Physiological Functions and Role of Matriptase in Cancer

Varela, Fausto A.; Hyland, Thomas E.; List, Karin

doi:10.1002/9781119300229.ch4

Cited by 1 publication

(3 citation statements)

References 124 publications

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“…Regarding the potential mechanisms by which KLK5 can contribute to tumorigenesis, we show that KLK5 can induce PAR2 dependent activation of NFKB and Hippo-YAP1. Indeed, it has been shown that PAR-2 can lead to NFκB activation in inflammation and SCCs, and PAR-2 can be activated by KLK5 in OSCC [7,33,36,40,41]. In addition, PAR-2 activation by SLIGRL (PAR-2 peptide agonist) can result in YAP1 activation [42].…”

Section: Discussionmentioning

confidence: 99%

“…Matriptase expression and activity are dysregulated in several human cancers [7]. In particular, matriptase was previously found to be ubiquitously expressed in HNSCCs of different anatomical locations and different presumed etiology [9].…”

Section: Lekti But Not Matriptase Is Differentially Expressed In Human Osccsmentioning

confidence: 99%

“…Several studies demonstrated that dysregulated expression of Type II Transmembrane Serine Proteases (TTSPIIs) is associated with different types of cancers [6]. Matriptase, a TTSPII, is indeed dysregulated in several cancers [7]. List et al (2005) showed that Matriptase induces malignant transformation when expressed in epithelial stem cells [8].…”

Section: Introductionmentioning

confidence: 99%

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Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis

Silva

Fraga-Silva

Yuan

et al. 2021

Cancers

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Head and neck squamous cell carcinoma remains challenging to treat with no improvement in survival rates over the past 50 years. Thus, there is an urgent need to discover more reliable therapeutic targets and biomarkers for HNSCC. Matriptase, a type-II transmembrane serine protease, induces malignant transformation in epithelial stem cells through proteolytic activation of pro-HGF and PAR-2, triggering PI3K-AKT-mTOR and NFKB signaling. The serine protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI) inhibits the matriptase-driven proteolytic pathway, directly blocking kallikreins in epithelial differentiation. Hence, we hypothesized LEKTI could inhibit matriptase-dependent squamous cell carcinogenesis, thus implicating kallikreins in this process. Double-transgenic mice with simultaneous expression of matriptase and LEKTI under the keratin-5 promoter showed a prominent rescue of K5-Matriptase+/0 premalignant phenotype. Notably, in DMBA-induced SCC, heterotopic co-expression of LEKTI and matriptase delayed matriptase-driven tumor incidence and progression. Co-expression of LEKTI reverted altered Kallikrein-5 expression observed in the skin of K5-Matriptase+/0 mice, indicating that matriptase-dependent proteolytic pathway inhibition by LEKTI occurs through kallikreins. Moreover, we showed that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. Collectively, our data identify a third signaling pathway for matriptase-dependent carcinogenesis in vivo. These findings are critical for the identification of more reliable biomarkers and effective therapeutic targets in Head and Neck cancer.

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