Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.350
Filtrar
1.
Anticancer Res ; 41(10): 4917-4928, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593439

RESUMO

BACKGROUND/AIM: The functions of interleukin 33 (IL-33) in cholangiocarcinoma (CCA) are unclear. This study aimed to evaluate the roles of IL-33 in CCA progression. MATERIALS AND METHODS: The effect of intracellular IL-33 using shIL-33 knocked down KKU-055 (IL-33KD-KKU-055) compared to parental (Pa) KKU-055 and extracellular IL-33 using recombinant human IL-33 (rhIL-33) treatment on the proliferation and invasion of CCA cells grown in 3D cultures was studied. Relevant markers were determined by western blot or ELISA. RESULTS: IL-33KD-KKU-055 cells showed increased proliferation and invasion in 3D cultures compared to Pa-KKU-055 cells, with NF-κB and IL-6 up-regulation. Treatment with 2 ng/ml rhIL-33 promoted Pa-KKU-055 cell proliferation by inducing NF-κB and IL-6 expressions. Upon GSK-3ß inactivation and increased nuclear full-length IL-33 (flIL-33), 20 ng/ml rhIL-33 had no effect on proliferation. Both 2 and 20 ng/ml rhIL-33 induced proliferation and invasion of IL-33-negative KKU-213 cells in 3D cultures, as well as NF-κB and IL-6 up-regulation. CONCLUSION: Intracellular and extracellular IL-33 have distinct roles in the mechanisms of CCA progression.


Assuntos
Neoplasias dos Ductos Biliares/prevenção & controle , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/prevenção & controle , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Interleucina-33/farmacologia , NF-kappa B/metabolismo , Apoptose , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Proliferação de Células , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Glicogênio Sintase Quinase 3 beta/genética , Humanos , NF-kappa B/genética , Invasividade Neoplásica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360994

RESUMO

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient's survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Glicina/análogos & derivados , Radiossensibilizantes/farmacologia , Sulfonas/farmacologia , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Glicina/farmacologia , Humanos
3.
BMC Cancer ; 21(1): 865, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34320944

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Proteomic remains partially unexplored; here, we analyzed the proteomic profile of five intrahepatic cholangiocarcinoma (ICC) derived from Italian patients undergone surgery and one normal bile duct cell line. METHODS: Proteome profile was investigated by using 2D electrophoresis followed by Mass Spectrometry (MS). To validate proteomic data, the expression of four overexpressed proteins (CAT, SOD, PRDX6, DBI/ACBP) was evaluated by immunohistochemistry in an independent cohort of formalin fixed, paraffin-embedded (FFPE) ICC tissues. We also compared proteomic data with those obtained by transcriptomic profile evaluated by microarray analysis of the same tissues. RESULTS: We identified 19 differentially expressed protein spots, which were further characterized by MS; 13 of them were up- and 6 were down-regulated in ICC. These proteins are mainly involved in redox processes (CAT, SODM, PRDX2, PRDX6), in metabolism (ACBP, ACY1, UCRI, FTCD, HCMS2), and cell structure and organization (TUB2, ACTB). CAT is overexpressed in 86% of patients, PRDX6 in 73%, SODM in 100%, and DBI/ACBP in 81% compared to normal adjacent tissues. A concordance of 50% between proteomic and transcriptomic data was observed. CONCLUSIONS: This study pointed out that the impairment of the metabolic and antioxidant systems, with a subsequent accumulation of free radicals, might be a key step in CCA development and progression.


Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais , Colangiocarcinoma/metabolismo , Metabolismo Energético , Oxirredução , Proteoma , Proteômica , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Eletroforese em Gel Bidimensional , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Espectrometria de Massas/métodos , Proteômica/métodos
4.
Anticancer Res ; 41(7): 3389-3400, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230134

RESUMO

BACKGROUND/AIM: Cholangiocarcinoma (CCA), a biliary cancer, is a health problem worldwide. The major problem in CCA treatment presents limited options. To date, targeting cancer metabolism is a promising anti-cancer strategy. To elucidate the functional importance of lipid metabolism in CCA, de novo lipogenesis was inhibited using 5-(tetradecyloxy)-2-furoic acid (TOFA), an acetyl CoA carboxylase inhibitor. MATERIALS AND METHODS: Anti-proliferative effects of TOFA were determined both in vitro and in vivo. Its inhibitory effect on cell-cycle and apoptosis was investigated by flow cytometry and western blot analysis of relevant markers. RESULTS: TOFA inhibited CCA cell growth, induced cell-cycle progression accompanied by apoptosis in a dose-dependent manner. Induction of p21, and caspase-3, -8, and -9 cleavages, while down-regulation of cyclin B1 and cyclin D1 were observed in TOFA-treated cells. The therapeutic potential was demonstrated in vivo. CONCLUSION: De novo lipogensis is essential for CCA cell growth and is an alternative target for CCA treatment.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Furanos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos
5.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203536

RESUMO

Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.


Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Colangite Esclerosante/metabolismo , Microbioma Gastrointestinal/fisiologia , Animais , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangite Esclerosante/genética , Microbioma Gastrointestinal/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Camundongos
6.
Anticancer Res ; 41(8): 3769-3778, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281836

RESUMO

BACKGROUND/AIM: Cholangiocarcinoma is a lethal disease with increasing incidence worldwide. New therapeutic compounds are urgently needed for this disease. Here, the inhibitory effect of adenosine on cholangiocarcinoma cells was studied. MATERIALS AND METHODS: Western blot analysis was used to study autophagy and flow cytometry to analyze cell death and the cell cycle. RESULTS: Cholangiocarcinoma and immortalized cholangiocytes responded to adenosine differently, and adenosine inhibited cholangiocarcinoma cell growth by inducing autophagy. Adenosine failed to activate adenylyl cyclase in cholangiocarcinoma cell lines, but activated this enzyme in immortalized cholangiocytes. Adenosine treatment activated AMPK and led to phosphorylation of its downstream proteins including ULK and Raptor. In addition, autophagy induced by adenosine appeared to be a survival mechanism. The combination of adenosine with autophagy inhibitors greatly increased cell death, as compared to the use of either agent alone. Interestingly, immortalized cholangiocytes were more resistant to adenosine. CONCLUSION: Adenosine may have potential for application in cholangiocarcinoma treatment.


Assuntos
Adenosina/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/fisiologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , AMP Cíclico/metabolismo , Humanos , Hidroxicloroquina/farmacologia , Macrolídeos/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Regulatória Associada a mTOR/metabolismo
7.
Am J Pathol ; 191(9): 1651-1667, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34129844

RESUMO

Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignant neoplasm with limited therapeutic options. Previous studies have found that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. The current study found that activation of the Yes-associated protein (Yap) proto-oncogene occurs during Notch1-driven iCCA progression. After co-expressing activated Notch1 intracellular domain (Nicd) and Yap (YapS127A) in the mouse liver, rapid iCCA formation and progression occurred in Nicd/Yap mice. Mechanistically, an increased expression of amino acid transporters and activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway was detected in Nicd/Yap mouse liver tumors. Significantly, the genetic deletion of Raptor, the major mTORC1 component, completely suppressed iCCA development in Nicd/Yap mice. Elevated expression of Notch1, YAP, amino acid transporters, and members of the mTORC1 pathway was also detected ubiquitously in a collection of human iCCA specimens. Their levels were associated with a poor patient outcome. This study demonstrates that Notch and YAP concomitant activation is frequent in human cholangiocarcinogenesis. Notch and YAP synergize to promote iCCA formation by activating the mTORC1 pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Idoso , Animais , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
8.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070643

RESUMO

Cholangiocarcinomas (CCAs) are heterogeneous biliary tract malignancies with dismal prognosis, mainly due to tumor aggressiveness, late diagnosis, and poor response to current therapeutic options. High-throughput technologies have been used as a fundamental tool in unveiling CCA molecular landscape, and several molecular classifications have been proposed, leading to various targeted therapy trials. In this review, we aim to analyze the critical issues concerning the status of precision medicine in CCA, discussing molecular signatures and clusters, related to both anatomical classification and different etiopathogenesis, and the latest therapeutic strategies. Furthermore, we propose an integrated approach comprising the CCA molecular mechanism, pathobiology, clinical and histological findings, and treatment perspectives for the ultimate purpose of improving the methods of patient allocations in clinical trials and the response to personalized therapies.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Terapia de Alvo Molecular , Medicina de Precisão , Neoplasias dos Ductos Biliares/classificação , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/classificação , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/terapia , Humanos , Microambiente Tumoral
9.
BMC Cancer ; 21(1): 608, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34034689

RESUMO

BACKGROUND: Long non-coding RNA (lncRNA) plays a critical role in the malignant progression of intrahepatic cholangiocarcinoma (iCCA). This study aimed to establish a 4-lncRNA prognostic signature and explore corresponding potential mechanisms in patients with iCCA. METHODS: The original lncRNA-seq and clinical data were collected from the TCGA and GEO databases. Overlapping and differentially expressed lncRNAs (DE-lncRNAs) were further identified from transcriptome data. Univariate regression analysis was performed to screen survival-related DE-lncRNAs, which were further selected to develop an optimal signature to predict prognosis using multivariate regression analysis. The Kaplan-Meier survival curve visualized the discrimination of the signature on overall survival (OS). The area under the curve (AUC) and C-index were used to verify the predictive accuracy of the signature. Combined with clinical data, multivariate survival analysis was used to reveal the independent predictive capability of the signature. In addition, a prognostic nomogram was constructed. Finally, the common target genes of 4 lncRNAs were predicted by the co-expression method, and the corresponding functions were annotated by GO and KEGG enrichment analysis. Gene set enrichment analysis (GSEA) was also performed to explore the potential mechanism of the signature. Quantitative real-time PCR was used to evaluated the expression of 4 lncRNAs in an independent cohort. RESULTS: We identified and constructed a 4-lncRNA (AC138430.1, AGAP2-AS1, AP001783.1, and AP005233.2) prognostic signature using regression analysis, and it had the capability to independently predict prognosis. The AUCs were 0.952, 0.909, and 0.882 at 1, 2, and 3 years, respectively, and the C-index was 0.808, which showed good predictive capability. Subsequently, combined with clinical data, we constructed a nomogram with good clinical application. Finally, 252 target genes of all four lncRNAs were identified by the co-expression method, and functional enrichment analysis showed that the signature was strongly correlated with metabolism-related mechanisms in tumourigenesis. The same results were also validated via GSEA. CONCLUSION: We demonstrated that a metabolism-related 4-lncRNA prognostic signature could be a novel biomarker and deeply explored the target genes and potential mechanism. This study will provide a promising therapeutic strategy for patients with intrahepatic cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/mortalidade , RNA Longo não Codificante/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/terapia , Carcinogênese/genética , Carcinogênese/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/terapia , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , RNA-Seq , Curva ROC , Medição de Risco/métodos , Taxa de Sobrevida
10.
Mar Drugs ; 19(5)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946151

RESUMO

Sulfated galactans (SG) isolated from red alga Gracilaria fisheri have been reported to inhibit the growth of cholangiocarcinoma (CCA) cells, which was similar to the epidermal growth factor receptor (EGFR)-targeted drug, cetuximab. Herein, we studied the anti-cancer potency of SG compared to cetuximab. Biological studies demonstrated SG and cetuximab had similar inhibition mechanisms in CCA cells by down-regulating EGFR/ERK pathway, and the combined treatment induced a greater inhibition effect. The molecular docking study revealed that SG binds to the dimerization domain of EGFR, and this was confirmed by dimerization assay, which showed that SG inhibited ligand-induced EGFR dimer formation. Synchrotron FTIR microspectroscopy was employed to examine alterations in cellular macromolecules after drug treatment. The SR-FTIR-MS elicited similar spectral signatures of SG and cetuximab, pointing towards the bands of RNA/DNA, lipids, and amide I vibrations, which were inconsistent with the changes of signaling proteins in CCA cells after drug treatment. Thus, this study demonstrates the underlined anti-cancer mechanism of SG by interfering with EGFR dimerization. In addition, we reveal that FTIR signature spectra offer a useful tool for screening anti-cancer drugs' effect.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Galactanos/farmacologia , Simulação de Acoplamento Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Compostos de Enxofre/farmacologia , Antineoplásicos/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cetuximab/farmacologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Galactanos/metabolismo , Humanos , Microespectrofotometria , Ligação Proteica , Multimerização Proteica , Transdução de Sinais , Compostos de Enxofre/metabolismo , Síncrotrons
11.
Cancer Sci ; 112(8): 3111-3124, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34051011

RESUMO

The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC-CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS- or HRAS/Myc-induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte-derived liver tumors were induced in heterozygous and homozygous p53-knockout (KO) mice by hydrodynamic tail vein injection of HRAS- or Myc-containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase-expressing plasmid. The HRAS-induced and HRAS/Myc-induced tumors in the wild-type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53-KO mice was consistent with cHCC-CCA. The expression of fetal/neonatal liver proteins, including delta-like 1, was detected in the HRAS/Myc-induced but not in the HRAS-induced cHCC-CCA tissues. The dedifferentiation in the HRAS/Myc-induced tumors was more marked in the homozygous p53-KO mice than in the heterozygous p53-KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte-derived tumor cells through either transdifferentiation or Myc-mediated dedifferentiation.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Desdiferenciação Celular , Transdiferenciação Celular , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Heterozigoto , Homozigoto , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
12.
Biochem Genet ; 59(5): 1311-1325, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33797690

RESUMO

Cholangiocarcinoma (CCA) is a malignant tumour with high recurrence and mortality rates and poor prognosis. However, the pathogenic mechanism remains unclear. In the present study, we aimed to investigate the roles and regulatory mechanism of SNHG16 in the occurrence and development of CCA. Gene Expression Profiling Interactive Analysis (GEPIA) was used to predict the expressions of SNHG16 and GATA6 in CCA samples from TCGA database. The levels of SNHG16, miR-146a-5p and GATA6 were evaluated using qRT-PCR. CCK-8 and flow cytometry assays were conducted to evaluate cell proliferation and apoptosis, respectively. Western blotting was applied to analyse the protein levels of GATA6 and apoptosis-related proteins. SNHG16 was significantly elevated in CCA tissues from TCGA database and CCA cell lines. Moreover, downregulation of SNHG16 restricted cell proliferation and increased apoptotic rate of RBE and HuCCT1 cells. miR-146a-5p, a downstream target of SNHG16, was shown to be an intermediate mediator of GATA6 expression regulated by SNHG16. In addition, either the miR-146a-5p inhibitor or overexpression of GATA6 obviously impaired the regulatory effects of SNHG16 downregulation in RBE and HuCCT1 cells. These data demonstrated that SNHG16 promoted cell proliferation and repressed apoptosis by regulating the miR-146a-5p/GATA6 axis, which provides some helpful insights for the diagnosis and treatment of CCA.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/patologia , Fator de Transcrição GATA6/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Apoptose , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Fator de Transcrição GATA6/genética , Humanos , Prognóstico , Células Tumorais Cultivadas
13.
Jpn J Clin Oncol ; 51(6): 911-917, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33822966

RESUMO

OBJECTIVE: Fibroblast growth factor receptor gene alterations have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer that has a poor prognosis. This study evaluated the frequency of fibroblast growth factor receptor 2 fusions in clinical specimens from Japanese patients with iCCA. METHODS: This study enrolled 116 patients who had histologically or cytologically confirmed adenocarcinoma and been diagnosed as relapsing after resection or with unresectable intrahepatic cholangiocarcinoma. We evaluated the frequency of fibroblast growth factor receptor 2 fusions-positive cells in their specimens using break-apart fluorescent in situ hybridization 'for 114 patients who met the study protocol'. RESULTS: Of a total of 114 cases, six (5.3%) were identified as fibroblast growth factor receptor 2 fusions-positive with a high frequency (87% or more) of fibroblast growth factor receptor 2 fusions-positive tumour cells whereas the remainder, with the exception of three cases with indeterminate results, were identified as fibroblast growth factor receptor 2 fusions-negative. The patients' baseline characteristics as well as their objective response rates, disease control rates, times to progression, and times to treatment failure with previous or ongoing first-line chemotherapy did not have any obvious relationship to the proportion of fibroblast growth factor receptor 2 fusions-positive case. CONCLUSIONS: Further detailed elucidation of fibroblast growth factor receptor 2 fusion status is expected to contribute to the development of promising therapeutic options for patients suffering from recurrent or unresectable intrahepatic cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Proteínas de Fusão Oncogênica/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/epidemiologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia
14.
Front Immunol ; 12: 647209, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841428

RESUMO

Background: Cholangiocarcinoma was a highly malignant liver cancer with poor prognosis, and immune infiltration status was considered an important factor in response to immunotherapy. In this investigation, we tried to locate immune infiltration related genes of cholangiocarcinoma through combination of bulk-sequencing and single-cell sequencing technology. Methods: Single sample gene set enrichment analysis was used to annotate immune infiltration status in datasets of TCGA CHOL, GSE32225, and GSE26566. Differentially expressed genes between high- and low-infiltrated groups in TCGA dataset were yielded and further compressed in other two datasets through backward stepwise regression in R environment. Single-cell sequencing data of GSE138709 was loaded by Seurat software and was used to examined the expression of infiltration-related gene set. Pathway changes in malignant cell populations were analyzed through scTPA web tool. Results: There were 43 genes differentially expressed between high- and low-immune infiltrated patients, and after further compression, PNOC and LAIR2 were significantly correlated with high immune infiltration status in cholangiocarcinoma. Through analysis of single-cell sequencing data, PNOC was mainly expressed by infiltrated B cells in tumor microenvironment, while LAIR2 was expressed by Treg cells and partial GZMB+ CD8 T cells, which were survival related and increased in tumor tissues. High B cell infiltration levels were related to better overall survival. Also, malignant cell populations demonstrated functionally different roles in tumor progression. Conclusion: PNOC and LAIR2 were biomarkers for immune infiltration evaluation in cholangiocarcinoma. PNOC, expressed by B cells, could predict better survival of patients, while LAIR2 was a potential marker for exhaustive T cell populations, correlating with worse survival of patients.


Assuntos
Linfócitos B/metabolismo , Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Precursores de Proteínas/genética , Receptores Imunológicos/genética , Receptores Opioides/genética , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Linfócitos B/imunologia , Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/metabolismo , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Prognóstico , Precursores de Proteínas/metabolismo , Receptores Imunológicos/metabolismo , Receptores Opioides/metabolismo , Análise de Sequência de DNA/métodos , Análise de Célula Única/métodos , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
15.
Anticancer Res ; 41(4): 2147-2155, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813426

RESUMO

BACKGROUND/AIM: Inflammation-based prognostic scores are proven prognostic biomarkers in various cancers. This study aimed to identify a useful prognostic score for patients with biliary tract cancer (BTC) after surgical resection. PATIENTS AND METHODS: This retrospective study recruited 115 patients with BTC during 2010-2020. The relationship between clinicopathological variables, including various prognostic scores and overall survival (OS), was investigated using univariate and multivariate analyses. RESULTS: BTC included 58 cholangiocarcinoma, 29 gallbladder carcinoma, 16 ampullary carcinoma, and 12 perihilar cholangiocarcinoma cases. A significant difference was detected in OS of patients with a Japanese modified Glasgow prognostic score (JmGPS) 0 (n=62) and JmGPS 1 or 2 (high JmGPS) (n=53). In the multivariate analysis, tumour differentiation (p=0.014) and a high JmGPS (p=0.047) were independent prognostic factors. CONCLUSION: The high JmGPS was an independent prognostic predictor after surgical resection and was superior to other prognostic scores.


Assuntos
Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/cirurgia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/cirurgia , Inflamação/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ampola Hepatopancreática/metabolismo , Ampola Hepatopancreática/patologia , Ampola Hepatopancreática/cirurgia , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Ductos Biliares Intra-Hepáticos/cirurgia , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/mortalidade , Biomarcadores Tumorais/metabolismo , Proteína C-Reativa/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidade , Neoplasias do Ducto Colédoco/diagnóstico , Neoplasias do Ducto Colédoco/metabolismo , Neoplasias do Ducto Colédoco/mortalidade , Neoplasias do Ducto Colédoco/cirurgia , Feminino , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Inflamação/metabolismo , Japão/epidemiologia , Tumor de Klatskin/diagnóstico , Tumor de Klatskin/metabolismo , Tumor de Klatskin/mortalidade , Tumor de Klatskin/cirurgia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Valor Preditivo dos Testes , Prognóstico , Projetos de Pesquisa , Estudos Retrospectivos , Sensibilidade e Especificidade , Análise de Sobrevida , Resultado do Tratamento
16.
Cell Death Dis ; 12(3): 256, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33692336

RESUMO

Chromosomal translocations involving fibroblast growth factor receptor 2 (FGFR2) gene at the breakpoints are common genetic lesions in intrahepatic cholangiocarcinoma (ICC) and the resultant fusion protein products have emerged as promising druggable targets. However, predicting the sensitivity of FGFR2 fusions to FGFR kinase inhibitors is crucial to the prognosis of the ICC-targeted therapy. Here, we report identification of nine FGFR2 translocations out of 173 (5.2%) ICC tumors. Although clinicopathologically these FGFR2 translocation bearing ICC tumors are indistinguishable from the rest of the cohort, they are invariably of the mass-forming type originated from the small bile duct. We show that the protein products of FGFR2 fusions can be classified into three subtypes based on the breaking positions of the fusion partners: the classical fusions that retain the tyrosine kinase (TK) and the Immunoglobulin (Ig)-like domains (n = 6); the sub-classical fusions that retain only the TK domain without the Ig-like domain (n = 1); and the non-classical fusions that lack both the TK and Ig-like domains (n = 2). We demonstrate that cholangiocarcinoma cells engineered to express the classical and sub-classical fusions show sensitivity to FGFR-specific kinase inhibitors as evident by the suppression of MAPK/ERK and AKT/PI3K activities following the inhibitor treatment. Furthermore, the kinase-deficient mutant of the sub-classical fusion also lost its sensitivity to the FGFR-specific inhibitors. Taken together, our study suggests that it is essential to determine the breakpoint and type of FGFR2 fusions in the small bile duct subtype of ICC for the targeted treatment.


Assuntos
Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Fusão Gênica , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Resistencia a Medicamentos Antineoplásicos/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Células NIH 3T3 , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais
17.
Oncology ; 99(6): 365-372, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33730723

RESUMO

BACKGROUND: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. PATIENTS AND METHODS: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity. RESULTS: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer. CONCLUSION: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno B7-H1/metabolismo , Neoplasias dos Ductos Biliares/tratamento farmacológico , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias da Vesícula Biliar/tratamento farmacológico , Platina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Platina/uso terapêutico , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
18.
Cancer Treat Rev ; 95: 102170, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33735689

RESUMO

Cholangiocarcinomas (CCAs) are rare but aggressive tumours of the bile ducts, which are often diagnosed at an advanced stage and have poor outcomes on systemic therapy. Somatic alterations with therapeutic implications have been identified in almost half of CCAs, in particular in intrahepatic CCA (iCCA), the subtype arising from bile ducts within the liver. Among patients with CCA, fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements occur almost exclusively in iCCA, where they are estimated to be found in up to 10-15% of patients. Clinical trials for selective FGFR kinase inhibitors have shown consistent activity of these agents in previously treated patients with iCCA harbouring FGFR alterations. Current FGFR kinase inhibitors show differences in their structure, mechanisms of target engagement, and specificities for FGFR1, 2, 3 and 4 and other related kinases. These agents offer the potential to improve outcomes in FGFR-driven CCA, and the impact of variations in the molecular profiles of the FGFR inhibitors on efficacy, safety, acquired resistance mechanisms, and patients' health-related quality of life remains to be fully characterized. The most common adverse event associated with FGFR inhibitors is hyperphosphatemia, an on-target off-tumour effect of FGFR1 inhibition, and strategies to manage this include dose adjustment, chelators, and the use of a low phosphate diet. As FGFR inhibitors and other targeted agents enter the clinic for use in FGFR-driven CCA, molecular testing for actionable mutations and monitoring for the emergence of acquired resistance will be essential.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Humanos
19.
Biomed Res Int ; 2021: 8298737, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681380

RESUMO

Preoperative evaluation of hepatic functional reserve in patients with hilar cholangiocarcinoma (hCCA) has vital clinical significance for prevention of posthepatectomy liver failure (PHLF) and mortality. The aim of the present study was to evaluate the clinical significance of the indocyanine green retention rate at 15 minutes (ICG R15) and related factors of postoperative outcomes in patients with hCCA. 147 patients who scheduled for hCCA resection underwent a preoperative ICG test between May 2015 and May 2020 and were prospectively analyzed. Single-factor analysis was used to evaluate the risk factors for PHLF and postoperative outcomes in hCCA. After univariate analysis, significant differences in ICG R15 were found between the PHLF group and the liver function recovered well (LFRW) group (P ≤ 0.05). In terms of postoperative complications, ICG R15 was also a risk factor for moderate-to-severe postoperative complications. Preoperative ICG R15 was significantly associated with PHLF and moderate-to-severe postoperative complications. ICG R15 may become an ideal clinical indicator for the evaluation of liver function reserve before hCCA and can better predict the postoperative complications.


Assuntos
Neoplasias dos Ductos Biliares , Verde de Indocianina/administração & dosagem , Tumor de Klatskin , Falência Hepática , Complicações Pós-Operatórias , Cuidados Pré-Operatórios , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Feminino , Humanos , Tumor de Klatskin/metabolismo , Tumor de Klatskin/patologia , Tumor de Klatskin/cirurgia , Falência Hepática/etiologia , Falência Hepática/metabolismo , Falência Hepática/patologia , Falência Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/patologia
20.
PLoS One ; 16(3): e0245871, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33780455

RESUMO

CD44 is a transmembrane glycoprotein, the phosphorylation of which can directly trigger intracellular signaling, particularly Akt protein, for supporting cell growth, motility and invasion. This study examined the role of CD44 on the progression of Cholangiocarcinoma (CCA) using metabolic profiling to investigate the molecular mechanisms involved in the Akt signaling pathway. Our results show that the silencing of CD44 decreases Akt and mTOR phosphorylation resulting in p21 and Bax accumulation and Bcl-2 suppression that reduces cell proliferation. Moreover, an inhibition of cell migration and invasion regulated by CD44. Similarly, the silencing of CD44 showed an alteration in the epithelial-mesenchymal transition (EMT), e.g. an upregulation of E-cadherin and a downregulation of vimentin, and the reduction of the matrix metalloproteinase (MMP)-9 signal. Interestingly, a depletion of CD44 leads to metabolic pathway changes resulting in redox status modification and Trolox (anti-oxidant) led to the recovery of the cancer cell functions. Based on our findings, the regulation of CCA progression and metastasis via the redox status-related Akt signaling pathway depends on the alteration of metabolic profiling synchronized by CD44.


Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Receptores de Hialuronatos/metabolismo , Redes e Vias Metabólicas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Progressão da Doença , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...