RESUMO
Liver cirrhosis causes include alcoholism, viral infections (hepatitis B virus (HBV) and hepatitis C virus (HCV)), alcohol-associated liver disease (ALD), and metabolic dysfunction associated with steatotic liver disease (MASLD), among others. Cirrhosis frequency has increased in recent years, with a prevalence of 1395 cases per 100,000 and a mortality rate of 18 per 100,000, which corresponded to 1,472,000 deaths during 2017. In Mexico, liver disease is a public health problem since it was associated to 41,890 deaths in 2022, including liver cirrhosis (>25,000) and ALD (14,927). This represents 114 daily deaths due to these causes, and corresponds to the 4th or 5th place of all causes. The global prevalence of MASLD is estimated to affect 25% of the world's population, while in the pediatric population it could be higher. In Mexican population it is more prevalent since estimations were around 41.3% in 2023. Alcohol consumption, a global health issue due to its high prevalence and associated morbidities, is associated to ALD in 32.9%, with a mortality rate of 23.9%, primarily due to liver-related causes. In Mexico, ALD is present in 23% of all cirrhosis cases, already surpassed by hepatitis B cases in 2009. HCV and HBV frequencies changed due to programs implementing screening detection, vaccines and direct-acting antivirals during the last years. A switch of causes has occurred, increasing MASLD and diminishing viral causes. Efficient performed liver transplantation has grown as a response to increasing cirrhosis cases, including recent authorized centers. These efforts are necessary, whereas preventive strategies should be implemented according to leading causes.
RESUMO
Alzheimer's disease (AD) is the leading cause of dementia, mainly affecting elderly individuals. AD is characterized by ß-amyloid plaques, abnormal tau tangles, neuronal loss, and metabolic disruptions. Recent studies have revealed the involvement of the kynurenine (KP) pathway and the aryl hydrocarbon receptor (AhR) in AD development. The KP pathway metabolizes tryptophan to produce neuroactive substances like kynurenine, kynurenic acid, and quinolinic acid. In AD, high levels of kynurenine and the neurotoxic quinolinic acid are associated with increased neuroinflammation and excitotoxicity; conversely, reduced levels of kynurenic acid, which acts as a glutamate receptor antagonist, compromise neuroprotection. Research has indicated elevated KP metabolites and enzymes in the hippocampus of AD patients and other tissues such as blood, cerebrospinal fluid, and urine. However, the finding that KP metabolites are AD biomarkers in blood, cerebrospinal fluid, and urine has been controversial. This controversy, stemming from the lack of consideration of the specific stage of AD, details of the patient's treatment, cognitive deficits, and psychiatric comorbidities, underscores the need for more comprehensive research. AhR, a ligand-activated transcription factor, regulates immune response, oxidative stress, and xenobiotic metabolism. Various ligands, including tryptophan metabolites, can activate it. Some studies suggest that AhR activation contributes to AD, while others propose that it provides neuroprotection. This discrepancy may be explained by the specific ligands that activate AhR, highlighting the complex relationship between the KP pathway, AhR activation, and AD, where the same pathway can produce both neuroprotective and harmful effects.
RESUMO
Persistent infection with high-risk human papillomavirus remains the primary factor associated with the progression of cervical squamous intraepithelial lesions and the development of cervical cancer. Nevertheless, a combination of factors, including genetic predisposition, immune response, hormonal influences, and nutritional status, contribute synergistically to the development of cervical cancer. Among the various factors involved in the pathogenesis and therapy of cervical cancer, retinoids have gained considerable attention due to their multifaceted roles in different cellular processes. This review investigates defects within the vitamin A metabolism pathway and their correlation with cervical cancer. Additionally, it integrates epidemiological and experimental findings to discuss the potential utility of retinoid-based therapies, either alone or combined with other therapies, as agents against premalignant lesions and cervical cancer.
Assuntos
Lesões Pré-Cancerosas , Retinoides , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Feminino , Retinoides/uso terapêutico , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/patologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Vitamina A/uso terapêuticoRESUMO
Cervical cancer is a public health problem diagnosed in advanced stages, and its main risk factor is persistent high-risk human papillomavirus infection. Today, it is necessary to study new treatment strategies, such as immunotherapy, that use different targets of the tumor microenvironment. In this study, the K14E7E2 mouse was used as a cervical cancer model to evaluate the inhibition of indolamine-2,3-dioxygenase 1 (IDO-1) and C-X-C chemokine receptor type 2 (CXCR-2) as potential anti-tumor targets. DL-1MT and SB225002 were administered for 30 days in two regimens (R1 and R2) based on combination and single therapy approaches to inhibit IDO-1 and CXCR-2, respectively. Subsequently, the reproductive tracts were resected and analyzed to determine the tumor areas, and IHCs were performed to assess proliferation, apoptosis, and CD8 cellular infiltration. Our results revealed that combined inhibition of IDO-1 and CXCR-2 significantly reduces the areas of cervical tumors (from 196.0 mm2 to 58.24 mm2 in R1 and 149.6 mm2 to 52.65 mm2 in R2), accompanied by regions of moderate dysplasia, decreased papillae, and reduced inflammation. Furthermore, the proliferation diminished, and apoptosis and intra-tumoral CD8 T cells increased. In conclusion, the combined inhibition of IDO-1 and CXCR-2 is helpful in the antitumor response against preclinical cervical cancer.
RESUMO
FAM20C (family with sequence similarity 20, member C) is a serine/threonine-specific protein kinase that is ubiquitously expressed and mainly associated with biomineralization and phosphatemia regulation. It is mostly known due to pathogenic variants causing its deficiency, which results in Raine syndrome (RNS), a sclerosing bone dysplasia with hypophosphatemia. The phenotype is recognized by the skeletal features, which are related to hypophosphorylation of different FAM20C bone-target proteins. However, FAM20C has many targets, including brain proteins and the cerebrospinal fluid phosphoproteome. Individuals with RNS can have developmental delay, intellectual disability, seizures, and structural brain defects, but little is known about FAM20C brain-target-protein dysregulation or about a potential pathogenesis associated with neurologic features. In order to identify the potential FAM20C actions on the brain, an in silico analysis was conducted. Structural and functional defects reported in RNS were described; FAM20C targets and interactors were identified, including their brain expression. Gene ontology of molecular processes, function, and components was completed for these targets, as well as for potential involved signaling pathways and diseases. The BioGRID and Human Protein Atlas databases, the Gorilla tool, and the PANTHER and DisGeNET databases were used. Results show that genes with high expression in the brain are involved in cholesterol and lipoprotein processes, plus axo-dendritic transport and the neuron part. These results could highlight some proteins involved in the neurologic pathogenesis of RNS.
Assuntos
Microcefalia , Proteínas Quinases , Humanos , Proteínas Quinases/metabolismo , Microcefalia/genética , Encéfalo/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Caseína Quinase I/genética , Caseína Quinase I/metabolismoRESUMO
Persistent infection with Helicobacter pylori (H. pylori) is an important factor in gastric diseases. The vacA and cagA virulence factors of H. pylori contribute to the development of these diseases. Triple therapy containing clarithromycin has been used to eradicate this infection. Unfortunately, resistance to this antibiotic is the primary cause of treatment failure. This study aimed to determine the prevalence of clarithromycin resistance-associated mutations and to assess the relationship between virulence factors and Mexican patients infected with H. pylori. The cagA and vacA genotypes were determined by multiplex PCR. Furthermore, a qPCR was used to identify mutations of the 23S rRNA gene. This study reported a prevalence of 84.3% of H. pylori among patients with gastric diseases, and the vacA s1m1/cagA+ genotype was the most frequent (44.8%) in antrum and corpus. Analysis of the 23S rRNA gene revealed a 19.8% prevalence of clarithromycin resistance-associated mutations. The most prevalent mutations were A2143G (56%) and A2142C (25%). A significant association (p < 0.05) between the A2142G and the vacA s1m1/cagA+ genotype was detected. In conclusion, we report a high prevalence (>15%) of clarithromycin resistance-associated mutations, and we found an association between the genotypes of virulence factors and a mutation in the 23S rRNA gene.
RESUMO
FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.
Assuntos
Anormalidades Múltiplas , Caseína Quinase I , Fissura Palatina , Exoftalmia , Proteínas da Matriz Extracelular , Variação Genética , Microcefalia , Osteosclerose , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Fissura Palatina/genética , Fissura Palatina/metabolismo , Fissura Palatina/mortalidade , Fissura Palatina/patologia , Exoftalmia/genética , Exoftalmia/metabolismo , Exoftalmia/mortalidade , Exoftalmia/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/mortalidade , Microcefalia/patologia , Osteosclerose/genética , Osteosclerose/metabolismo , Osteosclerose/mortalidade , Osteosclerose/patologiaRESUMO
According to their oncogenic properties, Human Papillomaviruses (HPVs) are classified into two types: Low-Risk (LR-HPVs) and High-Risk Human Papillomaviruses (HR-HPVs). The immune system naturally controls the majority of HPV infections; however, when the HR-HPV infection is persistent, the risk of developing cervical cancer increases. Previous studies indicate that multiple-infection or coinfection with HR-HPV occurs frequently and can potentiate the development of cervical lesions. This study aimed to establish the HPV coinfection rate in squamous intraepithelial lesions from Mexican patients. For HPV detection, we performed PCR on 55 cervical lesions diagnosed by colposcopy. We detected the presence of HPV infection in 87.27% (48/55) of the lesions; interestingly, HPV coinfection was observed in 70.83% (34/48) of these samples. We also evaluated HPV infection in adjacent areas without morphological changes from 25 samples. The results showed that 80% (20/25) of these were HPV-positive and, curiously, all presented HPV-16 infection. In conclusion, our results revealed a high prevalence of HPV coinfection in cervical lesions in Mexican patients, and these results contribute to future research focused on the role that HPV coinfection plays in the development of cervical cancer.
Assuntos
Alphapapillomavirus/fisiologia , Coinfecção/virologia , Infecções por Papillomavirus/complicações , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/virologia , Adulto , Coinfecção/epidemiologia , Feminino , Humanos , México , Infecções por Papillomavirus/epidemiologia , Prevalência , Neoplasias do Colo do Útero/epidemiologia , Displasia do Colo do Útero/epidemiologiaRESUMO
Two siblings from a Mexican family who carried lethal Raine syndrome are presented. A newborn term male (case 1) and his 21 gestational week brother (case 2), with a similar osteosclerotic pattern: generalized osteosclerosis, which is more evident in facial bones and cranial base. Prenatal findings at 21 weeks and histopathological features for case 2 are described. A novel combination of biallelic FAM20C pathogenic variants were detected, a maternal cytosine duplication at position 456 and a paternal deletion of a cytosine in position 474 in exon 1, which change the reading frame with a premature termination at codon 207 and 185 respectively. These changes are in concordance with a negative detection of the protein in liver and kidney as shown in case 2. Necropsy showed absence of pancreatic Langerhans Islets, which are reported here for the first time. Corpus callosum absence is added to the few reported cases of brain defects in Raine syndrome. This report shows two new FAM20C variants not described previously, and negative protein detection in the liver and the kidney. We highlight that lethal Raine syndrome is well defined as early as 21 weeks, including mineralization defects and craniofacial features. Pancreas and brain defects found here in FAM20C deficiency extend the functional spectrum of this protein to previously unknown organs.
Assuntos
Anormalidades Múltiplas/genética , Caseína Quinase I/genética , Fissura Palatina/genética , Exoftalmia/genética , Proteínas da Matriz Extracelular/genética , Microcefalia/genética , Osteosclerose/genética , Anormalidades Múltiplas/metabolismo , Doenças do Desenvolvimento Ósseo , Caseína Quinase I/metabolismo , Fissura Palatina/metabolismo , Cisteína/genética , Exoftalmia/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Família , Feminino , Humanos , Recém-Nascido , Ilhotas Pancreáticas/patologia , Rim/patologia , Fígado/patologia , Masculino , Microcefalia/metabolismo , Mutação , Osteosclerose/metabolismo , Linhagem , Fenótipo , Polimorfismo Genético/genéticaRESUMO
OBJECTIVE: This work aimed to determine if cataractous changes associated with EMT occurring in the K14E6 mice lenses are associated with TGF-ß and Wnt/ß-catenin signaling activation. MATERIALS AND METHODS: Cataracts of K14E6 mice were analysed histologically; and components of TGF-ß and Wnt/ß-catenin signaling were evaluated by Western blot, RT-qPCR, in situ RT-PCR, IHC, or IF technics. Metalloproteinases involved in EMT were also assayed using zymography. The endogenous stabilisation of Smad7 protein was also assessed using an HDAC inhibitor. RESULTS: The K14E6 mice, which displayed binocular cataracts in 100% of the animals, exhibited loss of tissue organisation, cortical liquefaction, and an increase in the number of hyperproliferative-nucleated cells with mesenchymal-like characteristics in the lenses. Changes in lenses' cell morphology were due to actin filaments reorganisation, activation of TGF-ß and Wnt/ß-catenin pathways, and the accumulation of MTA1 protein. Finally, the stabilisation of Smad7 protein diminishes cell proliferation, as well as MTA1 protein levels. CONCLUSION: The HPV16-E6 oncoprotein induces EMT in transgenic mice cataracts. The molecular mechanism may involve TGF-ß and Wnt/ß-catenin pathways, suggesting that the K14E6 transgenic mouse could be a useful model for the study or treatment of EMT-induced cataracts.
Assuntos
Catarata/metabolismo , Transição Epitelial-Mesenquimal , Papillomavirus Humano 16/metabolismo , Proteínas Oncogênicas Virais/biossíntese , Proteínas Repressoras/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt , Animais , Catarata/genética , Catarata/patologia , Modelos Animais de Doenças , Papillomavirus Humano 16/genética , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas Virais/genética , Proteínas Repressoras/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
OBJECTIVE: The aim of this work was to compare the early gene expression profiles in the skin of HPV16-E6 transgenic mice regulated by the E6 PDZ-binding motif. MATERIALS AND METHODS: The global transcriptional profiles in dorsal skin biopsies from K14E6 and K14E6Δ146-151 transgenic mice were compared using microarrays. Relevant genes obtained from the most differentially expressed processes were further examined by RT-qPCR, in situ RT-PCR, Western blot, or immunofluorescence. RESULTS: The transcriptomic landscape of K14E6 versus K14E6Δ146-151 shows that the most affected expression profiles were those related to keratinocyte differentiation, stem cell maintenance, and keratinization. Additionally, downregulation of epidermal stemness markers such as K15 and CD34, as well as the upregulation of cytokeratin 6b, appeared to be dependent on the E6 PDZ-binding motif. Finally, wound healing, a physiological process linked to stemness, is impaired in the K14E6 mice compared to K14E6Δ146-151. CONCLUSION: The E6 PDZ-binding motif appears to affect stemness and keratinization during early stages of skin carcinogenesis. As E6 plays a significant role in HPV-induced skin carcinogenesis, the K14E6 versus K14E6Δ146-151 transcriptional profile provides a source of valuable data to uncover novel E6 functions in the skin.
Assuntos
Queratinas/metabolismo , Proteínas Oncogênicas Virais/química , Proteínas Oncogênicas Virais/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Células-Tronco/metabolismo , Transcrição Gênica , Motivos de Aminoácidos , Animais , Antígenos CD34/metabolismo , Biomarcadores/metabolismo , Caderinas/metabolismo , Diferenciação Celular , Queratinócitos/citologia , Queratinas/genética , Camundongos Transgênicos , Domínios PDZ , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/metabolismo , Relação Estrutura-Atividade , Transcriptoma , Cicatrização , beta Catenina/metabolismoRESUMO
Na+, K+-ATPase, or the Na+ pump, is a key component in the maintenance of the epithelial phenotype. In most epithelia, the pump is located in the basolateral domain. Studies from our laboratory have shown that the ß1 subunit of Na+, K+-ATPase plays an important role in this mechanism because homotypic ß1-ß1 interactions between neighboring cells stabilize the pump in the lateral membrane. However, in the retinal pigment epithelium (RPE), the Na+ pump is located in the apical domain. The mechanism of polarization in this epithelium is unclear. We hypothesized that the apical polarization of the pump in RPE cells depends on the expression of its ß2 subunit. ARPE-19 cells cultured for up to 8 weeks on inserts did not polarize, and Na+, K+-ATPase was expressed in the basolateral membrane. In the presence of insulin, transferrin and selenic acid (ITS), ARPE-19 cells cultured for 4 weeks acquired an RPE phenotype, and the Na+ pump was visible in the apical domain. Under these conditions, Western blot analysis was employed to detect the ß2 isoform and immunofluorescence analysis revealed an apparent apical distribution of the ß2 subunit. qPCR results showed a time-dependent increase in the level of ß2 isoform mRNA, suggesting regulation at the transcriptional level. Moreover, silencing the expression of the ß2 isoform in ARPE-19 cells resulted in a decrease in the apical localization of the pump, as assessed by the mislocalization of the α2 subunit in that domain. Our results demonstrate that the apical polarization of Na+, K+-ATPase in RPE cells depends on the expression of the ß2 subunit.
RESUMO
Objective. The aim of this study was to analyze the effects of the HPV16 E7 oncoprotein on dendritic cells (DCs) and CD11b(+)Gr1(+) cells using the K14E7 transgenic mouse model. Materials and Methods. The morphology of DCs was analyzed in male mouse skin on epidermal sheets using immunofluorescence and confocal microscopy. Flow cytometry was used to determine the percentages of DCs and CD11b(+)Gr1(+) cells in different tissues and to evaluate the migration of DCs. Results. In the K14E7 mouse model, the morphology of Langerhans cells and the migratory activity of dendritic cells were abnormal. An increase in CD11b(+)Gr1(+) cells was observed in the blood and skin of K14E7 mice, and molecules related to CD11b(+)Gr1(+) chemoattraction (MCP1 and S100A9) were upregulated. Conclusions. These data suggest that the HPV16 E7 oncoprotein impairs the function and morphology of DCs and induces the systemic accumulation of CD11b(+)Gr1(+) cells.
Assuntos
Antígeno CD11b/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Proteínas E7 de Papillomavirus/metabolismo , Animais , Antígenos de Superfície/metabolismo , Contagem de Células , Movimento Celular , Proliferação de Células , Forma Celular , Células Dendríticas/patologia , Epiderme/patologia , Hiperplasia , Lectinas Tipo C/metabolismo , Linfonodos/patologia , Masculino , Lectinas de Ligação a Manose/metabolismo , Camundongos Transgênicos , Modelos Animais , Baço/patologiaRESUMO
In addition to being a very well-known ion pump, Na(+), K(+)-ATPase is a cell-cell adhesion molecule and the receptor of digitalis, which transduces regulatory signals for cell adhesion, growth, apoptosis, motility and differentiation. Prolonged ouabain (OUA) blockage of activity of Na(+), K(+)-ATPase leads to cell detachment from one another and from substrates. Here, we investigated the cellular mechanisms involved in tight junction (TJ) disassembly upon exposure to toxic levels of OUA (≥300 nM) in epithelial renal canine cells (MDCK). OUA induces a progressive decrease in the transepithelial electrical resistance (TER); inhibitors of the epidermal growth factor receptor (EGFR, PD153035), cSrc (SU6656 and PP2) and ERK1/2 kinases (PD98059) delay this decrease. We have determined that the TER decrease depends upon internalization and degradation of the TJs proteins claudin (CLDN) 2, CLDN-4, occludin (OCLN) and zonula occludens-1 (ZO-1). OUA-induced degradation of proteins is either sensitive (CLDN-4, OCLN and ZO-1) or insensitive (CLDN-2) to ERK1/2 inhibition. In agreement with the protein degradation findings, OUA decreases the cellular content of ZO-1 and CLDN-2 mRNAs but surprisingly, increases the mRNA of CLDN-4 and OCLN. Changes in the mRNA levels are sensitive (CLDN-4, OCLN and ZO-1) or insensitive (CLDN-2) to ERK1/2 inhibition as well. Thus, toxic levels of OUA activate the EGFR-cSrc-ERK1/2 pathway to induce endocytosis, internalization and degradation of TJ proteins. We also observed decreases in the levels of CLDN-2 protein and mRNA, which were independent of the EGFR-cSrc-ERK1/2 pathway.
Assuntos
Endocitose/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ouabaína/farmacologia , Proteólise/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Animais , Células Cultivadas , Cães , Células Madin Darby de Rim CaninoRESUMO
BACKGROUND: Mammals have limited epithelial regeneration capacity. The K6b-E6/E7 mice model has been described as useful for the study of epithelial regeneration. The objective of this study is to compare the expression of E6/E7 oncogenes with those of cell proliferation and apoptosis during epithelization. The hypothesis of this study is that alterations in cell proliferation and apoptosis in K6b-E6/E7 mice will only occur during epithelization. METHODS: Deep 2 mm punches were performed in the middle of transgenic and control mice's ears. A biopsy was collected from the epithelization zone 72 hours and 2 weeks post-injury. Assays for cell proliferation and apoptosis were carried out by immunohistochemistry and TUNEL techniques, respectively. RT-PCR in situ was performed to compare E6/E7 expressions in the areas studied. RESULTS: Transgenic strain K6b-E6/E7 presented more proliferative cells and less apoptotic cells in epithelizated zones. This effect was limited to suprabasal stratum only, and correlates with E6/E7 oncogenes expression. Two weeks post-injury, cell proliferation and apoptosis were similar in both samples as the E6/E7 expression went down. CONCLUSION: K6b-E6/E7 mouse model is useful for epithelial regeneration. Its mechanisms should be considered for the treatment of deep wounds.
Assuntos
Orelha Externa/fisiologia , Células Epiteliais/citologia , Animais , Apoptose/genética , Biópsia , Divisão Celular/genética , Orelha Externa/lesões , Epitélio/fisiologia , Regulação da Expressão Gênica , Papillomavirus Humano 16/genética , Marcação In Situ das Extremidades Cortadas , Queratina-6/genética , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas Virais/biossíntese , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/biossíntese , Proteínas E7 de Papillomavirus/genética , Regeneração , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , TransgenesRESUMO
Mammals have limited regeneration capacity. We report here that, in transgenic mice (Tg(bK6-E6/E7)), the expression of the E6/E7 oncogenes of human papilloma virus type 16 (HPV16) under the control of the bovine keratin 6 promoter markedly improves the mouse's capacity to repair portions of the ear after being wounded. Increased repair capacity correlates with an increased number of epidermal proliferating cells. In concordance with the expected effects of the E6 and E7 oncogenes, levels of p53 decreased and those of p16 in epidermal cells increased. In addition, we observed that wound re-epithelization proceeded faster in transgenic than in wild-type animals. After the initial re-epithelization, epidermal cell migration from the intact surrounding tissue appears to be a major contributor to the growing epidermis, especially in the repairing tissue of transgenic mice. We also found that there is a significantly higher number of putative epidermal stem cells in Tg(bK6-E6/E7) than in wild-type mice. Remarkably, hair follicles and cartilage regenerated within the repaired ear tissue, without evidence of tumor formation. We propose that the ability to regenerate ear portions is limited by the capacity of the epidermis to repair itself and grow.