Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 34
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Metab ; 31: 24-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31918919

RESUMO

OBJECTIVE: Long-term glucocorticoids (GCs) therapy usually causes many metabolic side effects, including fatty liver. However, the molecular mechanisms remain poorly understood. Herein, we explored the molecular basis of GCs in the development of fatty liver. METHODS: C57BL/6 male mice were injected with Dexamethasone (DEX) while mouse primary hepatocytes (MPHs), HepG2 and Hep1-6 cells were cultured in the presence of DEX. Genes expression in liver tissues and hepatocytes were assessed by quantitative real-time PCR and western blotting, respectively. To explore whether Periostin is involved in the development of GCs-induced fatty liver, wild-type and Periostin knockout mice were treated with DEX or vehicle control. Luciferase reporter and chromatin immunoprecipitation assays were used to determine the regulatory roles of GCs on Periostin expression. RESULTS: We show that treatment of dexamethasone (DEX), a synthetic analog of GCs, led to the accumulation of triglycerides in the livers of mice, but not in cultured hepatocytes, suggesting that GCs may promote liver steatosis through integrative organ crosstalk mediated by systemic factors. We further found that DEX upregulated the expression levels of Periostin in white adipose tissues, which in turn promoted liver steatosis. Administration of a Periostin-neutralizing antibody or genetic ablation of Periostin largely attenuated DEX-induced hepatic steatosis in mice. CONCLUSIONS: Our findings provided a novel insight that GCs could promote liver steatosis through integrative organ crosstalk mediated by white fat-secreted Periostin. These results establish Periostin as an endocrine factor with therapeutic potential for the treatment of GCs-associated fatty liver.

2.
HPB (Oxford) ; 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31843444

RESUMO

BACKGROUND: To compare outcomes of patients with arterially hyperenhancing intrahepatic cholangiocarcinomas (ICC) and arterially hypoenhancing ICCs after partial hepatectomy in a cohort with an analysis of prognostic factors. METHODS: From June 2009 to October 2011, a prospective cohort of 68 patients with single resectable ICCs (≤5 cm in diameter) underwent gadolinium contrast-enhanced dynamic-phase magnetic resonance imaging and were treated with partial hepatectomy. Patients were divided into those with arterially hyperenhancing ICCs (n = 28) or arterially hypoenhancing ICCs (n = 40). Clinic-radiologic-pathologic results and survival of these patients were compared and statistically analyzed. RESULTS: The median overall survival (OS) time was significantly longer in the arterially hyperenhancing ICCs (56.8 vs. 37.0 months) (p = 0.044). At pathologic evaluation, arterially hyperenhancing ICCs showed significantly higher microvessel count (MVC) than arterially hypoenhancing ICCs (106.2 ± 47.5 vs. 46.9 ± 21.6/mm2, p = 0.001). Arterial enhancement of ICCs was found to be an independent prognostic factor for longer survival. CONCLUSION: The presence of arterially hyperenhancing ICCs is related to higher MVC and exhibit a better OS time than arterially hypoenhancing ICCs after partial hepatectomy.

3.
Theranostics ; 9(12): 3526-3540, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281495

RESUMO

Circular RNA (circRNA) possesses great pre-clinical diagnostic and therapeutic potentials in multiple cancers. It has been reported playing roles in multiple malignant behaviors including proliferation, migration, metastasis and chemoresistance. However, the underlying correlation between circRNAs and cancer stem cells (CSCs) has not been reported yet. Methods: circZKSCAN1 level was detected in HCC tissue microarrays to clarify its prognostic values. Gain and loss function experiments were applied to investigate the role of circZKSCAN1 in HCC stemness. Bioinformatic analysis was used to predict the possible downstream RNA binding protein and further RNA immunoprecipitation sequencing was carried out to identify the RBP-regulated genes. Results: The absence of circZKSCAN1 endowed several malignant properties including cancer stemness and tightly correlated with worse overall and recurrence-free survival rate in HCC. Bioinformatics analysis and RNA immunoprecipitation-sequencing (RIP-seq) results revealed that circZKSCAN1 exerted its inhibitive role by competitively binding FMRP, therefore, block the binding between FMRP and ß-catenin-binding protein-cell cycle and apoptosis regulator 1 (CCAR1) mRNA, and subsequently restrain the transcriptional activity of Wnt signaling. In addition, RNA-splicing protein Quaking 5 was found downregulated in HCC tissues and responsible for the reduction of circZKSCAN1. Conclusion: Collectively, this study revealed the mechanisms underlying the regulatory role of circZKSCAN1 in HCC CSCs and identified the newly discovered Qki5-circZKSCAN1-FMRP-CCAR1-Wnt signaling axis as a potentially important therapeutic target for HCC treatment.

4.
Psychooncology ; 28(6): 1269-1277, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30946503

RESUMO

OBJECTIVE: Cancer survivors (CSs) often face the dual physical burden of cancer and other comorbid chronic disease (CCD) and have a great deal of psychological distress, such as anxiety and depression. However, the association between CCD and psychological problems remain less clear in CS. This study was performed to investigate the prevalence of anxiety and depression in Chinese CS, and whether CCD have impact on CSs' anxiety and depression. METHODS: A cross-sectional study was conducted among 1546 CSs in Shanghai, China. All participants were asked to complete a questionnaire containing Zung self-rating anxiety scale (SAS), Zung self-rating depression scale (SDS), and questions on sociodemographic characteristics and CCD. Associations between CCDs, and anxiety and depression, were evaluated by using logistic regression, adjusted for confounding factors. RESULTS: The prevalence of anxiety and depression in CSs were 28.2 % and 48.2%, respectively. 74.9% CSs had one or more comorbidities. Almost all CCDs examined showed associations with anxiety, except for CSs with diabetes. CSs with hyperlipidemia, diabetes, heart and cardiovascular diseases, and musculoskeletal diseases had significantly greater depression scores. When compared with those without CCD, CSs with one to two CCDs and greater than or equal to three CCDs had higher risks of anxiety and depression. CONCLUSIONS: Anxiety and depression were more prevalent among CSs who also had CCDs. CCD have significantly negative association with CSs' anxiety and depression. Further cohort research will help deduce the causal relationships between CCDs, and anxiety and depression.

5.
Cell Death Dis ; 9(2): 59, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29352111

RESUMO

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is typically diagnosed at advanced stages. Identification and characterisation of genes within amplified and deleted chromosomal loci can provide new insights into the pathogenesis of cancer and lead to new approaches for diagnosis and therapy. In our previous study, we found a recurrent region of copy number amplification at 19p13.2 in hepatocellular carcinoma (HCC). In the present study, we performed integrated copy number analysis and expression profiling at this locus and a putative cancer gene, SMARCA4/BRG1, was uncovered in this region. BRG1 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF. The function of BRG1 in various cancers is unclear, including its role in HCC tumorigenesis. Here, we found that BRG1 is upregulated in HCC and that its level significantly correlates with cancer progression in HCC patients. Importantly, we also found that nuclear expression of BRG1 predicts early recurrence for HCC patients. Furthermore, we demonstrated that BRG1 promotes HCC cell proliferation in vitro and in vivo. BRG1 was observed not only to facilitate S-phase entry but also to attenuate cell apoptosis. Finally, we discovered that one of the mechanisms by which BRG1 promotes cell proliferation is the upregulation of SMAD6. These findings highlight the important role of BRG1 in the regulation of HCC proliferation and provide valuable information for cancer prognosis and treatment.


Assuntos
Carcinoma Hepatocelular/genética , DNA Helicases/metabolismo , Neoplasias Hepáticas/genética , Proteínas Nucleares/metabolismo , Proteína Smad6/metabolismo , Fatores de Transcrição/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Humanos , Neoplasias Hepáticas/patologia , Prognóstico
6.
Mol Clin Oncol ; 7(4): 615-622, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29046795

RESUMO

The effect of cirrhosis on the characteristics of intrahepatic cholangiocarcinoma (ICC) has not been fully elucidated. The purpose of this study was to investigate how cirrhosis affects the clinicopathological characteristics and survival of surgically treated ICC patients. A total of 1,312 ICC patients surgically treated between January 2007 and December 2011 at a single institution were retrospectively reviewed and the clinicopathological data were compared between cirrhotic and non-cirrhotic patients. Univariate and multivariate analyses were performed to identify significant and independent prognostic factors in this cohort. A total of 302 patients (23.0%) were cirrhotic. Compared with cirrhotic patients, the tumors in non-cirrhotic patients were usually larger, less differentiated, and more likely to have lymphatic metastasis, vascular and perineural invasion. Following resection, cirrhotic patients achieved a longer survival compared with non-cirrhotic patients (16.0 vs. 13.0 months, respectively; P<0.038). Multivariate analysis demonstrated that hepatitis B virus infection and cirrhosis were independent favorable prognostic factors, while the presence of cholelithiasis, elevated carbohydrate antigen 19-9 and carcinoembryonic antigen levels, multiple tumors, lymphatic metastasis, vascular invasion and positive surgical margin status were independent unfavorable prognostic factors. Overall, the clinicopathological characteristics of ICC patients with and without cirrhosis differed significantly. Compared with cirrhotic patients, in whom the biological behavior of ICC was similar to that of HCC, non-cirrhotic patients exhibited higher-risk pathological characteristics, lower curative resection rate and worse survival.

7.
Hepatology ; 66(6): 1934-1951, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28714104

RESUMO

The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6-positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted tumor necrosis factor-α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6-positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. CONCLUSION: Our results not only clarify the cellular and molecular mechanisms underlying the inflammation-mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934-1951).


Assuntos
Transformação Celular Neoplásica , Inflamação/patologia , Neoplasias Hepáticas/metabolismo , Fígado/patologia , Células-Tronco Neoplásicas , Animais , Antígenos de Diferenciação/metabolismo , Antineoplásicos/uso terapêutico , Autorrenovação Celular , Instabilidade Cromossômica , Doença Crônica , Feminino , Humanos , Interleucina-6/fisiologia , Queratina-19/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Macrófagos/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Ratos Wistar , Fator de Transcrição STAT3/metabolismo , Sorafenibe , Fator de Necrose Tumoral alfa/fisiologia , Quinases da Família src/metabolismo
8.
Cancer Res ; 77(16): 4498-4505, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28522754

RESUMO

Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor-dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498-505. ©2017 AACR.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Modelos Animais de Doenças , Éxons , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Terapia de Alvo Molecular , Mutação , Transfecção
9.
JGH Open ; 1(2): 76-78, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30483539

RESUMO

A 61-year-old Chinese male was found to have a lesion in the left liver during a routine body check-up. Laboratory tests revealed no abnormalities except for a rise in C-reactive protein. Computed tomography showed features suggestive of hepatocellular carcinoma. The patient underwent liver IVb segmentectomy and cholecystectomy. Histopathology showed features of hepatic inflammatory pseudotumor. The C-reactive protein decreased to close to normal on postoperative day 9. A patient with hepatic inflammatory pseudotumor who presented with features mimicking hepatocellular carcinoma was reported. A preoperatively raised C-reactive protein was the only hint which suggested that our patient might have had hepatic inflammatory pseudotumor instead of hepatocellular carcinoma.

10.
Front Pharmacol ; 8: 973, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29375378

RESUMO

The long-term survival rate of hepatocellular carcinoma (HCC) is poor. One of the reasons for the poor rate of survival is the high rate of recurrence caused by intrahepatic metastas is that adversely affects long-term outcome. Many studies have indicated that microRNAs play an important role in HCC, but there has been no research of clonal origins on recurrent HCC (RHCC) by analzing microRNAs. In the present study, we found that miR-483-5p was significantly upregulated in RHCC tissues of short-term recurrence (≤ 2 years) by miRNA microarray screening, and can significantly promote migration and invasion of HCC cells in vitro and increase intrahepatic metastasis in nude mice in vivo. Furthermore, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM), which significantly suppressed migration and invasion of HCC cells, was a direct target of miR-483-5p, and the re-introduction of ALCAM expression could antagonize the promoting effects of miR-483-5p on the capacity of HCC cells for migration and invasion. In addition, expression level of ALCAM was negatively correlated with microvascular invasion and tumor size recognized as prognostic factors. The cases which were negative for ALCAM expression had shorter time to recurrence than positive cases, and univariate and multivariate survival analyses showed that ALCAM was an independent risk factor of HCC recurrence. qRT-PCR and Western blotting showed that the expression of EMT related genes (MMP-2, MMP-9, E-caherin and vimentin) significantly changed as a result of interfering or overexpression of ALCAM, and ALCAM was significantly associated with EMT in HCC. These results suggest that the miR-483-5p/ALCAM axis is an important regulator in invasion and metastasis and biomarker for recurrence risk assessment of HCC.

11.
Cell Cycle ; 16(2): 213-223, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-28027003

RESUMO

The phosphatase Wip1 attenuates the DNA damage response (DDR) by removing phosphorylation marks from a number of DDR proteins (p53, MDM2, Chk1/2, p38). Wip1 also dephosphorylates and inactivates RelA. Notably, LZAP, a putative tumor suppressor, has been linked to dephosphorylation of several of these substrates, including RelA, p38, Chk1, and Chk2. LZAP has no known catalytic activity or functional motifs, suggesting that it exerts its effects through interaction with other proteins. Here we show that LZAP binds Wip1 and stimulates its phosphatase activity. LZAP had been previously shown to bind many Wip1 substrates (RelA, p38, Chk1/2), and our results show that LZAP also binds the previously identified Wip1 substrate, MDM2. This work identifies 2 novel Wip1 substrates, ERK1 and HuR, and demonstrates that HuR is a binding partner of LZAP. Pleasingly, LZAP potentiated Wip1 catalytic activity toward each substrate tested, regardless of whether full-length substrates or phosphopeptides were utilized. Since this effect was observed on ERK1, which does not bind LZAP, as well as for each of 7 peptides tested, we hypothesize that LZAP binding to the substrate is not required for this effect and that LZAP directly binds Wip1 to augment its phosphatase activity.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Biocatálise , Linhagem Celular Tumoral , Células HEK293 , Humanos , Fosfopeptídeos/metabolismo , Fosforilação , Ligação Proteica , Especificidade por Substrato
12.
Oncol Rep ; 36(5): 2663-2672, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27666632

RESUMO

Intrahepatic cholangiocarcinoma (ICC) is usually confirmed in advanced stage at the time of diagnosis or after surgical exploration, however, indication of surgical treatment is usually controversial for ICC in advanced stages. This retrospective study aims to evaluate clinical value of surgery for such tumors, in order to identify the appropriate patients who will benefit from surgery, and to evaluate the prognostic accuracy of the current staging system for advanced ICC. From January 2007 to December 2011, 387 consecutive surgically treated patients with ICC in AJCC­stage â…£ were evaluated. Survival was compared among different patients grouped by different elements of AJCC staging system. The prognostic importance of extent of lymph node (LN) metastasis relative to the AJCC N and M classification system was assessed. Our data showed that survival was much better for patients in AJCC­stage â…£A group (median survival time, MST, 9.0 months) than in AJCC­stage â…£B group (MST, 5.0 months) (P<0.001). While in AJCC­stage â…£B group, survival for patients in AnyTN2­3M0 subgroup (MST, 9.0 months) was much better than in AnyTN0M1 subgroup (MST, 3.0 months); and better than in AnyTN2­3M1 subgroup (MST, 4.0 months) (P<0.001). Overall, R0 and R1 liver resection should be indicated for patients in AJCC­stage â…£A group and AnyTN2­3M0 subgroup in AJCC­stage â…£B group, as patients in these groups will benefit from surgery with relatively better survival. Staging of advanced ICC by N2­3 instead of M1 for extended LN metastasis classification is superior in comparison with the AJCC staging system.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Neoplasias Hepáticas/cirurgia , Prognóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/patologia , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
13.
Chin J Cancer ; 35(1): 82, 2016 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-27552844

RESUMO

BACKGROUND: Combined hepatocellular and cholangiocarcinoma (CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its cellular origin remains unclear. The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC. METHODS: The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC (SHC). Loss of heterozygosity (LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC. Expression of hepatocyte markers [hepatocyte paraffin 1 (Hep Par 1) and glypican 3 (GPC3)] and cholangiocyte markers [cytokeratin (CK)7 and 19] in tumor tissues was examined by immuno histochemical analysis. RESULTS: In the 16 CHC specimens, the difference in LOH patterns between HCC and ICC was less than 30%, suggesting the same clonal origin of HCC and ICC. Consistent with this finding, immunohistochemical analysis revealed that hepatocyte markers (Hep Par 1 and GPC3) and cholangiocyte markers (CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9% of CHC specimens, suggesting that the two components shared a similar phenotype with hepatic progenitor cells (HPCs). On the contrary, in all 10 SHC cases, the difference in LOH patterns between the HCC and ICC components was greater than 30%, suggesting different clonal origins of HCC and ICC. Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC (P < 0.05). CONCLUSIONS: Our results suggest that the HCC and ICC components of CHC may originate from the same clone, having the potential for dual-directional differentiation similar to HPCs. CHC tended to exhibit the biological behaviors of both HCC and ICC, which may enhance the infiltrative capacity of tumor cells, leading to poor clinical outcomes for patients with CHC.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/secundário , Colangiocarcinoma/secundário , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/cirurgia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
14.
Radiology ; 281(1): 150-7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27077381

RESUMO

Purpose To assess the accuracy of magnetic resonance (MR) imaging-based differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in a cohort of patients with focal liver lesions and cirrhosis. Materials and Methods This study was institutional review board approved, and the requirement for informed consent was waived. Between January 2009 and December 2014, a cohort of cirrhotic patients, including 71 with ICC and 612 with HCC, underwent unenhanced T1- and T2-weighted MR imaging, gadolinium-based contrast material-enhanced dynamic phase imaging, and partial hepatectomy. Results of pathologic examinations were obtained for all patients. Clinical, radiologic, and pathologic results in these patients were analyzed and compared comprehensively. Differences in signal intensity on baseline and contrast material-enhanced images and dynamic enhancement patterns were evaluated and compared by using the χ(2) test or the Fisher exact test. Results The preoperative diagnoses of 517 of 683 lesions were confirmed pathologically. Five ICCs and 481 HCCs displayed contrast material washout in delayed phases (P < .001). Thirty-six ICCs and 23 HCCs displayed a progressive enhancement pattern (P < .001). Twenty-six ICCs and 63 HCCs displayed a stable enhancement pattern (P < .001). ICCs displayed significantly different enhancement patterns according to size (P = .022). Conclusion The accurate discrimination of small ICCs from HCCs in the setting of cirrhosis at MR imaging is difficult, as substantial proportions of ICCs and HCCs have similar enhancement patterns. Absence of contrast material washout at MR imaging is not a factor that prevents the misdiagnosis of HCC. (©) RSNA, 2016 Online supplemental material is available for this article.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico por imagem , Colangiocarcinoma/diagnóstico por imagem , Cirrose Hepática/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Biomarcadores Tumorais/análise , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Meios de Contraste , Diagnóstico Diferencial , Feminino , Hepatectomia/métodos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
Gut ; 65(7): 1186-201, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26860770

RESUMO

OBJECTIVE: Precancerous lesion, a well-established histopathologically premalignant tissue with the highest risk for tumourigenesis, develops preferentially from activation of DNA damage checkpoint and persistent inflammation. However, little is known about the mechanisms by which precancerous lesions are initiated and their physiological significance. DESIGN: Laser capture microdissection was used to acquire matched normal liver, precancerous lesion and tumour tissues. miR-484(-/-), Ifnar1(-/-) and Tgfbr2(△hep) mice were employed to determine the critical role of the interferon (IFN)-microRNA pathway in precancerous lesion formation and tumourigenesis. RNA immunoprecipitation (RIP), pull-down and chromatin immunoprecipitation (ChIP) assays were applied to explore the underlying mechanisms. RESULTS: miR-484 is highly expressed in over 88% liver samples clinically. DEN-induced precancerous lesions and hepatocellular carcinoma were dramatically impaired in miR-484(-/-) mice. Mechanistically, ectopic expression of miR-484 initiates tumourigenesis and cell malignant transformation through synergistic activation of the transforming growth factor-ß/Gli and nuclear factor-κB/type I IFN pathways. Specific acetylation of H3K27 is indispensable for basal IFN-induced continuous transcription of miR-484 and cell transformation. Convincingly, formation of precancerous lesions were significantly attenuated in both Tgfbr2(△hep) and Ifnar1(-/-) mice. CONCLUSIONS: These findings demonstrate a new protumourigenic axis involving type I IFN-microRNA signalling, providing a potential therapeutic strategy to manipulate or reverse liver precancerous lesions and tumourigenesis.


Assuntos
Carcinoma Hepatocelular/genética , Transformação Celular Neoplásica/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Lesões Pré-Cancerosas/genética , Transdução de Sinais , Acetilação , Animais , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/química , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Hepatócitos , Humanos , Interferon Tipo I/metabolismo , Fígado/química , Neoplasias Hepáticas/química , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Knockout , MicroRNAs/análise , NF-kappa B/metabolismo , Células NIH 3T3 , Pentanonas , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Regiões Promotoras Genéticas , Proteínas Serina-Treonina Quinases/genética , Receptor de Interferon alfa e beta/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Fator de Crescimento Transformador beta/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo
16.
Pathol Res Pract ; 211(12): 918-24, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26608415

RESUMO

Hepatocellular adenoma (HCA) is a benign hepatocyte-derived tumor commonly seen in reproductive-aged women with long-term use of oral contraceptives (OCs) in European and North American countries. Accordingly, HCA is currently classified into four molecular subtypes as adopted by the World Health Organization. The present study was firstly to characterize and determine the genetic alterations and clinicopathological features of the largest series of HCAs in China. We reviewed 189 patients with HCA who underwent hepatectomies at our liver center from January 1984 to January 2012, among which 36 HCAs were randomly selected for the sequencing of HNF1α, ß-catenin and gp130 genes, and 60 HCAs were randomly selected for detecting microsatellite instability (MSI). Compared with Western studies, our data showed distinctive findings including male (69.8%) and overweight/obese (50.3%) predominance. Only 3.5% of female patients had a documented history of OCs use for 2-4 years. All 36 sequenced HCAs showed HNF1α mutations (72% missense, 28% synonymous), 2 hotspot polymorphisms of HNF1α (I27L: rs1169288 and S487N: rs2464196) were seen in 17 (47%) and 10 (27.8%) cases, respectively, and a novel single nucleotide polymorphism site (rs1169304) in intron 9 of HNF1α was detected in 32 (88%) cases, but no ß-catenin or gp130 gene mutation was detected, and no nuclear ß-catenin staining was detected by immunohistochemistry. The frequency of MSI was 75% for D12S1398 (HNF1α inactivated pathway) and 78.5% for D6S1064 (HIPPO signaling pathway) in 34 overweight/obese patients with HCA. Our results firstly indicate that patients with HCA in China frequently occur in male overweigh and obese adult population, lack an association with OCs use and exhibit unique genetic alterations. Taken together, these observations suggest that alternative pathogenetic pathways involve in HCA tumorigenesis in Chinese patients.


Assuntos
Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Adenoma de Células Hepáticas/complicações , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/análise , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/complicações , Perda de Heterozigosidade , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Reação em Cadeia da Polimerase , Fatores de Risco , Adulto Jovem
17.
Pathol Res Pract ; 211(12): 905-10, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26452486

RESUMO

AIMS: Hepatic carcinosarcoma (HCS) is an aggressive tumor for which a consensus regarding the clonal origin has not yet been reached. The aim of the study was to identify the origin of the hepatocellular carcinoma (HCC) and sarcoma components in HCS. METHODS: We chose microsatellite technique containing loss of heterozygosity (LOH) and microsatellite instability (MSI) on three HCS patients who underwent curative resection confirmed by pathological examination. Tumors were firstly analyzed for Hep Par 1, CK18, CD10, CD117, SMA and vimentin expression by immunohistochemistry. LOH and MSI were then investigated. The incidence rate of LOH/MSI in all nine MS was calculated as the fractional allelic loss (FAL) index, which was internationally recognized standard. A FAL<30% was representative of a monoclonal origin and a FAL≥30% indicated a polyclonal origin. RESULTS: All patients were positive for HBsAg. Microscopic examination showed HCS containing two different cell types: a fibrosarcoma component with spindle cells and an HCC population of cells with a trabecular pattern. In the HCC tumor portions, Hep Par 1, CK18, CD10 were expressed while vimentin was not. In contrast, the spindle cell populations were positive for vimentin and negative for Hep Par 1, CK18, CD10. The highest frequencies of LOH and MSI were at the D16S505 (2/3; 66.7%), D17S831 (2/3; 66.7%) and D17S938 MS (2/3; 66.7%). The FALs for the three cases of HCS were 50% (4/8), 55.6% (5/9) and 33.3% (3/9), suggesting a polyclonal origin. CONCLUSIONS: Immunohistochemistry and analysis of LOH and MSI strongly demonstrated that the three HCS samples were consistent with a polyclonal origin for all three cases.


Assuntos
Biomarcadores Tumorais/análise , Carcinossarcoma/genética , Carcinossarcoma/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Masculino , Microdissecção , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Polimorfismo Conformacional de Fita Simples , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Cancer Discov ; 5(8): 850-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25971938

RESUMO

UNLABELLED: Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting. SIGNIFICANCE: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.


Assuntos
Processamento Alternativo , Antineoplásicos/uso terapêutico , Éxons , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Análise por Conglomerados , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Imuno-Histoquímica , Masculino , Mutação , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Tomografia Computadorizada por Raios X
19.
Genes Dev ; 29(6): 658-71, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25792600

RESUMO

Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.


Assuntos
Carcinoma Ductal Pancreático/fisiopatologia , Transformação Celular Neoplásica/genética , DNA Helicases/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/fisiopatologia , Fatores de Transcrição/metabolismo , Animais , Azepinas/farmacologia , Azepinas/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Transformação Celular Neoplásica/efeitos dos fármacos , DNA Helicases/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Proteínas Nucleares/genética , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição/genética , Triazóis/farmacologia , Triazóis/uso terapêutico , Células Tumorais Cultivadas
20.
Nat Genet ; 47(3): 250-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25665005

RESUMO

Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , MAP Quinase Quinase Quinases/antagonistas & inibidores , Fosfoproteínas/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Técnicas de Silenciamento de Genes , Genes ras , Células HEK293 , Células HT29 , Xenoenxertos , Humanos , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular , Mutação , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Fatores de Transcrição
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA