INTRODUCTION:

Stem cells are special undifferentiated biological cells that can differentiate and divide (through mitosis) to produce more stem cells. Cancer stem cells (CSCs) are cells within the tumor that can self-renew and cause the heterogeneous cancer cell lineages in solid tumors. Nowadays, human malignancy remains a major cause of mortality in the world^1-4. Because of toxic effects owing to non-specificity on normal cells and failure to target cancer stem cells all of the conventional cancer therapies such as anti-angiogenic therapy, hormonal therapy, immunotherapy and surgery indicate a deficit of effectiveness for long term use.

On other hand, there is an urgent need for development of treatment modalities which are used to identify cancer stem cells and target them^5-8. Over expression and activity levels of proteases plays major role in the development of cancer, with regard to alteration of the extracellular matrix, metastasis and invasion⁹. The mechanism of proteolysis is favored by hydrolysis of specific peptide bonds. Proteases are a diverse and important group of enzymes involved in proteolytic activity¹⁰. The human degradome contains information about 569 proteases and their cognates classified into five groups based on mechanism of catalysis:150 cysteine, 176 serine, 194 metallo, 21 aspartic and 28 threonine proteases although not all of them have been associated with cancer^11-14. A healthy cell has to go through multiple alterations to get transformed, thus undergone metamorphosis after erasgiving rise to mass localization and at last penetration by cancer cells into other tissues and metastasize^15-16.

In cancer invasion and metastasis, extracellular proteolytic enzymes, such as serine proteases and matrix metalloproteinases (MMPs) have an important role toplay^17-18. At some instance, epithelial mesenchymal transformations also take place in the cancerous cell at certain time. The epithelial–mesenchymal transition is an important process by means of which epithelial cells losing out their cell polarity and cell-cell adhesion, and acquires migratory and invasive characteristics to become mesenchymal stem cells. Epithelial mesenchymal transition is associated with breakdown of intercellular network and the amplification of motility of individual cells, therefore releasing of cells from the parent epithelial tissue¹⁹. As a result, mesenchyme-like phenotype promotes cell migration and invasion that leads to tumor cell dissemination, permitting development of metastasis. It is well known that proteases play an important role in degradation of extracellular matrix, the basement membrane and tissue remodeling. Proteases by virtue of direct proteolytic activity as well as regulation of cellular functions and processes make a major contribution in cancer development and progression, comprising tumor growth, survival, invasion, migration, vascularization and metastasis^20-22. Though cancer cells do not generally expressed proteases. At some time, cancerous cells stimulate the expression of proteolytic enzymes in anti-neoplastic cells, apprehending their activity to sustain neoplasm growth. Serine proteases are classified into three groups type I, type II and type III based on transmembrane structure. Type II consists of 20 members which are subdivided into four subfamilies; transmembrane protease/serine, hepsin, HAT/DESC (differentially implicated in squamous cell carcinomas) andmatriptase^23-24. Furthermore, in this review, we will discuss regarding biological role, composition, catalytic action, prominence and prognostic value of transmembrane protease serine 4 (TMPRSS4) in carcinomas, hence relevance of the membrane bounded transmembrane serine protease is to be reconnoitered as part of novel cancer treatment.

Biology of TMPRSS4:

TMPRSS4, a single-pass type 2 membrane bound protein is regarded as an unprecedented serine protease. TMPRSS4, originally designated as TMPRSS3 mapped in the stretched chromosomal arm 11 (11q23.3)²⁵. The genomic structure of TMPRSS4 gene includes 48,597 base pairs, containing 12 introns and 13 exons. TMPRSS4 gene can generate eighteen different transcripts, 2 of are ruined owing to nonsense-mediated decay and eight of them do not produce a protein as a product²⁶. Out of the rest eight transcripts, three possess incomplete coding sequence (CDS) in 5′ or 3′, moreover do not hold start or stop codon sequences. As a result, the TMPRSS4 gene codes only for 5 isoenzymes having complete CDS. The canonic protein (TMPRSS4-1) is made up of 437 amino acids (with a predictive size of 48kDa and two glycosylation sites at 130 and 178 amino acids), whereas isoenzymes 2 and 3 vary in five or two amino acids, accordingly^27-30. TMPRSS4 substrates or interacting proteins in humans are still under investigation, three proteins have been recognized yet: (a) viral infection is caused due to hemagglutinin of the influenza virus, (b) cancer cell invasion is enhanced by activation of the urokinase-type plasminogen activator (uPA) and (c) On cleavage of the γ subunit, the epithelial sodium channel^31-32. Cells in culture can release the active TMPRSS4 protease domain and originate in the conditioned medium³³. Therefore, TMPRSS4 might be proposed as an emergent diagnostic biomarker because of the anticipation that soluble protein fragments may be identified in serum of cancer bearing patients.

TMPRSS4 as a pro-metastatic enzyme:

Initially, TMPRSS4 was recognized as a gene encoded in the majority of pancreatic tumors except in the healthy tissue. The mRNA was identified in stomach, esophagus, small intestine, kidney, colon, bladder, lung, skin, and eye in humans^25,34-35. Moreover, in tumors of lung, thyroid, liver, ovarian, colon and in gastric cancer tissues TMPRSS4 is highly expressed, thus stimulating cancer cell proliferation, invasion, migration and metastasis by assisting an epithelial to mesenchymal transition, an essential step throughout metastasis^36-37. The epithelial cadherins on the surface of one cell can bind with those of the same kind on another to form networks. TMPRSS4 persuades the degradation of E-cadherin, promoting epithelial to mesenchymal transition events comprising actin reorganization and morphological changes in colon cancer cells. [30] In addition, over expression of TMPRSS4 is associated with human colorectal carcinoma with enhanced expression of integrin-α5 and has revealed a crucial role in metastatic hepatocellular carcinoma as well as radiation-provoked long lasting dissemination^39-41. Furthermore, Jia and coworkers demonstrated that tyroserleutide, an inhibitory compound diminish the progress of cancerous cells in malignant hepatoma via down regulating the expression of TMPRSS4 protein⁴².

Biological role of TMPRSS4 in cancer:

A transposition in the TMPRSS4 gene has related with autosomal recessive cerebral atrophy (ARCA) disease but biological role of TMPRSS4 is still not recognized, due to such wide expression outline in tumor, TMPRSS4 have been spotlight of anti-neoplastic investigations today⁴³. Cell proliferation in lung and thyroid carcinomas has been revealed to be upgraded by TMPRSS4, although TMPRSS4 targeting with shRNA accounts for abatement in cancer development and progression^44-47. Despite of the fact that the physiological substrates for TMPRSS4 are not explicated completely so far, targeting these proteases may found beneficial in the treatment of numerous kinds of carcinomas. TMPRSS4 inhibitors may represent a hallmark in oncology as a number of studies showed that silencing of TMPRSS4 help in reducing tumor invasion and proliferation in thyroid and lung carcinomas^47-49. Furthermore, in cultured cells over expression of TMPRSS4 induces cancerous cells to be more and more insusceptible to numerous chemotherapeuticagents⁴⁵. TMPRSS4 has been known to affect various signaling pathways including cyclic AMP response element-binding protein (CREB)-cyclin D1; therefore, TMPRSS4 inhibition may influence various subsequent processes necessary for various pro-oncogenic and anti-oncogenic pathways⁴⁷.

Prominence of TMPRSS4 in cancer:

TMPRSS4 have major contribution in cell motility, proliferation, invasion and metastasis according to existing manifestations^{17,33,41-43,45}. Most of the information regarding TMPRSS4 resided in cancer initiation, development and tumor cells migration. TMPRSS4 has been reflected as a promising therapeutic target in cancer⁴⁵. It is highly expressed inovarian³⁸, breast⁴⁸, colorectal⁴⁹, pancreatic⁵⁰, thyroid^38-39, lung^51-53, gallbladder⁵⁴, liver^55-56 and gastric cancer^44,51. Suppression of TMPRSS4 diminish tumor cell migration and invasion in lung and colon cancer^21,38. Geneknockout of TMPRSS4 by short interfering RNA treatment in lung and colon cancerous cell lines was associated with impediment in tumor cell proliferation⁴⁸. Inversely, over expression of this protease play pivotal role in development, invasion and migration of lung cancer cells⁴². Some of the unknown mechanisms accountable for increased expression of TMPRSS4 in cancer includes Chromosome rearrangements, transcriptional intracellular dysregulation, gene amplification. TMPRSS13 and TMPRSS4 activators has proven to be methylated in normal liver, although in hepatocellular cancer these genes arehypomethylated⁵⁷. These data reveals that epigenetic factors affecting gene expression are dysregulated in cancer that could be the reason for enhanced expression of TMPRSS4 observed in cancer. At the biomolecular level, TMPRSS4 overexpression was shown to stimulate numerous pro-oncogenic and anti-oncogenic signalling pathways, such as ERK1/2, focal adhesion kinase (FAK), Rac1 and Akt processes³⁹. Metastasis, tumor cell invasion and epithelial to mesenchymal transition mediated by TMPRSS4 was due to activation of Rac1 and FAK³⁹.

TMPRSS4 have an important role to play in tumor invasion and migration. TMPRSS4 is expressed by numerous the lung, colon and breast cancerous cell lines and modulates in vitro cell growth to exploreit’s signaling and function^39,61-62. TMPRSS4 inhibition diminishes tumor cell development, invasion, proliferation and migration in lung and colorectal cancer by means of collagen type I, fibrnectin-1 and matrigel³⁹. On the other hand, overexpression of TMPRSS4 increases invasion and migration in colorectal cancer Therefore, it can be concluded that inhibition of TMPRSS4 play key role in proliferation of lung cancer cells mediated by shRNAs targeting⁴⁸. Earlier reports showed that urokinase plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) are most significant factors for tumor invasion and metastasis in breast cancer. Urokinase plasminogen activator is being regulated by TMPRSS4 through high gene expression as well as conversion of pro-uPA into its active form that results in increased invasion³³. Thus, both uPA and PAI-1 are the ideal predictive immunohistochemical biomarkers presently accessible for breast cancer. Furthermore, both these proteases are higly expressed in human lung and prostate cancer tissues³³ Therefore, in the end we conclude that both TMPRSS4 and uPA contribute in cancer growth and development. TMPRSS4 is accountable for the attainment of an epithelial to mesenchymal transition^38,48. Epithelial to mesenchymal transition is a process in which epithelial cells undergo changes at molecular level and gain migratory and invasive properties to become mesenchymal stem cells. Loss of E-cadherin is a key event in epithelial to mesenchymal transition. These changes generally involve epithelial to mesenchymal transition-inducing transcription factors directly or indirectly^41,48.

Clinical assessment of TMPRSS4:

Data from preclinical studies have revealed increased malignancies in cells with raised expression of TMPRSS4 are also implicated in the studies of human subject. It has been mentioned earlier that over expression of TMPRSS4 in numerous solid tumors are linked with poor consequence. The raised levels of TMPRSS4 protein were strongly associated with disease-free survival shorter overall survival and advanced stage of malignant tumors. TMPRSS4, is reflected as a non-dependent interpreter of both disease-free survival and overall survival according to multiple analyses which includes cox regression analysis too⁵⁸. Similar outcomes would have been communicated in patients with adenoid cystic carcinoma of salivary glands^59-60. TMPRSS4 levels in tumor tissues enhanced by 430-fold in comparison to non-cancerous tissues as indicated by western blot analysis. This analysis also demonstrates that TMPRSS4 levels are closely inter-related with malignant tumor stage, lymphnode metastasis except progesterone or HER2 receptors and oestrogen. Recent studies implemented in breast cancer have shown the predictive importance of TMPRSS4 protein^52-53. Clinical tests conducted within a range of 109 patients prognosticate that extent of TMPRSS4 in cancerous cells were substantially greater than benign tumors. In the in vitro studies, TMPRSS4 signaling resulted in stimulation of ERK1/2 and overexpression of these proteins in clinical samples from gastric adenocarcinoma patients (n¼436) revealed that both are associated with each other⁵⁵. In addition to this multivariate investigation on these patients, it was illustrated that expression of TMPRSS4 was not dependent on the prognosis element. Further, several reports have revealed that poor prognosis in gastric cancer was indicated by TMPRSS4 protein⁵⁴. Currently clinical relevance of TMPRSS4 has been appeared in gallbladder carcinomas⁵⁴, therefore TMPRSS4 is an emergent type 2 transmembrane serine protease which is overexpressed in a different type of cancer and is involved in their pathogenesis and invasion^37-38,48-49. Park et al. (2014) discovered a potent anticancer agent that will act against TMPRSS4 and can be efficiently employed for treating cancer via preventing the expression of TMPRSS4 in cancer cells^61-63. However, current meta-analysis data has indicating that raised expression of TMPRSS4 is linked to poor life and rapid progression of solid tumor⁶⁴. Univariate and multivariate investigation shown that raised TMPRSS4 concentrations were linked to DFS as well as overall survival⁵³. Further study has shown that presence of raise TMPRSS4 concentrations was 62.4% in breast cancer tissue in a total of 181 patients. The occurrence rate of breast cancer patient with raised expression of TMPRSS4 was greater in triple-negative breast cancer patients (73.2%) as compared to non-triple-negative patients. Further they prove the relationship within tumor size and the lymph node metastasis raised expression of TMPRSS4.

Recent drugs targeting TMPRSS4 in cancer:

Screening of a library of compounds against TMPRSS4 serine proteas activity identified several classes of inhibitory compounds, in particular a novel series of 2-hydroxydiarylamide derivatives (Kang et al, 2013). The leader compounds exhibited a relatively decent IC₅₀ (6-12μM), but invasion assays in matrigel using TMPRSS4-overexpressing SW480 cells revealed a modest inhibitory effect. Therefore, new families of more effective compounds should be developed and tested in different in vitro and in vivo models to support the translation of anti-TMPRSS4 therapy in clinical settings⁶⁵. Kim et al, 2019 demonstrated the anticancer activity of KRT1853 and IMD-0354, as TMPRSS4 serine protease inhibitors against in lung, prostate and colon carcinomas through suppression of tumor cell invasion, migration, proliferation and endurance. Prominently KRT1853 efficiently minimize cancer growth in vivo cells. These current findings concluded that TMPRSS4 acts as a promising therapeutic target for anti-cancer treatment and suggest KRT1853 for further advancement in the domain of anti-tumorresearch⁶⁶.

CONCLUSION:

In view of the fact that proteases make a substantial contribution in development of cancer and progression, we attempt to find out the clinical significance of TMPRSS4 in cancer. It was authenticated as an indicator of poor patient prognosis in neoplasm and contribute significantly in cancer growth and metastasis, and proposed that its inhibition may increase chemotherapy sensitivity. Even though little is known about biological role of TMPRSS4 in cancer, multiple data sources substantiate this statement: (a) In preclinical models TMPRSS4 play an important role in tumor invasion and metastasis; (b) TMPRSS4 is highly expressed in numerous cancerous cells as compared to other normal tissues; (c) Reduced disease free survival and overall survival is co-related with high levels of TMPRSS4; (d) TMPRSS4 is likely to be found in serum samples from patients since its extracellular parts are discharged into conditioned media obtained from the harvest of cultured cells; and (e) TMPRSS4 is a membrane- protein, thus making it as a novel target for antibodies or any other physiological inhibitors. Future research would be needed to clarify the biological role of TMPRSS4 in order to determine its full clinical usefulness.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 31.12.2019 Modified on 27.01.2020

Research J. Pharm. and Tech. 2020; 13(7): 3449-3453.

DOI: 10.5958/0974-360X.2020.00612.5