Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 85
Filtrar
1.
Lancet Oncol ; 22(4): 548-557, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33794208

RESUMO

BACKGROUND: Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls. METHODS: We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer. FINDINGS: We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0·87, 95% CI 0·84-0·91; p=1·07 × 10-9) and rs27069 (CLPTM1L; 0·88, 0·84-0·92; p=2·51 × 10-9), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21-1·32; p=2·51 × 10-28), rs6938453 (MICA; 0·79, 0·75-0·83; p=1·97 × 10-17), rs55986091 (HLA-DQB1; 0·66, 0·60-0·72; p=6·42 × 10-28), and rs9266183 (HLA-B; 0·73, 0·64-0·83; p=1·53 × 10-6). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0·015), CLPTM1L (rs27069; p=2·54 × 10-7), and HLA-DQA1 (rs9272050; p=7·90 × 10-8). Mendelian randomisation further supported the complementary role of smoking (OR 2·46, 95% CI 1·64-3·69), older age at first pregnancy (0·80, 0·68-0·95), and number of sexual partners (1·95, 1·44-2·63) in the risk of developing cervical cancer. INTERPRETATION: Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions. FUNDING: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.


Assuntos
Neoplasia Intraepitelial Cervical/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Fator de Transcrição PAX8/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Neoplasia Intraepitelial Cervical/patologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Neoplasias do Colo do Útero/patologia
2.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
3.
Anticancer Res ; 40(10): 5925-5932, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988924

RESUMO

BACKGROUND/AIM: Paired box 8 (PAX8) is an organ-specific marker discriminating Müllerian and breast carcinomas. Recent studies have described PAX8 expression in a small subset of breast carcinomas, which may cause a diagnostic pitfall in the determination of cancer origin. The aim of this study was to investigate characteristics of PAX8-expressing metastatic breast carcinomas (MBCs) to help elucidate the primary site of occurrence. PATIENTS AND METHODS: Using immunohistochemistry, we examined PAX8 status in 80 MBCs and 52 matched primary breast carcinomas (PBCs). RESULTS: A total of 20% of MBCs displayed PAX8 expression and the concordance rate of PAX8 expression between MBCs and PBCs was 92.3%. In MBCs, PAX8 expression was significantly associated with high-grade features (p=0.042), estrogen and progesterone receptor negativities (p=0.005 and p=0.017, respectively). CONCLUSION: PAX8 may be identified in MBCs with high-grade and non-luminal molecular subtypes. Careful assessment is needed when designating a primary site relying principally on PAX8 positivity.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Imuno-Histoquímica , Fator de Transcrição PAX8/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade
4.
J Clin Pathol ; 73(9): 527-530, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32699115

RESUMO

The GLIS 1-3 genes belong to a family of transcription factors, the Krüppel-like zinc finger proteins. The GLIS proteins function primarily as activators of transcription (GLIS 1 and 3), while GLIS 2 functions as a repressor. Collectively, the GLIS proteins are involved in a variety of diseases in several organs ranging from Alzheimer's disease, facial dysmorphism, neonatal diabetes mellitus, breast and colon cancers and leukaemia. In particular, loss-of-function mutations in GLIS2 are responsible for an autosomal recessive cystic kidney disease called nephronophthisis, which is characterised by tubular atrophy, interstitial fibrosis and corticomedullary cysts.Of diagnostic value in current practice are the presence of GLIS 3 and 1 fusions with PAX8 in almost 100% of hyalinising trabecular tumours of the thyroid gland. This enables its separation from papillary thyroid cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Fatores de Transcrição Kruppel-Like/genética , Proteínas Repressoras/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Fusão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Mutação com Perda de Função , Fator de Transcrição PAX8/genética , Fator de Transcrição PAX8/metabolismo , Proteínas Repressoras/metabolismo , Glândula Tireoide/patologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo
5.
Pol J Pathol ; 71(1): 69-74, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32429658

RESUMO

Molecular next gene sequencing was used to evaluate mutations in 409 common mutated cancer-related genes in malignant mesothelioma of tunica vaginalis testis (MMTVT) of 81-year-old man. Multifocal papillary-solid areas contained necrosis among highly cellular fields with multiple mitoses. It was positive for WT1, CKAE1/AE3, calretinin, CK7 with negativity for CK5, PSA, TTF-1. Following mutations were revealed in PARP1 (NM_001618: c.2285TG, p.K135R), MTRR (NM_024010: c.147A>G, p.I49M) and two sorts of mutations in structure of KMT2C gene (NM_170606: c.2447_2448insA (c.2447dupA), p.Y816fs and NM_170606: c.1042G>A, p.D348N) for the first time in MMTVT.


Assuntos
Mesotelioma/genética , Neoplasias Testiculares/genética , Adenosina Trifosfatases/genética , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Ferredoxina-NADP Redutase/genética , Humanos , Masculino , Mutação , Fator de Transcrição PAX8/genética , Poli(ADP-Ribose) Polimerase-1/genética , Ubiquitina-Proteína Ligases/genética
6.
Indian J Pathol Microbiol ; 63(Supplement): S41-S43, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32108625

RESUMO

Paraganglioma is a rare neuroendocrine tumor arising from undifferentiated cells of the primitive neural crest. We report a case of renal paraganglioma in a 67-year-old patient. Computed tomography demonstrated a solid mass in the middle and lower pole of the right kidney. Sonography revealed an enlarged right kidney with an irregular shape but distinct border. Renal cell carcinoma was diagnosed provisionally; the tumor was completely resected and submitted for pathological examination. Unexpectedly, histopathology and immunohistochemistry confirmed paraganglioma arising from the renal parenchyma. In this study, we report the exceptional occurrence of Paired box gene 8 (PAX-8) expression in a renal paraganglioma. In addition, we demonstrated diffuse cytokeratin positivity in this renal paraganglioma. Although our report of a paraganglioma originating from the kidney is not unique, our finding expands the known immunophenotypic spectrum of this tumor. The awareness of the possible occurrence of cytokeratin diffuse positivity in paraganglioma is relevant to avoiding misdiagnosis of paraganglioma.


Assuntos
Queratinas/genética , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/genética , Paraganglioma/diagnóstico por imagem , Paraganglioma/genética , Idoso , Diagnóstico Diferencial , Técnicas Histológicas , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Fator de Transcrição PAX8/genética , Tomografia Computadorizada por Raios X
7.
BMC Mol Cell Biol ; 20(1): 61, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31881968

RESUMO

BACKGROUND: PAX8 was not only a mitotic factor, but identified as a transcription factor involved in the prognosis of human tumor patients. Elucidating the function of PAX8 on the pathology of stomach cancer was meaningful. RESULTS: PAX8 was found to be upregulated in primary stomach cancer tissue and the TCGA stomach cancer dataset. Interestingly, SOX13 and PAX8 showed consistent expression patterns, and the combined high PAX8 and SOX18 expression induced a worse prognosis of stomach cancer patients. SOX13 was further identified as a transcription factor of PAX8, and further affect Aurora B and Cyclin B1 expression, two cell cycle related factors of the downstream of PAX8, including. Furthermore, PAX8 depletion inducted G1-phase arrest and the decrease of EdU incorporation, cell viability and colony formation can be rescued by SOX13 overexpression. CONCLUSIONS: SOX13 participated in the elevated expression of PAX8, which promote the proliferation of stomach cancer cells. Therefore, SOX13 mediated PAX8 expression was recognized as a tumor-promoting role in stomach cancer.


Assuntos
Fator de Transcrição PAX8/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/fisiopatologia , Autoantígenos/genética , Autoantígenos/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Fator de Transcrição PAX8/metabolismo , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismo , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade
8.
Nat Commun ; 10(1): 5367, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772167

RESUMO

The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates. Here, by using genetically engineered mouse models and organoids, we assessed the tumor-forming properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation and Tp53 mutation in Pax8 + FTE caused Serous Tubal Intraepithelial Carcinoma (STIC), which metastasized rapidly to the ovarian surface. These events were recapitulated by orthotopic injection of mutant FTE organoids. Engineering the same genetic lesions into Lgr5 + OSE or OSE-derived organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. FTE- and OSE-derived tumors had distinct transcriptomes, and comparative transcriptomics and genomics suggest that human HGSOC arises from both cell types. Finally, FTE- and OSE-derived organoids exhibited differential chemosensitivity. Our results comport with a dualistic origin for HGSOC and suggest that the cell-of-origin might influence therapeutic response.


Assuntos
Cistadenocarcinoma Seroso/patologia , Tubas Uterinas/patologia , Neoplasias Ovarianas/patologia , Ovário/patologia , Animais , Diferenciação Celular/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Células Epiteliais/patologia , Epitélio , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Camundongos Transgênicos , Mutação , Organoides/efeitos dos fármacos , Organoides/patologia , Organoides/transplante , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Fator de Transcrição PAX8/genética , Receptores Acoplados a Proteínas-G/genética , Proteína Supressora de Tumor p53/genética
9.
BMC Res Notes ; 12(1): 770, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771640

RESUMO

OBJECTIVES: It is challenging to distinguish between primary ovarian mucinous tumors and metastatic mucinous neoplasms from the lower gastrointestinal tract, including appendiceal tumors. A combination of PAX8 and SATB2 immunohistochemical stains can be used as a diagnostic tool to distinguish between these cases. RESULTS: Immunostaining for SATB2, PAX8, CK7, CK20 and CDX2 was performed on 50 ovarian mucinous neoplasms (OMN) (39 cystadenomas, 4 borderline and 7 adenocarcinomas), 63 mucinous colorectal carcinoma (CRC), and 9 appendiceal mucinous neoplasms (AMN) [8 low grade appendiceal mucinous neoplasms (LAMN) and 1 adenocarcinoma]. PAX8 was positive in 32% of OMN and negative in all CRC and AMN cases. SATB2 was expressed in 2.0% of OMN, 77.8% of AMN, and 49.2% of CRC cases. CK7 was positive in 78.0% of OMN, 33.3% of AMN, and 9.5% of CRC cases. CK20 was expressed in 24.0% of OMN, 88.9% of OMN, and 87.3% of CRC cases. CDX2 was positive in 14.0% of OMN, 100% of AMN, and 90.5% of CRC cases. PAX8 can differentiate between OMN and AMN with high specificity but low sensitivity. CDX2 is the most sensitive marker for CRC and AMN, whereas SATB2 has better specificity.


Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Neoplasias do Apêndice/diagnóstico , Neoplasias do Colo/diagnóstico , Cistadenoma Mucinoso/diagnóstico , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Neoplasias Ovarianas/diagnóstico , Fator de Transcrição PAX8/metabolismo , Fatores de Transcrição/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Neoplasias do Apêndice/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Neoplasias do Colo/metabolismo , Cistadenoma Mucinoso/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Queratina-20/genética , Queratina-20/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Neoplasias Ovarianas/metabolismo , Fator de Transcrição PAX8/genética , Fatores de Transcrição/genética
10.
J Biol Chem ; 294(48): 18408-18420, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31615896

RESUMO

Although adipogenesis is mainly controlled by a small number of master transcription factors, including CCAAT/enhancer-binding protein family members and peroxisome proliferator-activated receptor γ (PPARγ), other transcription factors also are involved in this process. Thyroid cancer cells expressing a paired box 8 (PAX8)-PPARγ fusion oncogene trans-differentiate into adipocyte-like cells in the presence of the PPARγ ligand pioglitazone, but this trans-differentiation is inhibited by the transcription factor NK2 homeobox 1 (NKX2-1). Here, we tested whether NKX family members may play a role also in normal adipogenesis. Using quantitative RT-PCR (RT-qPCR), we examined the expression of all 14 NKX family members during 3T3-L1 adipocyte differentiation. We found that most NKX members, including NKX2-1, are expressed at very low levels throughout differentiation. However, mRNA and protein expression of a related family member, NKX1-2, was induced during adipocyte differentiation. NKX1-2 also was up-regulated in cultured murine ear mesenchymal stem cells (EMSCs) during adipogenesis. Importantly, shRNA-mediated NKX1-2 knockdown in 3T3-L1 preadipocytes or EMSCs almost completely blocked adipocyte differentiation. Furthermore, NKX1-2 overexpression promoted differentiation of the ST2 bone marrow-derived mesenchymal precursor cell line into adipocytes. Additional findings suggested that NKX1-2 promotes adipogenesis by inhibiting expression of the antiadipogenic protein COUP transcription factor II. Bone marrow mesenchymal precursor cells can differentiate into adipocytes or osteoblasts, and we found that NKX1-2 both promotes ST2 cell adipogenesis and inhibits their osteoblastogenic differentiation. These results support a role for NKX1-2 in promoting adipogenesis and possibly in regulating the balance between adipocyte and osteoblast differentiation of bone marrow mesenchymal precursor cells.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Diferenciação Celular/genética , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Osteoblastos/metabolismo , Fatores de Transcrição/genética , Células 3T3-L1 , Adipócitos/citologia , Animais , Linhagem Celular , Células Cultivadas , Regulação da Expressão Gênica , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/metabolismo , Osteoblastos/citologia , Fator de Transcrição PAX8/genética , Fator de Transcrição PAX8/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Interferência de RNA , Fatores de Transcrição/metabolismo
11.
Trends Cancer ; 5(9): 547-557, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31474360

RESUMO

GLI-similar 1-3 (GLIS1-3), a subfamily of Krüppel-like zinc finger transcription factors, function as key regulators of several biological processes important to oncogenesis, including control of cell proliferation, differentiation, self-renewal, and epithelial-mesenchymal transition. This review provides a short overview of the critical roles genetic changes in GLIS1-3 play in the development of several malignancies. This includes intrachromosomal translocations involving GLIS2 and ETO2/CBFA2T3 in the development of pediatric non-Down's syndrome (DS), acute megakaryoblastic leukemia (AMKL), a malignancy with poor prognosis, and an association of interchromosomal translocations between GLIS3, GLIS1, and PAX8, and between GLIS3 and CLPTM1L with hyalinizing trabecular tumors (HTTs) and fibrolamellar hepatocellular carcinoma (FHCC), respectively. Targeting upstream signaling pathways that regulate GLIS signaling may offer new therapeutic strategies in the management of cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/genética , Leucemia Megacarioblástica Aguda/genética , Neoplasias Hepáticas/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias da Glândula Tireoide/genética , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Leucemia Megacarioblástica Aguda/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Mutação , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/metabolismo , Fator de Transcrição PAX8/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Dedos de Zinco/genética
12.
Cancer Res ; 79(22): 5746-5757, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31558562

RESUMO

Klhl14-AS is a long noncoding RNA expressed since early specification of thyroid bud and is the most enriched gene in the mouse thyroid primordium at E10.5. Here, we studied its involvement in thyroid carcinogenesis by analyzing its expression in cancer tissues and different models of neoplastic transformation. Compared with normal thyroid tissue and cells, Klhl14-AS was significantly downregulated in human thyroid carcinoma tissue specimens, particularly the anaplastic histotype, thyroid cancer cell lines, and rodent models of thyroid cancer. Downregulating the expression of Klhl14-AS in normal thyroid cells decreased the expression of thyroid differentiation markers and cell death and increased cell viability. These effects were mediated by the binding of Klhl14-AS to two miRNAs, Mir182-5p and Mir20a-5p, which silenced Pax8 and Bcl2, both essential players of thyroid differentiation. MIR182-5p and MIR20a-5p were upregulated in human thyroid cancer and thyroid cancer experimental models and their effects on Pax8 and Bcl2 were rescued by Klhl14-AS overexpression, confirming Klhl14-AS as a ceRNA for both Pax8 and Bcl2. This work connects deregulation of differentiation with increased proliferation and survival in thyroid neoplastic cells and highlights a novel ceRNA circuitry involving key regulators of thyroid physiology. SIGNIFICANCE: This study describes a new ceRNA with potential tumor suppression activity and helps us better understand the regulatory mechanisms during thyroid differentiation and carcinogenesis.


Assuntos
Carcinogênese/genética , Fator de Transcrição PAX8/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Longo não Codificante/genética , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Animais , Biomarcadores Tumorais/genética , Carcinogênese/patologia , Morte Celular/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HeLa , Humanos , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Regulação para Cima/genética
13.
Clin Endocrinol (Oxf) ; 91(6): 851-859, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31483883

RESUMO

OBJECTIVE: Fine needle cytology (FNC) is the first-line diagnostic method to determine the benign or malignant nature of thyroid nodules. The gray zone of cytological classifications remains, however, a crucial and challenging area for cytopathologists. DESIGN, PATIENTS AND MEASUREMENTS: In the present study, 141 thyroid cytological samples, with ultrasonographic suspicious features, have been prospectively analysed. Molecular analyses were performed by an innovative technology using two multiplex PCRs for the amplification of BRAF, N-H-K-RAS and RET exon genes. RNA samples were studied for RET/PTC1 and RET/PTC3 rearrangements by PCR amplification, and the conditions were set-up to study, with a single experiment, both wild-type PAX8 and PAX8/PPARÉ£ rearrangements. In total, 111 samples were examined for BRAF, N-H-KRAS and RET genes. An ultrasonographic, cytological and molecular correlation was also carried out in an attempt to suggest a possible way to manage the patients with thyroid nodules. Cyto-histological correlation was available in 115 cases, and it was used to verify the global diagnostic accuracy of this combined approach. RESULTS: According to the histopathological diagnosis, FNC accuracy was 100% for TIR5 and metastases; 89% for TIR4; 84% for TIR3A and 58% for TIR3B. About 11% of the studied samples showed either RET-PTC1 or RET/PTC3 chromosomal rearrangements, and only one sample simultaneously presented RET/PTC1 and RET/PTC3 rearrangements. PAX8/PPARÉ£ rearrangement was found in 6% of the samples. CONCLUSIONS: A multidisciplinary approach to the thyroid is therefore necessary to develop innovative methods suitable for an improved diagnostic and prognostic definition of thyroid cancer.


Assuntos
Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Análise Mutacional de DNA , Éxons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX8/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/genética , Adulto Jovem
14.
Aging (Albany NY) ; 11(18): 7746-7779, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31518338

RESUMO

An inverse correlation between thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness. However, hypothyroidism is a medical condition associated with compromised health and reduced life expectancy. Herein, we show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan. Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan. These pathophysiological conditions were precipitated by hepatic mitochondrial dysfunction and oxidative damage accumulation. These findings indicate that individuals carrying mutations on PAX8 may be susceptible to develop liver cancer and/or diabetes and raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan in mammals.


Assuntos
Envelhecimento/metabolismo , Fígado Gorduroso/patologia , Resistência à Insulina/fisiologia , Neoplasias Hepáticas/patologia , Fígado/patologia , Hormônios Tireóideos/sangue , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/sangue , Masculino , Camundongos , Camundongos Knockout , Fator de Transcrição PAX8/genética , Fator de Transcrição PAX8/metabolismo
15.
Cancer Cytopathol ; 127(9): 560-566, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31373774

RESUMO

Hyalinizing trabecular tumor (HTT) is a rare thyroid neoplasm with peculiar morphologic features that overlap with those of papillary thyroid carcinoma (PTC). Specifically, the presence of enlarged oval nuclei, nuclear grooves, and intranuclear pseudoinclusions makes precise cytopathologic diagnosis challenging. If the cytopathologic diagnosis is suspicious for malignancy (Bethesda V) or is malignant (Bethesda VI), a total thyroidectomy, which would be considered an overtreatment, may follow. The recent discovery of the strong association between GLIS fusions and HTT sheds light on its pathogenesis and offers a pathway for its presurgical identification. Although the number of cases analyzed is limited, the recent landmark study shows that GLIS fusions are highly specific for HTT and that lobectomy is the likely appropriate surgical treatment, because these neoplasms, which lack invasion, are benign. For overall success, cytopathologic recognition of the subtle features is important to avoid false-positive diagnoses and directing potential HTT cases toward indeterminate cytopathologic diagnoses, which would trigger further molecular testing. Additional studies are needed to determine whether a malignant counterpart of GLIS fusion-positive HTT exists and if more conservative approaches may be taken.


Assuntos
Biomarcadores Tumorais/genética , Fusão Gênica , Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/diagnóstico , Biópsia por Agulha Fina , Tomada de Decisão Clínica , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Humanos , Fator de Transcrição PAX8/genética , Guias de Prática Clínica como Assunto , Proteínas Repressoras/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/cirurgia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/cirurgia , Tireoidectomia/normas , Transativadores/genética , Fatores de Transcrição/genética , Dedos de Zinco/genética
16.
Nat Commun ; 10(1): 3739, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431624

RESUMO

Transcription factor networks shape the gene expression programs responsible for normal cell identity and pathogenic state. Using Core Regulatory Circuitry analysis (CRC), we identify PAX8 as a candidate oncogene in Renal Cell Carcinoma (RCC) cells. Validation of large-scale functional genomic screens confirms that PAX8 silencing leads to decreased proliferation of RCC cell lines. Epigenomic analyses of PAX8-dependent cistrome demonstrate that PAX8 largely occupies active enhancer elements controlling genes involved in various metabolic pathways. We selected the ferroxidase Ceruloplasmin (CP) as an exemplary gene to dissect PAX8 molecular functions. PAX8 recruits histone acetylation activity at bound enhancers looping onto the CP promoter. Importantly, CP expression correlates with sensitivity to PAX8 silencing and identifies a subset of RCC cases with poor survival. Our data identifies PAX8 as a candidate oncogene in RCC and provides a potential biomarker to monitor its activity.


Assuntos
Carcinoma de Células Renais/genética , Ceruloplasmina/genética , Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Renais/genética , Fator de Transcrição PAX8/genética , Acetilação , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Ceruloplasmina/metabolismo , Histonas/metabolismo , Humanos , Regiões Promotoras Genéticas/genética , Interferência de RNA , RNA Interferente Pequeno/genética
17.
J Pediatr Endocrinol Metab ; 32(11): 1265-1273, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31430255

RESUMO

Background Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods From an initial cohort of 79 patients with permanent CH (3-19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH.


Assuntos
Autoantígenos/genética , Hipotireoidismo Congênito/genética , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Mutação , Fator de Transcrição PAX8/genética , Simportadores/genética , Tireoglobulina/genética , Fator Nuclear 1 de Tireoide/genética , Adolescente , Adulto , Biomarcadores/análise , Criança , Pré-Escolar , Estudos de Coortes , Hipotireoidismo Congênito/epidemiologia , Feminino , Seguimentos , Testes Genéticos , Humanos , Masculino , Prognóstico , Adulto Jovem
18.
Anticancer Res ; 39(8): 4095-4100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366493

RESUMO

BACKGROUND/AIM: Ethacridine is used as a topical antiseptic as well as for second-trimester abortion. Recent studies showed that ethacridine is an inhibitor of poly(ADP-ribose) glycohydrolase (PARG) and an activator of the transcriptional coactivator with PDZ-binding motif (TAZ). This study examined the effects of ethacridine on thyroid cancer cells. MATERIALS AND METHODS: Thyroid cancer cell lines (FTC133 and SW1736) and thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with ethacridine. Viability, clonogenicity, cell-cycle distribution, and apoptosis were evaluated. The expression of thyroid differentiation markers (TTF-1, PAX8, and NIS) was determined by real-time PCR. RESULTS: Ethacridine suppressed cell growth and clonogenic ability of thyroid cancer cells in a time- and dose-dependent manner (p<0.001). No cell-cycle arrest was found, but ethacridine dose-dependently induced apoptosis of thyroid cancer cells (p<0.001). The PAX8 and NIS expressions were significantly increased in SW1736 (3.41-fold and 1.53-fold, respectively) and Nthy-ori 3-1 cells (2.73-fold and 4.12-fold, respectively). CONCLUSION: Ethacridine elicits apoptotic cell death in thyroid cancer cells and promotes differentiation in a subset of thyroid follicular cells.


Assuntos
Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Etacridina/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Transcrição PAX8/genética , Simportadores/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fator Nuclear 1 de Tireoide/genética
19.
Oncogene ; 38(32): 6003-6016, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31296958

RESUMO

High grade serous ovarian cancer (HGSOC) is the fifth leading cause of cancer deaths among women yet effective targeted therapies against this disease are limited. The heterogeneity of HGSOC, including few shared oncogenic drivers and origination from both the fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE), has hampered development of targeted drug therapies. PAX8 is a lineage-specific transcription factor expressed in the FTE that is also ubiquitously expressed in HGSOC where it is an important driver of proliferation, migration, and cell survival. PAX8 is not normally expressed in the OSE, but it is turned on after malignant transformation. In this study, we use proteomic and transcriptomic analysis to examine the role of PAX8 leading to increased migratory capabilities in a human ovarian cancer model, as well as in tumor models derived from the OSE and FTE. We find that PAX8 is a master regulator of migration with unique downstream transcriptional targets that are dependent on the cell's site of origin. Importantly, we show that targeting PAX8, either through CRISPR genomic alteration or through drug treatment with micelle encapsulated thiostrepton, leads to a reduction in tumor burden. These findings suggest PAX8 is a unifying protein driving metastasis in ovarian tumors that could be developed as an effective drug target to treat HGSOC derived from both the OSE and FTE.


Assuntos
Movimento Celular/genética , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/patologia , Fator de Transcrição PAX8/fisiologia , Peritônio/patologia , Tioestreptona/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Tubas Uterinas/patologia , Feminino , Perfilação da Expressão Gênica , Camundongos , Camundongos Nus , Micelas , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Fator de Transcrição PAX8/genética , Peritônio/efeitos dos fármacos , Peritônio/metabolismo , Proteoma/análise , Proteoma/metabolismo , Proteômica , Tioestreptona/administração & dosagem
20.
Artif Cells Nanomed Biotechnol ; 47(1): 3180-3187, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31353958

RESUMO

PAX8 is identified as a regulator in the pathogenesis of human tumours and an indicator of the prognosis for patients. However, the role of PAX8 on proliferation in gastric cancer have not been studied. This study was aimed to explore the expression pattern of PAX8 in gastric cancer, and investigate the effect of PAX8 on the proliferation of gastric cancer cells. PAX8 and SOX13 were identified to be synchronously up-regulated in primary gastric cancer in human gastric cancer tissues and the gastric cancer datasets of TCGA, and gastric cancer patients of combined high PAX8 and SOX13 expression showed poor prognosis. Furthermore, SOX13 can mediate PAX8 and its targeted genes, Aurora B and Cyclin B1, expression in AGS and MGC803 cell lines. Flow cytometry and EdU incorporation assays showed that silencing PAX8 can block the cell cycle of gastric cancer cell in G1 phase and SOX13 expression can rescue the arrested proliferative process induced by PAX8 silenced in CCK8 and colony formation assays. Thus, combined SOX13 and PAX8 expression regulate the proliferation of gastric cancer cells, and both SOX13 and PAX8 play an oncogene function in gastric cancer.


Assuntos
Autoantígenos/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator de Transcrição PAX8/genética , Fatores de Transcrição SOXD/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Análise de Sobrevida , Regulação para Cima
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...