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1.
Ann Palliat Med ; 10(9): 9544-9552, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34628880

RESUMO

BACKGROUND: The purpose of this study is to investigate the correlation between cytokeratin 7 (CK7) and marker of proliferation Ki67 protein expression and clinical characteristics and prognosis of patients with cervical adenocarcinoma after surgery. METHODS: A total of 126 patients with cervical adenocarcinoma treated by surgery in our hospital from June 2011 to September 2015 were enrolled in this study. Immunohistochemistry (IHC) was used to detect the expression of CK7 and Ki67 in 126 cases of cervical adenocarcinoma tissues. The chi-square (χ2) test was used to compare the relationship between the positive expression rate of CK7 or Ki67 and clinicopathological features. Kaplan-Meier method was used to analyze the survival of different protein expression groups and Cox proportional hazards regression model was used to analyze the risk factors affecting the prognosis. RESULTS: The positive rate of CK7 was correlated with muscle invasion, vascular invasion, differentiation, and lymph node metastasis (all P<0.05). The positive expression rate of Ki67 was related to the degree of myometrial invasion and International Federation of Gynecology and Obstetrics (FIGO) stage (both P<0.05). Both CK7 and Ki67 may be independent risk factors for the prognosis of patients with cervical adenocarcinoma after surgery (both P<0.05), and their high expression heralds worse prognosis. CONCLUSIONS: The CK7 and Ki67 proteins may be key regulatory factors in the development of cervical adenocarcinoma after surgery, and their overexpression may lead to worse prognosis. Both CK7 and Ki67 may provide new markers for prognosis evaluation of cervical adenocarcinoma.


Assuntos
Adenocarcinoma , Adenocarcinoma/patologia , Feminino , Humanos , Queratina-7 , Antígeno Ki-67 , Estadiamento de Neoplasias , Gravidez , Prognóstico
2.
Sci Rep ; 11(1): 17863, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504224

RESUMO

Colorectal carcinoma (CRC) is associated with significant morbidity and mortality worldwide. Cytokeratins (CKs) are widely expressed in various types of carcinomas, whereas in CRC it is usually CK7 - and CK20 + . A subset of CRCs is CK7 + . This study aims to determine the prevalence of CK7 expression in CRC and its impact on overall survival. We analyzed 300 randomly selected surgically treated CRC cases using paraffin embedded tumor tissue samples and evaluated CK7 and CK20 expression using the tissue microarray method. Tumors with positivity > 10% and > 25% of tumor cells were considered CK7 and CK20 positive, respectively. Expression of both CKs and several clinical-pathological variables (stage, grade, laterality, mismatch-repair/MMR status) were evaluated using patient follow up data (Kaplan-Meier analysis of cancer-specific survival (CSS)). Significant results include shorter CSS (restricted mean 4.98 vs. 7.74 years, P = 0.007) and 5-year survival (29.4% vs. 64.6%, P = 0.0221) in CK7 + tumors compared to CK7 - tumors, respectively; without significant association with grade, stage or right-sided location. These results were significant in a multivariate analysis. CK20 + tumors are more frequently MMR-proficient and left-sided. MMR-deficient tumors are more frequently right-sided and had longer survival. CK7 expression, right-sided location (rmean CSS 6.83 vs. 8.0 years, P = 0.043), MMR-proficiency (rmean CSS 7.41 vs. 9.32 years, P = 0.012), and UICC stages III + IV (rmean CSS 6.03 vs. 8.92 years, P < 0.001) of the tumor correlated with negative prognostic outcomes, whereas the most significant results concern stage and CK7 positivity. The result concerning negative prognostic role of CK7 differs from those obtained by several previous studies focused on this topic.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Queratina-7/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Queratinas/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico
3.
Science ; 373(6556): 760-767, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34385390

RESUMO

The origin of human metaplastic states and their propensity for cancer is poorly understood. Barrett's esophagus is a common metaplastic condition that increases the risk for esophageal adenocarcinoma, and its cellular origin is enigmatic. To address this, we harvested tissues spanning the gastroesophageal junction from healthy and diseased donors, including isolation of esophageal submucosal glands. A combination of single-cell transcriptomic profiling, in silico lineage tracing from methylation, open chromatin and somatic mutation analyses, and functional studies in organoid models showed that Barrett's esophagus originates from gastric cardia through c-MYC and HNF4A-driven transcriptional programs. Furthermore, our data indicate that esophageal adenocarcinoma likely arises from undifferentiated Barrett's esophagus cell types even in the absence of a pathologically identifiable metaplastic precursor, illuminating early detection strategies.


Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Cárdia/citologia , Neoplasias Esofágicas/patologia , Esôfago/patologia , Esôfago de Barrett/genética , Esôfago de Barrett/metabolismo , Cárdia/química , Diferenciação Celular , Linhagem da Célula , Transformação Celular Neoplásica , Epigênese Genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Esôfago/citologia , Esôfago/metabolismo , Glândulas Exócrinas/química , Glândulas Exócrinas/citologia , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Queratina-7/análise , Metaplasia , Fenótipo , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA-Seq , Análise de Célula Única , Transcrição Genética , Transcriptoma
4.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360548

RESUMO

Keratin (K) 7 is an intermediate filament protein expressed in ducts and glands of simple epithelial organs and in urothelial tissues. In the pancreas, K7 is expressed in exocrine ducts, and apico-laterally in acinar cells. Here, we report K7 expression with K8 and K18 in the endocrine islets of Langerhans in mice. K7 filament formation in islet and MIN6 ß-cells is dependent on the presence and levels of K18. K18-knockout (K18‒/‒) mice have undetectable islet K7 and K8 proteins, while K7 and K18 are downregulated in K8‒/‒ islets. K7, akin to F-actin, is concentrated at the apical vertex of ß-cells in wild-type mice and along the lateral membrane, in addition to forming a fine cytoplasmic network. In K8‒/‒ ß-cells, apical K7 remains, but lateral keratin bundles are displaced and cytoplasmic filaments are scarce. Islet K7, rather than K8, is increased in K18 over-expressing mice and the K18-R90C mutation disrupts K7 filaments in mouse ß-cells and in MIN6 cells. Notably, islet K7 filament networks significantly increase and expand in the perinuclear regions when examined in the streptozotocin diabetes model. Hence, K7 represents a significant component of the murine islet keratin network and becomes markedly upregulated during experimental diabetes.


Assuntos
Diabetes Mellitus Experimental/patologia , Células Secretoras de Insulina/patologia , Queratina-18/metabolismo , Queratina-7/metabolismo , Queratina-8/metabolismo , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Regulação da Expressão Gênica , Células Secretoras de Insulina/metabolismo , Queratina-18/genética , Queratina-7/genética , Queratina-8/genética , Camundongos , Camundongos Knockout , Regulação para Cima
5.
Cells ; 10(8)2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34440668

RESUMO

Considering that the heterogenic population of a hepatic progenitor cell line (HPCL) can play a vital role in autoimmune hepatitis (AIH), we decided to conduct pioneering retrospective evaluation of these cells in pediatric AIH by means of transmission electron microscopy (TEM). The aim of the study was to assess the ultrastructure of the HPCL in children with untreated AIH. Ultrastructural analysis of the HPCL population, preceded by immunohistochemical staining for cytokeratin 7 (CK7), was performed using pretreatment liver biopsies from 23 children with clinicopathologically diagnosed AIH. Immunohistochemical assessment for CK7 allowed detection of proliferating immature epithelial cells differentiating towards periportal and intralobular intermediate hepatocytes without marked formation of ductular reactions in AIH children. Using TEM, we distinguished three morphological types of HPCs: I-the most undifferentiated progenitor cells; III-intermediate hepatocyte-like cells; II-intermediate bile duct cells. Most frequent were the cells differentiating towards hepatocytes, most rare-those differentiating towards cholangiocytes. The results indicate that an HPCL may be an important source of hepatocyte regeneration. Ultrastructural analyses of the HPCL population, combined with immunohistochemistry for CK7, might be a useful tool to evaluate liver cell regeneration, including fibrogenesis, and may help better understand the morphological pattern of the disease, in pediatric AIH. Frequent appearance of an HPCL in the vicinity of fibrotic foci, often accompanied by hyperactive Kupffer cells and transitional hepatic stellate cells, may indicate their significant involvement in liver fibrogenesis.


Assuntos
Hepatite Autoimune/metabolismo , Imuno-Histoquímica , Queratina-7/metabolismo , Regeneração Hepática , Fígado/metabolismo , Microscopia Eletrônica de Transmissão , Células-Tronco/metabolismo , Adolescente , Fatores Etários , Biomarcadores/sangue , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Criança , Pré-Escolar , Feminino , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Humanos , Macrófagos do Fígado/imunologia , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/ultraestrutura , Fígado/imunologia , Fígado/ultraestrutura , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Células-Tronco/imunologia , Células-Tronco/ultraestrutura
6.
Virchows Arch ; 479(4): 815-824, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34312700

RESUMO

We evaluated keratin 7 (K7) hepatocellular expression in 92 patients with common types of acute and chronic cholestatic diseases caused by bile duct obstruction/destruction or parenchymal lesions [acute hepatitis (n=20), mixed/pure cholestasis (n=16), primary biliary cholangitis-PBC (n=35), primary sclerosing cholangitis-PSC (n=10), vanishing bile duct syndrome (n=3), complete large bile duct obstruction due to space-occupying lesions (n=8)]. K7 immunohistochemical hepatocellular expression and ductular reaction (DR) were semi-quantitatively assessed. Results were correlated with liver enzyme serum levels, cholestasis type, histological features, hepatocellular Ki67 labelling index (LI) and HepPar1 expression. Hepatocellular K7 expression was detected in 87% (81/92) cases and in all cholestatic disease types with lowest incidence in pure/mixed cholestasis and highest in incomplete bile duct obstruction (iBDO), reaching 100% in PSC. K7-positive hepatocytes had low Ki67 LI (0-5%) retaining HepPar1 expression, irrespective of disease type. PSC cases had high K7 hepatocellular expression even with intact bile ducts, a feature that may aid differential diagnosis of cholestatic syndromes. K7 hepatocellular expression significantly correlated with cholestasis type, bile duct loss and fibrosis stage. It was higher in milder acute cholestatic hepatitis showing inverse correlation with hepatocyte proliferation and serum transaminase levels. In iBDO, younger age independently correlated with high K7 expression, while serum GGT levels showed a nearly significant correlation. Correlation with DR findings implied that K7-positive hepatocytes may result through metaplasia. In conclusion, K7 hepatocellular expression is a sensitive though non-specific marker of cholestasis. It may represent a cytoprotective reaction of resting hepatocytes in cholestasis of longer duration especially in younger patients.


Assuntos
Colestase/genética , Queratina-7/genética , Adulto , Idoso , Ductos Biliares/metabolismo , Colangite Esclerosante/patologia , Colestase/metabolismo , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Hepatócitos/patologia , Humanos , Queratina-7/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/metabolismo , Masculino , Pessoa de Meia-Idade , Transcriptoma/genética
7.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070214

RESUMO

During tubo-ovarian high-grade serous carcinoma (HGSC) progression, tumoral cells undergo phenotypic changes in their epithelial marker profiles, which are essential for dissemination processes. Here, we set out to determine whether standard epithelial markers can predict HGSC patient prognosis. Levels of E-CADH, KRT7, KRT18, KRT19 were quantified in 18 HGSC cell lines by Western blot and in a Discovery cohort tissue microarray (TMA) (n = 101 patients) using immunofluorescence. E-CADH and KRT7 levels were subsequently analyzed in the TMA of the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158 patients) and in public datasets. Epithelial marker expression was highly variable in HGSC cell lines and tissues. In the Discovery cohort, high levels of KRT7 and KRT19 were associated with an unfavorable prognosis, whereas high E-CADH expression indicated a better outcome. Expression of KRT7 and E-CADH gave a robust combination to predict overall survival (OS, p = 0.004) and progression free survival (PFS, p = 5.5 × 10-4) by Kaplan-Meier analysis. In the COEUR cohort, the E-CADH-KRT7 signature was a strong independent prognostic biomarker (OS, HR = 1.6, p = 2.9 × 10-4; PFS, HR = 1.3, p = 0.008) and predicted a poor patient response to chemotherapy (p = 1.3 × 10-4). Our results identify a combination of two epithelial markers as highly significant indicators of HGSC patient prognosis and treatment response.


Assuntos
Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias das Tubas Uterinas/metabolismo , Queratina-7/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Cistadenocarcinoma Seroso/mortalidade , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Queratina-19/metabolismo , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Prognóstico , Intervalo Livre de Progressão , Neoplasias Gástricas/metabolismo , Vimentina/metabolismo
8.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071338

RESUMO

Although radiological diagnostics have been progressing, pathological diagnosis remains the most reliable method for diagnosing liver tumors. In some cases, definite pathological diagnosis cannot be obtained by histological evaluation alone, especially when the sample is a small biopsy; in such cases, immunohistochemical staining is very useful. Immunohistochemistry is the most frequently used technique for molecular pathological diagnosis due to its broad application, ease of performance and evaluation, and reasonable cost. The results occasionally reflect specific genetic mutations. The immunohistochemical markers of hepatocellular carcinoma include those of hepatocellular differentiation-such as hepatocyte paraffin 1 and arginase-1-and those of malignant hepatocytes-such as glypican-3, heat shock protein 70, and glutamine synthetase (GS). To classify the subtypes of hepatocellular adenoma, examination of several immunohistochemical markers, such as liver fatty acid-binding protein, GS, and serum amyloid A, is indispensable. Immunohistochemical staining for GS is also important for the diagnosis of focal nodular hyperplasia. The representative immunohistochemical markers of intrahepatic cholangiocarcinoma include cytokeratin (CK) 7 and CK19. In this article, we provide an overview of the application of immunohistochemistry in the pathological diagnosis of liver tumors referring to the association with genetic alterations. Furthermore, we aimed to explain the practical points in the differential diagnosis of liver tumors by immunohistochemical staining.


Assuntos
Adenoma de Células Hepáticas/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Colangiocarcinoma/metabolismo , Imuno-Histoquímica/métodos , Neoplasias Hepáticas/metabolismo , Adenoma de Células Hepáticas/diagnóstico , Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/diagnóstico , Diagnóstico Diferencial , Glipicanas/metabolismo , Humanos , Queratina-7/metabolismo , Neoplasias Hepáticas/diagnóstico
9.
Virchows Arch ; 479(4): 667-678, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33963925

RESUMO

Most Crohn's disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies.


Assuntos
Carcinoma/patologia , Doença de Crohn/complicações , Queratina-7/metabolismo , Mucina-5AC/metabolismo , Adenocarcinoma/patologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Neoplasias Duodenais/patologia , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Queratina-7/genética , Metaplasia/patologia , Mucina-5AC/genética , Lesões Pré-Cancerosas/patologia , Prognóstico , Análise de Sobrevida , Transcriptoma/genética
10.
Diagn Pathol ; 16(1): 41, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957930

RESUMO

BACKGROUND: The objective was to build a novel method for automated image analysis to locate and quantify the number of cytokeratin 7 (K7)-positive hepatocytes reflecting cholestasis by applying deep learning neural networks (AI model) in a cohort of 210 liver specimens. We aimed to study the correlation between the AI model's results and disease progression. The cohort of liver biopsies which served as a model of chronic cholestatic liver disease comprised of patients diagnosed with primary sclerosing cholangitis (PSC). METHODS: In a cohort of patients with PSC identified from the PSC registry of the University Hospital of Helsinki, their K7-stained liver biopsy specimens were scored by a pathologist (human K7 score) and then digitally analyzed for K7-positive hepatocytes (K7%area). The digital analysis was by a K7-AI model created in an Aiforia Technologies cloud platform. For validation, values were human K7 score, stage of disease (Metavir and Nakunuma fibrosis score), and plasma liver enzymes indicating clinical cholestasis, all subjected to correlation analysis. RESULTS: The K7-AI model results (K7%area) correlated with the human K7 score (0.896; p < 2.2e- 16). In addition, K7%area correlated with stage of PSC (Metavir 0.446; p < 1.849e- 10 and Nakanuma 0.424; p < 4.23e- 10) and with plasma alkaline phosphatase (P-ALP) levels (0.369, p < 5.749e- 5). CONCLUSIONS: The accuracy of the AI-based analysis was comparable to that of the human K7 score. Automated quantitative image analysis correlated with stage of PSC and with P-ALP. Based on the results of the K7-AI model, we recommend K7 staining in the assessment of cholestasis by means of automated methods that provide fast (9.75 s/specimen) quantitative analysis.


Assuntos
Biomarcadores/análise , Colestase/diagnóstico , Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Queratina-7/análise , Adolescente , Adulto , Idoso , Criança , Colangite Esclerosante/complicações , Colestase/etiologia , Feminino , Hepatócitos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Sci Rep ; 11(1): 8340, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863935

RESUMO

Invasive ductal carcinoma (IDC) constitutes the most frequent malignant cancer endangering women's health. In this study, a new spontaneously immortalized breast cancer cell line, DHSF-BR16 cells, was isolated from the primary IDC of a 74-years old female patient, treated with neoadjuvant chemotherapy and disease-free 5-years after adjuvant chemotherapy. Primary breast cancer tissue surgically removed was classified as ER-/PR-/HER2+, and the same phenotype was maintained by DHSF-BR16 cells. We examined DHSF-BR16 cell morphology and relevant biological and molecular markers, as well as their response to anticancer drugs commonly used for breast cancer treatment. MCF-7 cells were used for comparison purposes. The DHSF-BR16 cells showed the ability to form spheroids and migrate. Furthermore, DHSF-BR16 cells showed a mixed stemness phenotype (i.e. CD44+/CD24-/low), high levels of cytokeratin 7, moderate levels of cytokeratin 8 and 18, EpCAM and E-Cadh. Transcriptome analysis showed 2071 differentially expressed genes between DHSF-BR16 and MCF-7 cells (logFC > 2, p-adj < 0.01). Several genes were highly upregulated or downregulated in the new cell line (log2 scale fold change magnitude within - 9.6 to + 12.13). A spontaneous immortalization signature, mainly represented by extracellular exosomes-, plasma membrane- and endoplasmic reticulum membrane pathways (GO database) as well as by metabolic pathways (KEGG database) was observed in DHSF-BR16 cells. Also, these cells were more resistant to anthracyclines compared with MCF-7 cells. Overall, DHSF-BR16 cell line represents a relevant model useful to investigate cancer biology, to identify both novel prognostic and drug response predictive biomarkers as well as to assess new therapeutic strategies.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal/genética , Carcinoma Ductal/patologia , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Antígeno CD24/genética , Antígeno CD24/metabolismo , Carcinoma Ductal/tratamento farmacológico , Carcinoma Ductal/cirurgia , Linhagem Celular Tumoral , Movimento Celular , Quimioterapia Adjuvante , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Membranas Intracelulares/metabolismo , Queratina-7/genética , Queratina-7/metabolismo , Queratina-8/genética , Queratina-8/metabolismo , Terapia Neoadjuvante , Esferoides Celulares/patologia
13.
BMC Urol ; 21(1): 64, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33874920

RESUMO

BACKGROUND: Transitional cell carcinoma (TCC) of the bladder is the second most common genitourinary malignancy. Because of the low sensitivity of urinary cytology and the invasiveness and expense of frequent cystoscopies for the detection of low-grade superficial lesions, we aim to establish a sensitive molecular approach to detect bladder cancer noninvasively. METHODS: Voided urine samples were collected from 80 patients with bladder cancer at the time of diagnosis, in addition to 30 patients with non-bladder cancer urological diseases and 20 healthy volunteers. The level of hTERT, KRT7, and survivin (SVV) mRNAs were analyzed using a qRT-PCR assay. RESULTS: The optimal threshold values for hTERT, KRT7, and SVV in urine were calculated by ROC curves analysis. The overall sensitivity was 81.3%, 91.3%, and 68.8% for hTERT, KRT7, and SVV, respectively, which were significantly higher than urine cytology (22.2%, p < 0.001). A higher positive ratio was obtained using multi-marker detection in comparison to single marker detection. The combined use of markers increased the sensitivity of cytology from 22.2 to 100%. In contrast with the urine cytology method, the sensitivity of these biomarkers was not correlated with the grades and stages of the bladder tumors. CONCLUSIONS: Our data indicate that urinary hTERT, KRT7, and SVV have superior sensitivities over cytology. The combined use of these markers offers a powerful potential assay and promising tool for a sensitive, noninvasive, and highly specific diagnostic method and follow-up of low-grade TCC of the bladder.


Assuntos
Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/urina , Queratina-7/urina , Reação em Cadeia da Polimerase em Tempo Real , Survivina/urina , Telomerase/urina , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica
14.
Cancer Res ; 81(11): 2847-2860, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795252

RESUMO

The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them as BCLMF3 cells. In these cells, mRNA N6 -methyladenosine (m6A) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m6A-induced breast cancer lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation of KRT7 mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. In vivo and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, m6A promotes breast cancer lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7. SIGNIFICANCE: This study suggests that N6 -methyladenosine is a key driver and potential therapeutic target in breast cancer metastasis.


Assuntos
Adenosina/análogos & derivados , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Queratina-7/genética , Neoplasias Pulmonares/secundário , Processamento de Proteína Pós-Traducional , Estabilidade de RNA , Adenosina/química , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Animais , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Epigênese Genética , Feminino , Humanos , Queratina-7/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Transcriptoma , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Virchows Arch ; 479(3): 481-491, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33733343

RESUMO

Primary gastrointestinal neuroendocrine carcinoma (GI-NEC) cannot be distinguished morphologically from pulmonary neuroendocrine carcinoma (P-NEC). This can present a significant diagnostic challenge in cases where site of origin cannot be readily determined. To identify immunohistochemical (IHC) markers that can be used to reliably distinguish between GI-NECs and P-NECs, we constructed 3-mm tissue microarrays, one containing 13 GI-NECs and one containing 20 P-NECs. IHC was performed on both microarrays using 21 stains: AE1/AE3, CK7, CK20, synaptophysin, chromogranin, CD56, INSM1, SSTR2A, CDX2, SATB2, TTF1, Napsin A, PR, GATA3, PAX8, ISL1, beta-catenin, AFP, SMAD4, Rb, and p53. For GI-NEC, the most strongly expressed marker was synaptophysin (mean H-score 248), while AE1/AE3 was the most strongly expressed in P-NEC (mean H-score 230), which was stronger than in GI-NEC (p = 0.011). Other markers that were stronger overall in P-NEC than in GI-NEC included CK7 (p < 0.0001) and TTF1 (p < 0.0001). Markers that were stronger overall in GI-NEC than in P-NEC included SSTR2A (p = 0.0021), SATB2 (p = 0.018), CDX2 (p = 0.019), and beta-catenin (nuclear; p = 0.029). SMAD4, Rb, and p53 showed similar rates of abnormal protein expression. Based on these results, a stepwise algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A had a 91% overall accuracy in distinguishing these GI-NEC from P-NEC. This was tested on a second cohort of 10 metastatic GI-NEC and 10 metastatic P-NEC, with an accuracy in this cohort of 85% and an overall accuracy of 89% for the 53 cases tested. Our algorithm reasonably discriminates GI-NEC from P-NEC using currently available IHC stains.


Assuntos
Algoritmos , Biomarcadores Tumorais/análise , Fator de Transcrição CDX2/análise , Proteínas de Ligação a DNA/análise , Neoplasias Gastrointestinais/química , Imuno-Histoquímica , Queratina-7/análise , Neoplasias Pulmonares/química , Tumores Neuroendócrinos/química , Receptores de Somatostatina/análise , Fatores de Transcrição/análise , beta Catenina/análise , Diagnóstico Diferencial , Neoplasias Gastrointestinais/patologia , Humanos , Neoplasias Pulmonares/patologia , Tumores Neuroendócrinos/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Análise Serial de Tecidos
16.
Am J Surg Pathol ; 45(10): 1337-1347, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739781

RESUMO

Mucin-producing salivary adenocarcinomas were historically divided into separate colloid carcinoma, papillary cystadenocarcinoma, and signet ring cell carcinoma diagnoses based on histologic pattern, but have recently been grouped together in the adenocarcinoma not otherwise specified category. It is currently unclear if these tumors represent 1 or more distinct entities and how they are related to well-circumscribed papillary mucinous lesions with recurrent AKT1 E17K mutations that were recently described as salivary intraductal papillary mucinous neoplasm. Here, we sought to evaluate the clinicopathologic and molecular features of salivary mucinous adenocarcinomas to clarify their classification. We identified 17 invasive mucin-producing salivary adenocarcinomas, 10 with a single histologic pattern, and 7 with mixed patterns. While most tumors demonstrated papillary growth (n=15), it was frequently intermixed with colloid (n=6) and signet ring (n=3) architecture with obvious transitions between patterns. All were cytokeratin 7 positive (100%) and cytokeratin 20 negative (0%). Next-generation sequencing performed on a subset demonstrated recurrent AKT1 E17K mutations in 8 cases (100%) and TP53 alterations in 7 cases (88%). Of 12 cases with clinical follow-up (median: 17 mo), 4 developed cervical lymph node metastases, all of which had colloid or signet ring components. Overall, overlapping histologic and immunohistochemical features coupled with recurrent AKT1 E17K mutations across patterns suggests that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that is closely related to tumors described as salivary intraductal papillary mucinous neoplasm. We propose a unified mucinous adenocarcinoma category subdivided into papillary, colloid, signet ring, and mixed subtypes to facilitate better recognition and classification of these tumors.


Assuntos
Adenocarcinoma Mucinoso/genética , Biomarcadores Tumorais/genética , Mutação , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias das Glândulas Salivares/genética , Adenocarcinoma Mucinoso/química , Adenocarcinoma Mucinoso/classificação , Adenocarcinoma Mucinoso/secundário , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Queratina-20/análise , Queratina-7/análise , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mucinas/análise , Fenótipo , Neoplasias das Glândulas Salivares/química , Neoplasias das Glândulas Salivares/classificação , Neoplasias das Glândulas Salivares/patologia , Estados Unidos
17.
Ann Diagn Pathol ; 52: 151709, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33550111

RESUMO

Sinonasal low-grade non-intestinal-type adenocarcinomas (LG non-ITACs) are uncommon tumors with unclear histogenesis, although they are presumed to arise from seromucous glands or respiratory epithelium. We investigated the clinicopathological and immunohistochemical features of the tumors, with particular attention to the transition area from the normal epithelium to neoplastic cells and concurrent lesions; these features were compared with those of 10 patients with chronic sinusitis, who served as a control group. Seventeen patients with LG non-ITACs (17 tumors) were enrolled in this retrospective study (9 male patients and 8 female patients; mean age, 48 years [range, 16-74 years]). Tumor cells continuous with respiratory epithelium were detected in 10 tumors composed of a single layer of cells with papillary, tubular, or cystic growth pattern. The tumor cells were uniformly cuboidal to columnar and polar. In seven tumors without transition areas discerned, three tumors consisted of polygonal and flat cells with a solid, acinar, micropapillary and cribriform pattern. The others had the same morphology as those with transition areas. The tumor cells were positive for SOX10 (15/17), S100 protein (8/17), and CK7 (17/17). The normal epithelium connected to the respiratory epithelium was the terminal duct in the control group. Except for the lack of p63-positive cells, the immunophenotype and histomorphology of transition areas with LG non-ITACs were similar to those of the continuous areas between the terminal duct and the respiratory epithelium in the control group. LG non-ITACs are seromucinous tumors, some of which may originate from the terminal ducts of seromucinous glands.


Assuntos
Adenocarcinoma/diagnóstico , Linhagem Celular Tumoral/patologia , Neoplasias dos Seios Paranasais/patologia , Mucosa Respiratória/patologia , Sinusite/patologia , Adenocarcinoma/metabolismo , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral/metabolismo , Doença Crônica , Feminino , Humanos , Imuno-Histoquímica/métodos , Imunofenotipagem , Queratina-7/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Estudos Retrospectivos , Proteínas S100/metabolismo , Fatores de Transcrição SOXE/metabolismo , Sinusite/diagnóstico , Sinusite/metabolismo , Adulto Jovem
18.
Oncol Rep ; 45(2): 481-492, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33416175

RESUMO

Keratin 7 (KRT7) is a member of the keratin gene family. KRT7 is abnormally expressed in various types of cancer and promotes the malignant progression of tumors. However, the role of KRT7 in ovarian cancer remains unclear. The present study aimed to validate the role of KRT7 in ovarian cancer progression. KRT7 expression levels in patients with ovarian cancer were analyzed using data obtained from the Human Protein Atlas and The Cancer Genome Atlas databases. KRT7 mRNA and protein expression levels were upregulated in ovarian cancer tissue compared with normal tissue. KRT7 expression was associated with the grading, staging and poor prognosis of ovarian cancer. The differentially expressed genes affected by KRT7 were primarily enriched in the functions of cell migration, cell adhesion and cell growth. In vitro studies, including a CCK8 assay, were used to detect cell proliferation. In addition, wound healing and transwell assays were performed to analyze cell migration. The results demonstrated that KRT7 overexpression was associated with increased proliferation, migration and epithelial­mesenchymal transition (EMT) of ovarian cancer cells, and the migration and EMT of ovarian cancers cells were decreased following knockdown with KRT7 small interfering RNA. In vivo, knockdown of KRT7 inhibited tumor growth of ovarian cancer. Furthermore, KRT7 regulated EMT in ovarian cancer via the TGF­ß/Smad2/3 pathway, and regulated cell­matrix adhesion through integrin­ß1­focal adhesion kinase signaling. These results suggest that KRT7 may be a potential molecular marker for prognosis prediction in patients with ovarian cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Queratina-7/metabolismo , Neoplasias Ovarianas/patologia , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Queratina-7/genética , Camundongos , Neoplasias Ovarianas/mortalidade , Ovário/patologia , Prognóstico , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Nat Commun ; 12(1): 560, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33495473

RESUMO

The squamous-columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal-distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.


Assuntos
Células Epiteliais/metabolismo , Fator de Transcrição GATA4/genética , Regulação da Expressão Gênica , Junções Intercelulares/genética , Sistema de Sinalização das MAP Quinases/genética , Fatores de Transcrição SOXB1/genética , Animais , Células Cultivadas , Feminino , Fator de Transcrição GATA4/metabolismo , Mucosa Gástrica/metabolismo , Queratina-7/genética , Queratina-7/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Camundongos Transgênicos , Fatores de Transcrição SOXB1/metabolismo
20.
Pediatr Dev Pathol ; 24(2): 103-115, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33439108

RESUMO

BACKGROUND AND AIMS: Differentiating biliary atresia (BA) from idiopathic neonatal hepatitis (INH) is vital in routine pediatric practice. However, on liver biopsy, few cases offer a diagnostic challenge to discriminate these entities with certainty. Bile ductular reaction (DR), intermediate hepatobiliary cells (IHBC) and extra-portal ductules (EPD) indicate progenitor cell activation, as a response to various hepatic insults. The present study aims to quantify DR, IHBC and EPD by Keratin 7 (CK7) immunohistochemistry (IHC) in BA and INH and to devise a mathematical approach to better differentiate the two, especially in histologically equivocal cases. METHODS: A total of 98 cases were categorized on biopsy as BA, INH or equivocal histology, favoring BA or INH. CK7 DR mean, IHBC mean and EPD mean values were compared between BA and INH. A formula was derived to help distinguish these two entities, the cut-off value, sensitivity and specificity of which were determined by receiver operating characteristic (ROC) curve. This formula was applied and validated on histologically equivocal cases. RESULTS: Univariate logistic regression revealed significant difference between BA and INH with respect to CK7 DR and CK7 EPD mean (p < 0.001 in both); however, CK7 IHBC mean was not significant (p = 0.08). On multivariate logistic regression, only CK7 DR had significant impact on diagnosis (p < 0.001). A formula: (CK7 DR)2 + (CK7 EPD)/(CK7 IHBC) was derived to help distinguish BA from INH. Cut off value of 10.5 and above, determined by ROC curve, favored a diagnosis of BA (sensitivity= 93.4%, specificity= 94.6%). Histologically equivocal and discrepant cases could be correctly categorized using this formula. CONCLUSIONS: Formula using CK7 IHC parameters may aid pathologists better distinguish BA from INH, especially in histologically equivocal cases.


Assuntos
Atresia Biliar/diagnóstico , Regras de Decisão Clínica , Hepatite/diagnóstico , Queratina-7/metabolismo , Fígado/metabolismo , Atresia Biliar/metabolismo , Atresia Biliar/patologia , Biomarcadores/metabolismo , Biópsia , Diagnóstico Diferencial , Feminino , Seguimentos , Hepatite/metabolismo , Hepatite/patologia , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Fígado/patologia , Modelos Logísticos , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade
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