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Persistent infection with Human papillomavirus (HPV) is the main etiologic factor for pre-malignant and malignant cervical lesions. Moreover, HPV is also associated with oropharynx and other anogenital carcinomas. Cancer-causing HPV viruses classified as group 1 carcinogens include 12 HPV types, with HPV 16 and 18 being the most prevalent. High-risk HPVs express two oncoproteins, E6 and E7, the products of which are responsible for the inhibition of p53 and pRB proteins, respectively, in human keratinocytes and cellular immortalization. p53 and pRB are pleiotropic proteins that regulate the activity of several signaling pathways and gene expression. Among the important factors that are augmented in HPV-mediated carcinogenesis, proteases not only control processes involved in cellular carcinogenesis but also control the microenvironment. For instance, genetic polymorphisms of matrix metalloproteinase 1 (MMP-1) are associated with carcinoma invasiveness. Similarly, the serine protease inhibitors hepatocyte growth factor activator inhibitor-1 (HAI-1) and -2 (HAI-2) have been identified as prognostic markers for HPV-dependent cervical carcinomas. This review highlights the most crucial mechanisms involved in HPV-dependent carcinogenesis, and includes a section on the proteolytic cascades that are important for the progression of this disease and their impact on patient health, treatment, and survival.
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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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Aging is a gradual biological process characterized by a decrease in cellular and organism functions. Aging-related processes involve changes in the expression and activity of several proteins. Here, we identified the transmembrane protease serine 11a (TMPRSS11a) as a new age-specific protein that plays an important role in skin wound healing. TMPRSS11a levels increased with age in rodent and human skin and gingival samples. Strikingly, overexpression of TMPRSS11a decreased cell migration and spreading, and inducing cellular senescence. Mass spectrometry, bioinformatics, and functional analyses revealed that TMPRSS11a interacts with integrin ß1 through an RGD sequence contained within the C-terminal domain and that this motif was relevant for cell migration. Moreover, TMPRSS11a was associated with cellular senescence, as shown by overexpression and downregulation experiments. In agreement with tissue-specific expression of TMPRSS11a, shRNA-mediated downregulation of this protein improved wound healing in the skin, but not in the skeletal muscle of old mice, where TMPRSS11a is undetectable. Collectively, these findings indicate that TMPRSS11a is a tissue-specific factor relevant for wound healing, which becomes elevated with aging, promoting cellular senescence and inhibiting cell migration and skin repair.
Assuntos
Envelhecimento/patologia , Movimento Celular , Fibroblastos/patologia , Proteínas de Membrana/metabolismo , Serina Proteases/metabolismo , Pele/patologia , Cicatrização , Adolescente , Adulto , Idoso , Envelhecimento/metabolismo , Animais , Proliferação de Células , Fibroblastos/metabolismo , Gengiva/metabolismo , Gengiva/patologia , Humanos , Proteínas de Membrana/genética , Camundongos , Pessoa de Meia-Idade , Serina Proteases/genética , Transdução de Sinais , Pele/metabolismo , Adulto JovemRESUMO
Virtual microscopy (VM) is a widely used teaching method in Medical Education in many developed countries. In Brazil, however, this is not the case for most medical schools, considering Brazilian social inequality and uneven access to technology. Recently, the Covid-19 pandemic has also challenged Universities to seek and make a transition toward more effective methods of full-time online education. Thus, the main goal of this work was to verify student's perception and academic performance, assessed upon VM implementation in a Brazilian Medical School. Ribeirao Preto Medical School students answered a 26-question survey with regards to optical microscopy (OM) and VM. Academic performance was compared between participants that were (year of 2019) or were not (year of 2015) exposed to VM. Taken the results together, subjective impressions such as handling, suitability, learning effectiveness, and pleasure using the tools, have shown a higher score for virtual microscopy (median = 29), when compared to optical microscopy (median = 24) with a P-value < 0.001 by Wilcoxon rank test, upon measurement using an ordinal scale. Regarding academic performance, no statistically significant differences were found between groups (P-value = 0.38, Cohen's d = 0.19). Therefore, VM proved to be adequate to the Brazilian medical education in light of Brazilian social contexts and Covid-19 pandemic.
Assuntos
Educação a Distância/estatística & dados numéricos , Educação Médica/métodos , Histologia/educação , Microscopia , Adolescente , Brasil , COVID-19 , Feminino , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Oral squamous cell carcinoma (OSCC) remains a challenging cancer to treat despite all the advances of the last 50 years. Kallikrein 5 (KLK5) is among the serine proteases implicated in OSCC development. However, whether the activity of KLK5 promotes carcinogenesis is still controversial. Moreover, knowledge regarding the role of the KLK5 cognate inhibitor, Lympho-Epithelial Kazal-Type related Inhibitor (LEKTI), in OSCC is scarce. We have, thus, sought to investigate the importance of KLK5 and LEKTI expression in premalignant and malignant lesions of the oral cavity. METHODS: KLK5 and LEKTI protein expression was evaluated in 301 human samples, which were comprised of non-malignant and malignant lesions of the oral cavity. Moreover, a bioinformatic analysis of the overall survival rate from 517 head and neck squamous cell carcinoma (HNSCC) samples was performed. Additionally, to mimic the uncovered KLK5 to serine peptidase inhibitor (SPINK5) imbalance, the KLK5 gene was abrogated in an OSCC cell line using CRISPR-Cas9 technology. The generated cell line was then used for in vivo and in vitro carcinogenesis related experiments. RESULTS: LEKTI was found to be statistically downregulated in OSCCs, with increased KLK5/SPINK5 mRNA ratio being associated with a shorter overall survival (pâ¯=â¯0.091). Indeed, disruption of KLK5 to SPINK5 balance through the generation of KLK5 null OSCC cells led to smaller xenografted tumors and statistically decreased proliferation rates following multiple time points of BrdU treatment in vitro. CONCLUSION: The association of increased enzyme/inhibitor ratio with poor prognosis indicates KLK5 to SPINK5 relative expression as an important prognostic marker in OSCC.