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2.
Liver Int ; 38(7): 1273-1279, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29265678

RESUMO

BACKGROUND AND AIMS: It is rare but not uncommon to discover micro/small HNF1α-inactivated hepatocellular adenoma (H-HCA) outside the context of resected H-HCA. We aimed to review our cases of micro/small H-HCA discovered by chance on different kinds of liver resected specimens. METHODS: We retrieved cases of micro/small H-HCA discovered by chance on resected specimens outside the context of H-HCA. All these nodules were liver fatty acid binding protein (LFABP)-negative contrasting with normal positivity in the surrounding non-tumoural liver, ruling out the possibility of focal steatosis or other subtypes of micro-HCAs. RESULTS: We identified 19 micro/small H-HCA cases. In 16 cases they were discovered in patients who underwent surgery for benign nodules including one haemangioma, six focal nodular hyperplasia, seven inflammatory HCA (including one with b-catenin activation), one HCA, whose subtype could not be identified because of massive necrosis/hemorrhage, and one hepatocellular carcinoma. In two additional cases, patients followed up for a melanoma underwent liver surgery to remove micro nodules possibly related to a metastatic process. Finally in one case a micro nodule was seen and resected during a cholecystectomy. CONCLUSION: Taken together, H-HCAs are more frequent than we initially supposed as micro and small HCAs cannot all be detected by routine ultrasound. Despite no information on the potential growth of these micro/small H-HCAs, there is no argument to stop oral contraceptives or to ask for a specific regular surveillance. The association of different subtypes of HCAs with focal nodular hyperplasia suggests they share or have common etiological factors.


Assuntos
Adenoma de Células Hepáticas/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Neoplasias Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Adulto , Diagnóstico Diferencial , Fígado Gorduroso/patologia , Feminino , Hiperplasia Nodular Focal do Fígado/patologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade
3.
Histopathology ; 71(6): 989-993, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28618047

RESUMO

The identification of hepatocellular adenoma (HCA) with mutation in exon 3 of the CTNNB1 gene encoding for ß-catenin is clinically relevant due to a higher risk of malignant transformation. Inflammatory HCA (IHCA) can exhibit ß-catenin activation (ß-IHCA). We report two cases with multiple IHCA in which focal ß-catenin activation has been found in one of the IHCA. In both cases, the diagnosis of IHCA was confirmed on the resected nodules by routine stains, immunohistochemical detection of C-reactive protein (CRP) and molecular biology on frozen material. An additional molecular analysis was performed on formalin-fixed paraffin-embedded (FFPE) material that showed focal glutamine synthetase (GS) staining, the surrogate marker of ß-catenin activation. In case 1, it was a 1.8-cm area within the 7.5 cm IHCA, and in case 2 a small 0.3-cm area within a 1.8 cm resected IHCA located close to a larger IHCA, negative for GS. In both cases, nuclear ß-catenin expression and decreased reticulin network were observed in the GS expressing foci, together with cholestasis and diffuse CD34 expression in case 1. Molecular analysis by pyrosequencing on FFPE material using the GS-stained slides as reference to select areas with/without positive staining revealed a CTNNB1 exon 3 mutation restricted to the areas exhibiting both positive GS and CRP expression, whereas wild-type CTNNB1 was found in areas showing only CRP staining. These two cases illustrate focal ß-catenin activation that can occur within IHCAs. Additional data are needed to determine if ß-catenin mutation is a secondary event in IHCA.


Assuntos
Adenoma de Células Hepáticas/genética , Biomarcadores Tumorais/genética , Neoplasias Hepáticas/genética , beta Catenina/genética , Adenoma de Células Hepáticas/patologia , Adulto , Biomarcadores Tumorais/metabolismo , Proteína C-Reativa/metabolismo , Transformação Celular Neoplásica , Feminino , Formaldeído , Glutamato-Amônia Ligase/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Microdissecção , Pessoa de Meia-Idade , Mutação , Inclusão em Parafina , beta Catenina/metabolismo
6.
Histopathology ; 67(4): 562-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25704541

RESUMO

AIMS: Bile duct adenomas (BDA) and bile duct hamartomas (BDH) are benign bile duct lesions considered neoplastic or secondary to ductal plate malformation, respectively. We have reported previously a high prevalence of BRAF V600E mutations detected by allele-specific polymerase chain reaction assay in BDA, and suggested that BDA may be precursors to a subset of intrahepatic cholangiocarcinomas harbouring V600E mutations. The aim of the present study was to assess the existence of BRAF V600E mutations, using immunohistochemical methods, in additional BDA as well as in BDH. METHODS AND RESULTS: Fifteen BDA and 35 BDH were retrieved from the archives of the pathology departments of two French university hospitals. All cases were reviewed by two pathologists specialized in liver diseases. BRAF V600E mutational status was investigated by immunohistochemistry. Mutated BRAF mutant protein was detected in 53% of the BDA and in none of the cases of BDH. CONCLUSION: Our findings suggest that BDA and BDH are different processes, and that BDA represent true benign neoplasms. They also support the hypothesis that mutated BDA might precede the development of the subset of intrahepatic cholangiocarcinomas harbouring BRAF V600E mutations.


Assuntos
Adenoma de Ducto Biliar/genética , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/patologia , Hamartoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adenoma de Ducto Biliar/patologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Feminino , Hamartoma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade
7.
J Hepatol ; 61(3): 550-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24815876

RESUMO

BACKGROUND & AIMS: Non-invasive assessment of liver fibrosis by elastography is a rapidly developing field with frequent technological innovations. The aim of this study was to assess the diagnostic performances of Supersonic Shear Imaging (SSI) for the diagnosis of liver fibrosis in chronic liver disease. METHODS: A total of 349 consecutive patients with chronic liver diseases who underwent liver biopsy from November 2011 to October 2013 were prospectively enrolled. For each patient, liver stiffness was assessed by SSI, ARFI, FibroScan® (M probe for patients with BMI <30 kg/m(2), and XL probe for patients with BMI ⩾30 kg/m(2)), performed within two weeks of liver biopsy. Areas under the receiver operating curves (AUROCs) were performed and compared for each degree of liver fibrosis. RESULTS: SSI, FibroScan®, and ARFI correlated significantly with histological fibrosis score (r=0.79, p<0.00001; r=0.70, p<0.00001; r=0.64, p<0.00001, respectively). AUROCs of SSI, FibroScan®, and ARFI were 0.89, 0.86, and 0.84 for the diagnosis of mild fibrosis; 0.88, 0.84, and 0.81 for the diagnosis of significant fibrosis; 0.93, 0.87, and 0.89, for the diagnosis of severe fibrosis; 0.93, 0.90, and 0.90 for the diagnosis of cirrhosis, respectively. SSI had a higher accuracy than FibroScan® for the diagnosis of severe fibrosis (⩾F3) (p=0.0016), and a higher accuracy than ARFI for the diagnosis of significant fibrosis (⩾F2) (p=0.0003). No significant difference was observed for the diagnosis of mild fibrosis and cirrhosis. CONCLUSIONS: SSI is an efficient method for the assessment of liver fibrosis in chronic liver diseases, comparing favourably to FibroScan® and ARFI.


Assuntos
Diagnóstico por Imagem/métodos , Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/diagnóstico , Índice de Gravidade de Doença , Ultrassonografia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Biomarcadores/metabolismo , Biópsia , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Adulto Jovem
8.
Histopathology ; 64(6): 890-5, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24236804

RESUMO

AIMS: To report the coexistence of inflammatory hepatocellular adenoma (IHCA) and HNF1α-inactivated HCA (H-HCA) in cases from a multicentre study. METHODS AND RESULTS: We report nine cases with the coexistence of IHCA and H-HCA; eight occurred in women, and one in a man. The numbers of nodules and the sizes of the largest and smallest HCAs were variable. In one case, the nodules of the two different subtypes were discovered at different times. In all women, HCAs were histologically typical, regardless of their subtype, whereas H-HCA in the man differed histologically from classic H-HCA. CONCLUSIONS: These cases suggest that a predisposition to develop multiple adenomas, hypothetically caused by a 'benign tumorigenic field effect', although common to all HCAs, may result in different genotypes and phenotypes. Although this is rare, it is expected that more cases with the coexistence of different genotypes will emerge, owing to progress in the use of specific immunohistochemical approaches.


Assuntos
Adenoma de Células Hepáticas/patologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Neoplasias Hepáticas/patologia , Adenoma de Células Hepáticas/metabolismo , Adulto , Biomarcadores Tumorais , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade
9.
Ann Pathol ; 34(2): 119-23, 2014 Apr.
Artigo em Francês | MEDLINE | ID: mdl-24703021

RESUMO

Of all the gestational trophoblastic tumors, the gestational choriocarcinomas have the worst prognosis and the most uncommon. We report a case diagnosed on a full-term placenta, discovered incidentally. The patient, gravida 2, para 1, delivered a hypotrophic infant at 38 weeks gestation. The placenta was examined in the laboratory to perform anatomo-pathological examination in order to explain the growth retardation. This study revealed the presence of an intraplacental choriocarcinoma. Disease staging was negative for both mother and child, and beta-HCG levels remained at zero. These two factors are rather good prognosis for choriocarcinoma. With this observation, we highlight the added-value of placental examination, which seems essential for any fetal pathology, pathological pregnancy and intrapartum complications. Anatomo-pathological examination must be meticulous and systematized in order to not overlook an intraplacental tumor.


Assuntos
Coriocarcinoma/patologia , Doenças Placentárias/patologia , Adulto , Feminino , Humanos , Achados Incidentais , Gravidez , Nascimento a Termo
10.
Am J Surg Pathol ; 48(5): 551-561, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38497430

RESUMO

Recurrent gene fusions are common in salivary gland tumors including benign tumors, such as pleomorphic adenoma (PA) and myoepithelioma (ME). In cases where chromosomal rearrangement is identified in the pleomorphic adenoma gene 1 (PLAG1) gene, different gene partners are found. Oncocytic metaplasia, characterized by oncocytes with abundant eosinophilic granular cytoplasm and hyperchromatic nuclei, is a well-known phenomenon in salivary gland neoplasms. However, the pure oncocytic variant of PA/ME showed PLAG1 gene rearrangements involving various gene partners at the molecular level, without any recurrent fusion being found. Our study includes 20 cases of PA/ME, with 11 females and 9 males. The age of patients ranged from 37 to 96 years, with a median age of 62.8 years. Most tumors originate from the parotid gland. The median size of the tumor was 26.5 mm (range: 13 to 60 mm). Among the 20 cases, 14 were a pure oncocytic variant of PA/ME, whereas 6 cases showed focal oncocytic or oncocytic-like aspects. Molecular studies on 20 cases of PA/ME were conducted. A novel recurrent ZBTB47-AS1::PLAG1 fusion was identified in 6 of 12 cases with pure oncocytic metaplasia, whereas the other cases had PLAG1 gene fusion with different gene partners. The transcriptomic analysis of the cases harboring ZBTB47-AS1::PLAG1 fusion demonstrated that these tumors have a distinct molecular profile from conventional PA/ME. This study reveals a unique subset in the oncocytic PA/ME spectrum characterized by pure oncocytic morphology with larger oncocytic cells and recurrent ZBTB47-AS1::PLAG1 fusion. It also highlights the transcriptomic distinctness of salivary gland adenomas with pure oncocytic metaplasia in the spectrum of salivary gland neoplasms. Further studies are needed to better understand the oncocytic variant of PA/ME and to determine the true nature of oncocytic cells in PA/ME.


Assuntos
Adenoma Oxífilo , Adenoma Pleomorfo , Mioepitelioma , Neoplasias das Glândulas Salivares , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Adulto , Idoso , Idoso de 80 Anos ou mais , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/patologia , Mioepitelioma/genética , Mioepitelioma/patologia , Proteínas de Ligação a DNA/genética , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Fusão Gênica , Metaplasia
11.
Ann Pathol ; 33(4): 230-6, 2013 Aug.
Artigo em Francês | MEDLINE | ID: mdl-23954115

RESUMO

The indications of the pathological examination of the placenta are mainly represented by uteroplacental vascular deficiency. The clinical context is often evocative, but it can sometimes be solely an intra-uterine growth retardation or an unexplained in utero fetal death. So, the pathological lesions of this uteroplacental vascular deficiency must be well-known to be correctly interpreted, for none of these lesions is truly specific. The pathological diagnosis is based on a group of macroscopic and microscopic arguments. Various physiopathological mechanisms, often imperfectly known, can be at the origin of an uteroplacental vascular insufficiency, but in the current position, the pathological examination does not allow etiopathogenic orientation. The development of the trophoblastic biopsies gives us access to a new material which, in parallel with the cytogenetic analysis, often allows us, in front of an unexplained intra-uterine growth retardation, to direct the diagnosis towards uteroplacental vascular insufficiency. The histological analysis of the chorionic villous sampling taken precociously during pathological pregnancies is thus a major diagnostic contribution. But especially, this analysis gives access to new information which, in the near future, will enable us to better define the pathological evolution of the lesions of hypoxic chorionic villous and to contribute to a better knowledge of this pathology which, under many aspects, still conceals many mysteries.


Assuntos
Doenças Placentárias/patologia , Placenta/patologia , Circulação Placentária , Útero/patologia , Vilosidades Coriônicas/química , Vilosidades Coriônicas/patologia , Amostra da Vilosidade Coriônica , Cistos/patologia , Feminino , Morte Fetal/patologia , Hipóxia Fetal/etiologia , Fibrina/análise , Idade Gestacional , Humanos , Infarto/patologia , Necrose , Tamanho do Órgão , Placenta/irrigação sanguínea , Gravidez , Complicações na Gravidez/fisiopatologia , Trofoblastos/patologia , Útero/irrigação sanguínea
12.
Eur J Surg Oncol ; 49(12): 107108, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37866154

RESUMO

OBJECTIVES: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive disease requiring multimodal treatment, and multiple new entities once included in the spectrum of SNUC, such as SWI/SNF-deficient carcinomas, are emerging. We aimed to provide new data regarding the role of chemotherapy and surgery and the prognostic factors of disease-free survival. METHODS: This study was based on data from the REFCOR database and included patients with SNUC treated with curative intent from 2007 to 2021 across 22 centres in France. RESULTS: A total of 80 patients were included in the analysis. Among the entire cohort, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 58% and 63%, respectively. Of 100% of the patients treated with irradiation, 29% underwent surgery, 56% neoadjuvant chemotherapy (82% had either a partial or a complete response) and 76% chemoradiotherapy. No treatment modality was associated with a better OS or DFS, including surgery (p = 0.34). There was a trend for a better DFS for the patients treated with chemotherapy (neoadjuvant or concomitant, p = 0.062). Overall survival at 3 years was 58% for SWI/SNF deficient group and 86% for non deficient group (p = 0.14). The locoregional relapse rate without distant metastases was 21% in the exclusive radiotherapy group and 26% in the surgery group. Grade 3 or higher toxicities concerned 9%, 32% and 29% of patients for surgery, radiotherapy and chemotherapy respectively. CONCLUSION: In the management of localised SNUC among all patients treated with irradiation, surgery yielded no benefit, whereas the addition of chemotherapy tended to improve disease-free survival.


Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias do Seio Maxilar , Humanos , Recidiva Local de Neoplasia/terapia , Neoplasias do Seio Maxilar/terapia , Terapia Combinada , Estudos Retrospectivos
14.
Hepatol Commun ; 4(6): 809-824, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32490318

RESUMO

Until recently, 10% of hepatocellular adenomas (HCAs) remained unclassified (UHCA). Among the UHCAs, the sonic hedgehog HCA (shHCA) was defined by focal deletions that fuse the promoter of Inhibin beta E chain with GLI1. Prostaglandin D2 synthase was proposed as immunomarker. In parallel, our previous work using proteomic analysis showed that most UHCAs constitute a homogeneous subtype associated with overexpression of argininosuccinate synthase (ASS1). To clarify the use of ASS1 in the HCA classification and avoid misinterpretations of the immunohistochemical staining, the aims of this work were to study (1) the link between shHCA and ASS1 overexpression and (2) the clinical relevance of ASS1 overexpression for diagnosis. Molecular, proteomic, and immunohistochemical analyses were performed in UHCA cases of the Bordeaux series. The clinico-pathological features, including ASS1 immunohistochemical labeling, were analyzed on a large international series of 67 cases. ASS1 overexpression and the shHCA subgroup were superimposed in 15 cases studied by molecular analysis, establishing ASS1 overexpression as a hallmark of shHCA. Moreover, the ASS1 immunomarker was better than prostaglandin D2 synthase and only found positive in 7 of 22 shHCAs. Of the 67 UHCA cases, 58 (85.3%) overexpressed ASS1, four cases were ASS1 negative, and in five cases ASS1 was noncontributory. Proteomic analysis performed in the case of doubtful interpretation of ASS1 overexpression, especially on biopsies, can be a support to interpret such cases. ASS1 overexpression is a specific hallmark of shHCA known to be at high risk of bleeding. Therefore, ASS1 is an additional tool for HCA classification and clinical diagnosis.

15.
Clin Res Hepatol Gastroenterol ; 43(1): 12-19, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30213653

RESUMO

Hepatocellular adenomas (HCA) are rare benign hepatocellular tumors occurring mainly in women taking oral contraceptives with 2 major complications: severe bleeding and malignant transformation that can be avoided if nodules exceeding 5 cm are resected. This simple attitude has been challenged in the recent years with HCA in men, in young adolescent, in aged persons, and complications in hepatocellular adenomas below 5 cm. The discovery of specific mutations leading to specific phenotypes has modified the clinical spectrum of the disease. The phenotypic immune classification of HCA based on the molecular classification is being widely used in liver referral centers. The aim of this snapshot is to briefly present for each subtype the clinical, pathological, immuno-pathological criteria as well as the risk of complications and guidelines for treatment and management.


Assuntos
Adenoma de Células Hepáticas/patologia , Adenoma de Células Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Adenoma de Células Hepáticas/classificação , Humanos , Neoplasias Hepáticas/classificação
16.
Am J Surg Pathol ; 43(6): 747-754, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30829729

RESUMO

Biphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor.


Assuntos
Biomarcadores Tumorais , Cavidade Nasal , Neoplasias dos Seios Paranasais , Seios Paranasais , Sarcoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Diferenciação Celular , Feminino , Fusão Gênica , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteína MyoD/análise , Cavidade Nasal/química , Cavidade Nasal/patologia , Coativador 2 de Receptor Nuclear/genética , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição PAX3/genética , Fatores de Transcrição Box Pareados/genética , Neoplasias dos Seios Paranasais/química , Neoplasias dos Seios Paranasais/genética , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/terapia , Seios Paranasais/química , Seios Paranasais/patologia , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Sarcoma/química , Sarcoma/genética , Sarcoma/patologia , Sarcoma/terapia , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
17.
Case Rep Oncol ; 10(2): 790-794, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28966584

RESUMO

Regorafenib is a multikinase inhibitor which showed benefits in pretreated metastatic colorectal cancer patients. Hepatotoxicity has been described as a frequent side effect. We report the case of a 65-year-old patient presenting with jaundice, fever, and hepatocellular insufficiency which led to death of the patient. She had previously been treated with several lines of chemotherapy for sub- and diaphragmatic ganglionic metastases of a colon adenocarcinoma. There were no liver metastases. The fatal liver failure occurred at the beginning of treatment with regorafenib at a dosage of 3 tablets per day. No concomitant treatment was given, and other causes of liver damage were eliminated. The liver biopsy showed hepatocyte necrosis with lymphocyte infiltration. This observation illustrates the risk of severe hepatic involvement typically occurring within the first 2 months of treatment. Monitoring liver biology every 2 weeks is essential during the first 2 months to detect any hepatotoxicity.

18.
Mol Cancer Ther ; 11(12): 2610-20, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23041544

RESUMO

The molecular mechanisms and cellular targets of sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC), remain to be fully characterized. Recent studies have shown that sorafenib induces tumor cell death through the activation of endoplasmic reticulum stress signaling and/or autophagy in various cellular models. Using liver cancer-derived cell lines, we specifically show that the IRE1 and phosphorylated extracellular signal-regulated kinase arms of the unfolded protein response (UPR) become activated upon sorafenib treatment, whereas the ATF6 arm is inhibited. Our results also reveal that sorafenib treatment causes disruption to the secretory pathway, as witnessed by the fragmentation of the Golgi apparatus and the induction of autophagy. On the basis of these observations, we tested the relevance of the AAA⁺ ATPase p97/VCP as a potential functional target of sorafenib. Our results show that p97/VCP tyrosine phosphorylation is prevented upon sorafenib treatment, and that this can be correlated with enhanced membrane association. Moreover, we show that DBeQ, a recently discovered inhibitor of p97/VCP, enhances sorafenib-mediated toxicity in cultured cells. Our data show a novel mechanism for sorafenib-mediated cell death in HCC, which depends on the integrity of the secretory pathway; and we identify p97/VCP phosphorylation as a potential target for improved sorafenib treatment efficacy in patients.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Adenosina Trifosfatases/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Niacinamida/farmacologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Via Secretória/efeitos dos fármacos , Sorafenibe
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