Serine peptidase inhibitor Kunitz type 2 (SPINT2) in cancer development and progression

Roversi, Fernanda Marconi; Saad, Sara Teresinha Olalla; Machado-Neto, João Agostinho

doi:10.1016/j.biopha.2018.02.100

Cited by 32 publications

(37 citation statements)

References 70 publications

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“…However, the finding that SPINT2 is also expressed in brain and lymph node cells indicates that it might regulate other proteases than matriptase (Szabo et al, 2008). Recent reports associated the physiological role of SPINT2 with the inhibition of human serinetype proteases such as matriptase, plasmin, kallikreins (KLK) and coagulation factor XIa (Wu et al, 2017a(Wu et al, , 2019Roversi et al, 2018;Delaria et al, 1997). SPINT2 possesses one transmembrane domain and two kunitz-type inhibitor domains that are exposed to the extracellular space and which are believed to facilitate a potent inhibition of target proteases.…”

Section: Introductionmentioning

confidence: 99%

SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses

et al. 2020

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A B S T R A C TViruses possessing class I fusion proteins require proteolytic activation by host cell proteases to mediate fusion with the host cell membrane. The mammalian SPINT2 gene encodes a protease inhibitor that targets trypsin-like serine proteases. Here we show the protease inhibitor, SPINT2, restricts cleavage-activation efficiently for a range of influenza viruses and for human metapneumovirus (HMPV). SPINT2 treatment resulted in the cleavage and fusion inhibition of full-length influenza A/CA/04/09 (H1N1) HA, A/Aichi/68 (H3N2) HA, A/Shanghai/2/ 2013 (H7N9) HA and HMPV F when activated by trypsin, recombinant matriptase or KLK5. We also demonstrate that SPINT2 was able to reduce viral growth of influenza A/CA/04/09 H1N1 and A/X31 H3N2 in cell culture by inhibiting matriptase or TMPRSS2. Moreover, inhibition efficacy did not differ whether SPINT2 was added at the time of infection or 24 h post-infection. Our data suggest that the SPINT2 inhibitor has a strong potential to serve as a novel broad-spectrum antiviral.

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Section: Introductionmentioning

confidence: 99%

SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses

et al. 2020

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“…Pereira et al found that dysregulation of SPINT2 is a common event in both pediatric and adult HGG, in which SPINT2 may act as a tumor suppressor. SPINT2 gene expression was down-regulated, altering dysregulation of the HGF/MET signaling pathway, which contributes to cancer development and progression [37,38]. Whether these genes play the same role in the development and metastasis of OS deserves further study.…”

Section: Discussionmentioning

confidence: 99%

Expression profile analysis identifies key genes as prognostic markers for metastasis of osteosarcoma

Guan

Song

2020

Cancer Cell Int

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Background: OS is the most common malignant tumor of bone which was featured with osteoid or immature bone produced by the malignant cells, and biomarkers are urgently needed to identify patients with this aggressive disease. Methods: We downloaded gene expression profiles from GEO and TARGET datasets for OS, respectively, and performed WGCNA to identify the key module. Whereafter, functional annotation and GSEA demonstrated the relationships between target genes and OS. Results: In this study, we discovered four key genes-ALOX5AP, HLA-DMB, HLA-DRA and SPINT2 as new prognostic markers and confirmed their relationship with OS metastasis in the validation set. Conclusions: In conclusion, ALOX5AP, HLA-DMB, HLA-DRA and SPINT2 were identified by bioinformatics analysis as possible prognostic markers for OS metastasis.

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“…The regulatory role of HAI-2 in the activation of pro-HGF by inhibiting the activating proteases (including matriptase), which induces HGF/MET signaling axis, has been considered a major suppressive function in cancer progression [11,12]. Additionally, an alternative function such as the activation of caspase 3 in esophageal squamous cell carcinoma leading to the promotion of apoptosis and inhibition of proliferation was also reported [47,50]. However, HAI-2 has also been reported to be required for invasive growth in oral squamous cell carcinoma, which suggests that the role of HAI-2 may be tissue or cell-type specific and dependent on targeting TTSPs [51].…”

Section: Hgf/met Signaling and Hepsinmentioning

confidence: 99%

“…In addition, a correlation between downregulation of HAI-2 with upregulation of matriptase and increasing PC tumor grade has been reported [49,69]. However, the following evidence suggests that HAI-2 is a main regulator of matriptase [49,50,[68][69][70]. The role of HAI-2 in invasiveness and metastatic potential of PC cells was analyzed using human prostate cancer progression model cell lines and the xenograft model [49,68,69].…”

Section: Matriptase and Haismentioning

confidence: 99%

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

Mukai

Yamasaki

Fujisawa

et al. 2020

IJMS

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Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.

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Serine peptidase inhibitor Kunitz type 2 (SPINT2) in cancer development and progression

Cited by 32 publications

References 70 publications

SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses

SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses

Expression profile analysis identifies key genes as prognostic markers for metastasis of osteosarcoma

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

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