;18(1):70. doi: 10.1186/s12943-019-0994-2


71. Zhang Y, Weinberg RA. Epithelial-to-mesenchymal transition in cancer: Complexity and opportunities. Front Med. 2018;12(4):361-373. doi: 10.1007/s11684-018-0656-6


72. Phillips RM, Lam C, Wang H, Tran PT. Bittersweet tumor development and progression: Emerging roles of epithelial plasticity glycosylations. Adv Cancer Res. 2019;142:23-62. doi: 10.1016/bs.acr.2019.01.002


73. Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol. 2020;30(10):764-776. doi: 10.1016/j.tcb.2020.07.003


74. Zhang W, Huang X, Huang R, et al. MMP1 overexpression promotes cancer progression and associates with poor outcome in head and neck carcinoma. Comput Math Methods Med. 2022;2022:3058342. doi: 10.1155/2022/3058342


75. Tian R, Li X, Gao Y, Li Y, Yang P, Wang K. Identification and validation of the role of matrix metalloproteinase-1 in cervical cancer. Int J Oncol. 2018;52(4):1198-1208. doi: 10.3892/ijo.2018.4267


76. Du L, Liu N, Jin J, et al. ZNF3 regulates proliferation, migration and invasion through MMP1 and TWIST in colorectal cancer. Acta Biochim Biophys Sin (Shanghai). 2022;54(12):1889-1896. doi: 10.3724/abbs.2022187


77. Cierna Z, Mego M, Janega P, et al. Matrix metalloproteinase 1 and circulating tumor cells in early breast cancer. BMC Cancer. 2014;14:472. doi: 10.1186/1471-2407-14-472


78. Zhu Y, Tao Z, Chen Y, et al. Exosomal MMP-1 transfers metastasis potential in triple-negative breast cancer through PAR1-mediated EMT. Breast Cancer Res Treat. 2022;193(1):65-81. doi: 10.1007/s10549-022-06514-6

Conflict of interest
The authors declare that they have no competing interests.
Back to top
Tumor Discovery, Electronic ISSN: 2810-9775 Published by AccScience Publishing