Author(s): Sukhbir Singh, Neha Kanojia, Ikmeet Kaur Grewal, Neelam Sharma, Deepshikha, Sandeep Arora, Ajmer Singh Grewal

Email(s): ,

DOI: 10.5958/0974-360X.2020.00612.5   

Address: Sukhbir Singh, Neha Kanojia, Ikmeet Kaur Grewal, Neelam Sharma, Deepshikha, Sandeep Arora, Ajmer Singh Grewal*
Chitkara College of Pharmacy, Chitkara University, Punjab, India.
*Corresponding Author

Published In:   Volume - 13,      Issue - 7,     Year - 2020

Proteases expressed in healthy cells are significant for performing necessary biological functions. There exists equilibrium among proteases and anti-proteases in living systems, thus interruption of equilibrium results in numerous disorders such as cancer. One of the signs of cancer development is proteolysis due to dysregulation of proteases. All five categories of proteases including cysteine, aspartate, threonine, matrix metalloproteases and serine have been associated with solid tumor instigation, growth, development, invasiveness and metastasis. The set of genes expressed in neoplasm development is well-known as cancer ‘degradome’. Transmembrane protease serine 4 (TMPRSS4), a novel type II transmembrane serine protease present at the cellular membrane is upregulated in numerous kinds of human carcinoma and have an irreplaceable role in tumor development. Hepsin, matriptase and TMPRSS2 are other cancer-associated proteases interconnected to TMPRSS4.TMPRSS4 can be used as an emerging therapeutic drug target in human malignant neoplasms as over expression of TMPRSS4 contribute significantly in processes of cancer development including vascularization, metastasis and invasion. Nevertheless, the biological function of TMPRSS4 in solid tumors continues to be ambiguous. In this review, we will discuss about physiological function, gene expression, clinical significance and regulation mechanism of TMPRSS4 in cancer development. Our study provides the rationale for targeting TMPRSS4 in cancer.

Cite this article:
Sukhbir Singh, Neha Kanojia, Ikmeet Kaur Grewal, Neelam Sharma, Deepshikha, Sandeep Arora, Ajmer Singh Grewal. Transmembrane protease serine 4: An emergent diagnostic biomarker and Therapeutic drug target for cancer. Research J. Pharm. and Tech. 2020; 13(7): 3449-3453. doi: 10.5958/0974-360X.2020.00612.5

Sukhbir Singh, Neha Kanojia, Ikmeet Kaur Grewal, Neelam Sharma, Deepshikha, Sandeep Arora, Ajmer Singh Grewal. Transmembrane protease serine 4: An emergent diagnostic biomarker and Therapeutic drug target for cancer. Research J. Pharm. and Tech. 2020; 13(7): 3449-3453. doi: 10.5958/0974-360X.2020.00612.5   Available on:

1. Hu Y and Fu L. Targeting cancer stem cells: a new therapy to cure cancer patients. American Journal of Cancer Research. 2012;2(3):340-356.
2. Tiwari RK, et al. Stem cells: basics and its prospective uses in medical field. Research Journal of Pharmacy and Technology. 2018; 11(4): 1530-1534.
3. Reya T, et al. Stem cells, cancer, and cancer stem cells. Nature. 2001; 414(6859): 105-111.
4. Diksha and Patyar S. Role of stem cells in treatment of different diseases. Research Journal of Pharmacy and Technology. 2018; 11(8): 3667-3678.
5. Nag MK, et al. Lung cancer targeting: a review. Research Journal of Pharmacy and Technology. 2013; 6(11): 1302-1306.
6. Bhasker S, Sandeep G and Ranganath YS. Future of cancer therapy-COX-2 inhibitors: a review. Research Journal of Pharmacy and Technology. 2009; 2(4): 617-620.
7. Nirisha S, Gheena S and Samrithi Y. Effects of turmeric on oral submucous fibrosis: a systematic review. Research Journal of Pharmacy and Technology. 2015; 8(8): 1051-1055.
8. Rathee D, et al. Enzymatic inhibitory activity of iridoid glycosides from Picrorrhiza kurroa against matrix metalloproteinases: correlating in vitro targeted screening and docking. Computational Biology and Chemistry. 2019; 78: 28-36.
9. Aberasturi AL and Calvo A. TMPRSS4: an emerging potential therapeutic target in cancer. British Journal of Cancer. 2015; 112: 4-8.
10. Lopez-Otin C and Overall CM. Protease degradomics: a new challenge for proteomics. Nature Reviews Molecular Cell Biology. 2002;3(7):509-519.
11. Rakashanda S, et al. Role of proteases in cancer: a review. Biotechnology and Molecular Biology Review. 2012; 7(4): 90-101.
12. Puente XS, et al. Human and mouse proteases: a comparative genomic approach. Nature Reviews Genetics. 2003; 4(7):544-558.
13. Subash VK, et al. Nail toxicity induced by cancer chemotherapy patients: data from the two multispecialty hospital. Research Journal of Pharmacy and Technology. 2015; 8(1): 20-26.
14. Quesada V, et al. The Degradome database: mammalian proteases and diseases of proteolysis. Nucleic Acids Research. 2009; 37:D239-D243.
15. Al-Mehdi AB, et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nature Medicine. 2000; 6(2):100-102.
16. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nature Medicine. 2006; 12(8):895-904.
17. Jung H, et al. TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition. Oncogene. 2008; 27(18): 2635-2647.
18. Duffy MJ. Proteases as prognostic markers in cancer. Clinical Cancer Research. 1996; 2()4: 613-618.
19. Andreasen PA, et al. The urokinase-type plasminogen activator system in cancer metastasis: a review. International Journal of Cancer. 1997; 72(1): 1-22.
20. Stetler-Stevenson WG and Yu AE. Proteases in invasion: matrix metalloproteinases. Seminars in Cancer Biology. 2001; 11(2): 143-152.
21. Egeblad M and Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer.2002; 2(3): 161-174.
22. Deryugina EI and Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Reviews. 25(1): 9-34.
23. Netzel-Arnett S, et al. Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer. Cancer Metastasis Reviews. 2003; 22(2-3): 237-258.
24. Szabo R and Bugge TH. Type II transmembrane serine proteases in development and disease. International Journal of Biochemistry and Cell Biology. 2008; 40(6-7): 1297-1316.
25. Wallrapp C, et al. A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer. Cancer Research. 2000; 60(10): 2602-2606.
26. Gene: TMPRSS4. Available from: URL: index.html.
27. Lopez-Otin C and Bond JS. Proteases: multifunctional enzymes in life and disease. Journal of Biological Chemistry. 2008; 283(45):30433-30437.
28. Singh P, et al. Synthesis and evaluation of a series of caffeic acid derivatives as anticancer agents. Future Journal of Pharmaceutical Sciences. 2018; 4(2): 124-130. 
29. Lopez-Otin C and Matrisian LM. Emerging roles of proteases in tumour suppression. Nature Reviews Cancer. 2007; 7(10):800-808.
30. Mason SD and Joyce JA. Proteolytic networks in cancer. Trends in Cell Biology. 2011; 21(4):228-237.
31. Bertram S, et al. Novel insights into proteolytic cleavage of influenza virus hemagglutinin. Reviews in Medical Virology. 2010; 20(5): 298-310.
32. Passero CJ, et al. TMPRSS4-dependent activation of the epithelial sodium channel requires cleavage of the gamma-subunit distal to the furin cleavage site. American Journal of Physiology-Renal Physiology. 2012; 302(1): F1-F8.
33. Min HJ, et al. TMPRSS4 induces cancer cell invasion through pro-uPA processing. Biochemical and Biophysical Research Communications. 2014; 446(1): 1-7.
34. Ohler A and Beker-Pauly C.TMPRSS is a type II transmembrane serine protease involved in cancer and viral infections. Biological Chemistry. 2012; 393(9): 907-914.
35. Chaipan C, et al. Proteolytic activation of the 1918 influenza virus hemagglutinin. Journal of Virology. 2009; 83: 3200-3211.
36. Kebebew E, et al. ECM1 and TMPRSS4 are diagnostic markers of malignant thyroid neoplasms and improve the accuracy of fine needle aspiration biopsy. Annals of Surgery. 2005; 242(3): 353-353.
37. Choi SY, et al. Role of TMPRSS4 during cancer progression. Drug News and Perspectives. 2008; 21(8): 417-423.
38. Jung H, et al. TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition. Oncogene. 2008;27(18): 2635-2647.
39. Kim S, et al. TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin α5 and its signaling pathways. Carcinogenesis.2010; 31(4): 597-606.
40. Rathee D, et al. Targeting matrix metalloproteinases with novel diazepine substituted cinnamic acid derivatives: design, synthesis, in vitro and in silico studies. Chemistry Central Journal. 2018; 12(1): 41.
41. Li T, et al. Radiation enhances long-term metastasis potential of residual hepatocellular carcinoma in nude mice through TMPRSS4-induced epithelial-mesenchymal transition. Cancer Gene Therapy. 2011; 18(9): 617-626.
42. Jia JB, et al. A novel tripeptide, tyroserleutide, inhibits irradiation-induced invasiveness and metastasis of hepatocellular carcinoma in nude mice. Investigational New Drugs.2011; 29(5): 861-872.
43. Lahiry P, et al. A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder. Orphanet Journal of Rare Diseases. 2013; 8: 126.
44. Hamamoto J, et al. Methylation-induced downregulation of TFPI-2 causes TMPRSS4 overexpression and contributes to oncogenesis in a subset of non-small-cell lung carcinoma. Cancer Science. 2015; 106: 34-42.
45. de Aberasturi AL, et al. TMPRSS4 induces cancer stem cell-like properties in lung cancer cells and correlates with ALDH expression in NSCLC patients. Cancer Letters. 2016; 370(2): 165-176.
46. Ahirwar D, Ahirwar B and Chandy A. Microspheres for targeting an alkaloidal anticancer drug in colon cancer. Research Journal of Pharmacy and Technology. 2013; 6(6): 618-621.
47. Guan H, et al. Transmembrane protease serine 4 promotes thyroid cancer proliferation via CREB phosphorylation. Thyroid. 2015; 25(1): 85-94.
48. Larzabal L, et al. Overexpression of TMPRS4 in non small cell lung cancer is associated with poor prognosis in patients with squamous histology. British Journal of Cancer.2011;105(10):1608-1614.
49. Ohler A and Becker-Pauly C. Morpholino knockdown of the ubiquitously expressed transmembrane serine protease TMPRSS4a in zebrafish embryos exhibits severe defects in organogenesis and cell adhesion. Biological Chemistry. 2011; 392(7):653-664.
50. Takahashi T, Uehara H and Izumi K. Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and utility of TMPRSS4 as a combinatorial molecular target. International Journal of Oncology. 2013; 43(2): 416-424.
51. Cheng D, Liang B and Li Y. High TMPRSS4 expression is a predictor of poor prognosis in cervical squamous cell carcinoma. Cancer Epidemiology. 2013; 37(6): 993–997.
52. Mayasa V, et al. Tolerability assessment and anti cancer activity of the partially purified protease inhibitors from Soyabean (Glycine max) orally administered to rats. Research Journal of Pharmacy and Technology. 2016; 9(7):925-928.
53. Liang B, et al. Prognostic value of TMPRSS4 expression in patients with breast cancer. Medical Oncology. 2013; 30(2): 497
54. Wu XY, et al. Clinical implication of TMPRSS4 expression in human gallbladder cancer. Tumor Biology. 2014; 35(6): 5481-5486.
55. Luo ZY, et al. The expression of TMPRSS4 and ERK1 correlates with metastasis and poor prognosis in Chinese patients with gastric cancer. PLoS One. 2013; 8(7): e70311.
56. Sheng H, et al. Prognostic significance of TMPRSS4 in gastric cancer. Neoplasma. 2014; 61(2): 213-217.
57. Stefanska B, et al. Definition of the landscape of promoter DNA hypomethylation in liver cancer. Cancer Research. 2011; 71(17): 5891-5903.
58. Huang A, et al. High expression level of TMPRSS4 predicts adverse outcomes of colorectal cancer patients. Medical Oncology. 2013; 30(4): 712.
59. Kalyankar TM, et al. Application of nanotechnology in cancer treatment. Research Journal of Pharmacy and Technology. 2012; 5(9): 1161-1167.
60. Dai W, et al. Expression of TMPRSS4 in patients with salivary adenoid cystic carcinoma: correlation with clinicopathological features and prognosis. Medical Oncology. 2013; 30(4): 749.
61. LarzabalL, et al.TMPRSS4 regulates levels of integrin α5 in NSLC through miR-205 activity to promote metastatsis. British Journal of Cancer. 2014;110(3): 764-774.
62. Pagare MS, et al. Human milk: excellent anticancer alternative. Research Journal of Pharmacy and Technology. 2012; 5(1): 14-19.
63. Park YW, et al. Anticancer drug comprising inhibitor of TMPRSS4. United States Patents US00877901B2.Jul 15, 2014.
64. Chikaishi Y, et al. TMPRSS4 expression as a marker of recurrence in patients with lung cancer. Anticancer Research. 2016; 36(1):121-127.
65. Kang S, et al. Discovery of novel 2-hydroxydiarylamide derivatives as TMPRSS4 inhibitors. Bioorganic and Medicinal Chemistry Letters. 2013; 23(6): 1748-1751.
66. Kim S, et al. Anti-cancer activity of the novel 2-hydroxydiarylamide derivatives IMD-0354 and KRT1853 through suppression of cancer cell invasion, proliferation, and survival mediated by TMPRSS4.Scientific Reports.2019; 9: 10003.

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.5958/0974-360X 

56th percentile
Powered by  Scopus

SCImago Journal & Country Rank

Recent Articles


Not Available