TMPRSS4: an emerging potential therapeutic target in cancer

Abstract

Altered expression and activity of proteases is a key event in cancer, particularly in relation to invasion, modification of the extracellular matrix and metastasis. The transmembrane protease, serine 4 (TMPRSS4) is closely related to other cancer-associated proteases, such as hepsin, TMPRSS2 and matriptase. We review in this study up-to-date information about expression, role, regulation and clinical relevance of TMPRSS4 in cancer. Increased expression of this protease is associated with acquisition of epithelial to mesenchymal transition, invasion and metastasis in vivo. Signalling in cancer cells involves upregulation of integrin-α5 (ITG-α5) and urokinase-type plasminogen activator (uPA), downregulation of E-cadherin and activation of uPA enzymatic activity at the plasma membrane, as well as phosphorylation of FAK, Src, Akt and ERK1/2 intracellularly. Upregulation of miR-205 hinders the protumorigenic effects elicited by TMPRSS4 through restoration of E-cadherin levels and direct targeting of ITG-α5. High levels of TMPRSS4 have been found in several types of solid tumours in patients, and association with poor prognosis has been consistently described. On the basis of this information and the structural characteristics of this druggable protease, we suggest that TMPRSS4 could be a novel potential therapeutic target in solid tumours.

Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients

“…Expression of the serine protease TMPRSS4 is highly increased in a variety of solid tumors and is associated with poor prognosis in some cancer types such as breast, colon, cervix, thyroid and liver [8, 11]. Our present study shows for the first time that TMPRSS4 is an independent prognostic indicator of reduced survival in patients with squamous NSCLC at early stages, thus validating our previous findings by mRNA analysis [7].…”

TMPRSS4 as an emerging potential poor prognostic factor for solid tumors: A systematic review and meta-analysis

“…TMPRSS4 could be a useful prognostic biomarker or a promising therapeutic target for solid tumors [1]. However, further studies analyzing specific tumor types and perspectives are needed to further verify the clinical significance of TMPRSS4 expression in solid tumors.…”

“…It has been implied that TMPRSS4 could be an emerging potential therapeutic target in cancer [1]. ITMPRSS4 reduced migration and invasion of lung and colon cancer cells [9, 14].…”

“…Further, multiple studies have implied that elevated TMPRSS4 expression in tumor tissues was correlated with poor survival of cancer patients [1]. The results of those individual studies were however not conclusive.…”

Type II transmembrane serine proteases as potential targets for cancer therapy

“…Interestingly, increases in markers for cancer stem cells (CSCs) such as aldehyde dehydrogenase (ALDH) and octamer-binding transcription factor 4 (OCT-4) are strongly positively correlated with TMPRSS4 expression (de Aberasturi et al, 2016). Several reports have suggested that TMPRSS4 associates with poor prognosis and survival in a variety of different cancers (Cheng et al, 2013a,b; Wu et al, 2014; de Aberasturi and Calvo, 2015; Wang et al, 2015), which may be a result of an increase in the CSCs population, although the factors leading to TMPRSS4 upregulation are still not identified. One recent finding suggests that increased TMPRSS4 in cancer may result from gene-silencing of tissue factor pathway inhibitor 2 (TFPI-2), a consequence of improper methylation (Hamamoto et al, 2015).…”