RESUMO
Despite of massive emergence of molecular targeting drugs, the mainstay of advanced gastric cancer (GC) therapy is DNA-damaging drugs. Using a reverse-phase protein array-based proteogenomic analysis of a panel of eight GC cell lines, we identified genetic alterations and signaling pathways, potentially associated with resistance to DNA-damaging drugs, including 5-fluorouracil (5FU), cisplatin, and etoposide. Resistance to cisplatin and etoposide, but not 5FU, was negatively associated with global copy number loss, vimentin expression, and caspase activity, which are considered hallmarks of previously established EMT subtype. The segregation of 19,392 protein expression time courses by sensitive and resistant cell lines for the drugs tested revealed that 5FU-resistant cell lines had lower changes in global protein dynamics, suggesting their robust protein level regulation, compared to their sensitive counterparts, whereas the cell lines that are resistant to other drugs showed increased protein dynamics in response to each drug. Despite faint global protein dynamics, 5FU-resistant cell lines showed increased STAT1 phosphorylation and PD-L1 expression in response to 5FU. In publicly available cohort data, expression of STAT1 and NFκB target genes induced by proinflammatory cytokines was associated with prolonged survival in GC. In our validation cohort, total lymphocyte count (TLC), rather than PD-L1 positivity, predicted a better relapse-free survival rate in GC patients with 5FU-based adjuvant chemotherapy than those with surgery alone. Moreover, TLC+ patients who had no survival benefit from adjuvant chemotherapy were discriminated by expression of IκBα, a potent negative regulator of NFκB. Collectively, our results suggest that 5FU resistance observed in cell lines may be overcome by host immunity or by combination therapy with immune checkpoint blockade.
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Biomarkers that could detect the postoperative recurrence of upper tract urothelial carcinoma (UTUC) have not been established. In this prospective study, we aim to evaluate the utility of individualized circulating tumor DNA (ctDNA) monitoring using digital PCR (dPCR) as a tumor recurrence biomarker for UTUC in the perioperative period. Twenty-three patients who underwent radical nephroureterectomy (RNU) were included. In each patient, whole exome sequencing by next-generation sequencing and TERT promoter sequencing of tumor DNA were carried out. Case-specific gene mutations were selected from sequencing analysis to examine ctDNA by dPCR analysis. We also prospectively collected plasma and urine ctDNA from each patient. The longitudinal variant allele frequencies of ctDNA during the perioperative period were plotted. Case-specific gene mutations were detected in 22 cases (96%) from ctDNA in the preoperative samples. Frequently detected genes were TERT (39%), FGFR3 (26%), TP53 (22%), and HRAS (13%). In all cases, we obtained plasma and urine samples for 241 time points and undertook individualized ctDNA monitoring for 2 years after RNU. Ten patients with intravesical recurrence had case-specific ctDNA detected in urine at the time of recurrence. The mean lead time of urinary ctDNA in intravesical recurrence was 60 days (range, 0-202 days). Two patients with distal metastasis had case-specific ctDNA in plasma at the time of metastasis. In UTUC, tumor-specific gene mutations can be monitored postoperatively as ctDNA in plasma and urine. Individualized ctDNA might be a minimally invasive biomarker for the early detection of postoperative recurrence.
Assuntos
Carcinoma de Células de Transição , DNA Tumoral Circulante , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/cirurgia , DNA Tumoral Circulante/genética , Estudos Prospectivos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Biomarcadores , Biomarcadores Tumorais/genéticaRESUMO
Bortezomib is a potent proteasome inhibitor that has been extensively used to treat multiple myeloma. One of the most common grade 3 adverse events is cyclic thrombocytopenia. In this study, we studied the mechanism by which bortezomib induces thrombocytopenia in a mouse model. After the intravenous administration of bortezomib (2.5 mg/kg) via tail vein, platelet counts significantly decreased on days 2-4 and recovered to the normal range on day 6. Bortezomib (2.5 mg/kg) injected into mice in vivo did not affect colony-forming unit-megakaryocytes (CFU-Mk) or megakaryocytes in the bone marrow. However, proplatelet formation (PPF) significantly decreased on days 2 and 4, after bortezomib administration to mice. Meanwhile, CFU-Mk formation and the ploidy distribution of cultured megakaryocytes in vitro were not affected by bortezomib used at concentrations of ≤ 1 ng/mL. The PPF of megakaryocytes in vitro significantly decreased with 0.1, 1, 10, and 100 ng/mL bortezomib. Considering the bortezomib concentration in clinical studies, these data strongly suggest that decreased PPF activity induces thrombocytopenia. To elucidate the mechanism behind decreased PPF, Western blot was performed. Activated Rho expression increased after the incubation of murine platelets with bortezomib. Decreased PPF activity was eliminated by the addition of Y27632, a Rho kinase inhibitor, in vitro. Given that the Rho/Rho kinase pathway is a negative regulator of PPF, bortezomib increases activated Rho, inducing decreased PPF, which results in decreased platelet count.
Assuntos
Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Megacariócitos/efeitos dos fármacos , Pirazinas/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombopoese/efeitos dos fármacos , Amidas/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Medula Óssea/patologia , Bortezomib , Ensaio de Unidades Formadoras de Colônias , Modelos Animais de Doenças , Masculino , Células Progenitoras de Megacariócitos/citologia , Células Progenitoras de Megacariócitos/efeitos dos fármacos , Megacariócitos/metabolismo , Camundongos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Contagem de Plaquetas , Piridinas/farmacologia , Trombopoetina/sangue , Quinases Associadas a rho/metabolismoRESUMO
The aim of this study was to evaluate the clinical validity of monitoring urine pellet DNA (upDNA) of bladder cancer (BC) by digital PCR (dPCR) as a biomarker for early recurrence prediction, treatment efficacy evaluation, and no-recurrence corroboration. Tumor panel sequencing was first performed to select patient-unique somatic mutations to monitor both upDNA and circulating tumor DNA (ctDNA) by dPCR. For longitudinal monitoring using upDNA as well as plasma ctDNA, an average of 7.2 (range, 2 to 12) time points per case were performed with the dPCR assay for 32 previously treated and untreated patients with BC. Clinical recurrence based on imaging and urine cytology was compared using upDNA variant allele frequency (VAF) dynamics. A continuous increasing trend of upDNA VAF ≥1% was considered to indicate molecular recurrence. Most (30/32; 93.8%) cases showed at least one traceable somatic mutation. In 5 of 7 cases (71.4%) with clinical recurrence, upDNA VAF >1% was detected 7 to 15 months earlier than the imaging diagnosis. The upDNA VAF remained high after initial treatment for locally recurrent cases. The clinical validity of upDNA monitoring was confirmed with the observation that 26 of 30 cases (86.7%) were traceable. Local recurrences were not indicated by ctDNA alone. The results support the clinical validity of upDNA monitoring in the management of recurrent BC.
Assuntos
DNA Tumoral Circulante , Neoplasias da Bexiga Urinária , Humanos , Mutação , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , DNA Tumoral Circulante/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Biomarcadores Tumorais/genéticaRESUMO
A 37-year-old man with refractory classical Hodgkin lymphoma (cHL) underwent PD-1 blockade therapy with nivolumab, which resulted in a partial response. However, treatment was discontinued due to immune-related adverse events (irAEs), including myasthenia gravis and myositis. Retreatment with nivolumab resulted in a complete metabolic response and hepatic irAE. Subsequently, nivolumab was administered at extended dosing intervals. Intermittent infusion of ten doses of nivolumab for a total dose of 2400 mg/body helped control the relapsed/refractory cHL over three years. During nivolumab treatment, disease progression and emergence of irAEs were associated with the proportion of CD8 + T cells expressing nivolumab-free PD-1 relative to the total number of CD8 + T cells. The findings in this nivolumab-sensitive patient highlight the clinical utility of monitoring immune cells expressing nivolumab-free PD-1 in patients with cHL who have been treated with nivolumab and have experienced irAEs.
Assuntos
Doença de Hodgkin , Nivolumabe , Masculino , Humanos , Adulto , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Receptor de Morte Celular Programada 1 , Recidiva Local de Neoplasia/tratamento farmacológico , Linfócitos T CD8-Positivos/patologia , Linfócitos T/patologiaRESUMO
BACKGROUND: Paradoxically, Helicobacter pylori-positive (HP+) advanced gastric cancer patients have a better prognosis than those who are HP-negative (HP-). Immunologic and statistical analyses can be used to verify whether systemic mechanisms modulated by HP are involved in this more favorable outcome. METHODS: A total of 658 advanced gastric cancer patients who underwent gastrectomy were enrolled. HP infection, mismatch repair, programmed death-ligand 1 (PD-L1) and CD4/CD8 proteins, and microsatellite instability were analyzed. Overall survival (OS) and relapse-free survival (RFS) rates were analyzed after stratifying clinicopathological factors. Cox proportional hazards regression analysis was performed to identify independent prognostic factors. RESULTS: Among 491 patients that were analyzed, 175 (36%) and 316 (64%) patients were HP+ and HP-, respectively. Analysis of RFS indicated an interaction of HP status among the subgroups for S-1 dose (Pinteraction = .049) and PD-L1 (P = .02). HP+ patients in the PD-L1- group had statistically higher 5-year OS and RFS than HP- patients (81% vs 68%; P = .0011; hazard ratio [HR] = 0.48, 95% confidence interval [CI] = 0.303 to 0.751, and 76% vs 63%; P = .001; HR = 0.508, 95% CI = 0.335 to 0.771, respectively). The 5-year OS and RFS was also statistically higher for HP+ compared with HP- patients in the "PD-L1- and S-1-r educed" group (86% vs 46%; P = .001; HR = 0.205, 95% CI = 0.07 to 0.602, and 83% vs 34%; P = .001; HR = 0.190, 95% CI = 0.072 to 0.498, respectively). Thus, HP status was identified as one of the most potentially important independent factors to predict prolonged survival. CONCLUSION: This retrospective study suggests that an HP-modulated host immune system may contribute to prolonged survival in the absence of immune escape mechanisms of gastric cancer.
Assuntos
Helicobacter pylori , Neoplasias Gástricas , Antígeno B7-H1/metabolismo , Quimioterapia Adjuvante , Humanos , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirurgiaRESUMO
Salivary duct carcinoma (SDC) is a rare and highly aggressive malignancy. A 58-year-old man presented with a right-sided submandibular mass and metastatic lesions in the right supraclavicular and inferior internal jugular nodes. He underwent right submandibulectomy and right neck dissection followed by adjuvant chemoradiotherapy. However, relapse occurred in the hilar lymph node and lumbar spine. Although radiotherapy was performed, a second relapse appeared in the hilar lymph nodes and sacral bone. Immunohistochemical analysis revealed negativity for programmed death ligand-1 (PD-L1) in the primary tumor specimen. The patient then received the anti-programmed death-1 (PD-1) antibody nivolumab. His metastatic lesions were completely eliminated after 48 weeks of therapy. This case reveals that anti-PD-1 antibodies are effective even against PD-L1-negative SDC.
RESUMO
Hematopoietic stem cells (HSCs) can differentiate into many kinds of parenchymal cells populating several organs. Nevertheless, the differentiation mechanism of HSCs toward hepatocytes remains poorly understood. To identify specific microRNAs (miRNAs) contributing to the mechanism, we investigated the differential expression of miRNAs between side population (SP) cells of bone marrow and hepatocytes in adult mice. We used a miRNA microarray followed by stem-loop-mediated reverse transcription real-time PCR to identify 12 SP-specific and 2 hepatocyte-specific miRNAs. Of these, 3 (miR-451, -150 and -223) were strongly expressed (>10-fold relative enrichment) in SP cells. Two of these miRNAs (miR-451 and -223) were strongly associated with the hematic cell lineage but not with progenitor characteristics. Two-thirds (6/9) of the miRNAs that were moderately expressed in SP cells in comparison with hepatocytes were also up-regulated in potential hepatic stem cells (HSCEs). The single miRNA (miRNA-127) that was up-regulated in SP cells compared with lineage-positive bone marrow cells might be an SP marker, since it was markedly down-regulated in HSCEs. These results suggest that SP cells and HSCE share a common profile of miRNA expression and that miRNA-127 may contribute to the maintenance of a quiescent state in SP cells.
Assuntos
Células da Medula Óssea/metabolismo , Hepatócitos/metabolismo , MicroRNAs/biossíntese , Animais , Células da Medula Óssea/citologia , Diferenciação Celular , Linhagem da Célula , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Hepatócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de OligonucleotídeosRESUMO
The antigenic heterogeneity of the reticular framework of the white pulp and marginal zone is well documented in the human adult spleen. Immunostaining of α-smooth muscle actin characterizes the heterogeneity of the reticular framework of the white pulp and marginal zone. In the human spleen, the blood cells flow in an open circulation. T and B lymphocytes flow out from the arterial terminal, and migrate in the reticular framework. Homing of lymphocytes to lymphoid tissues is regulated by selective interactions between cell surface homing receptors and tissue vascular addressins at sites of lymphocyte recruitment from the blood. In the present study, mucosal addressin cell adhesion molecule-1 was selectively expressed on α-smooth muscle actin-positive reticular framework. The reticular framework may function in lymphocyte homing and segregation into the periarteriolar lymphoid sheath, lymph follicle and marginal zone.
Assuntos
Actinas/biossíntese , Linfócitos B/metabolismo , Moléculas de Adesão Celular/biossíntese , Regulação da Expressão Gênica , Mucoproteínas/biossíntese , Baço/metabolismo , Linfócitos T/metabolismo , Linfócitos B/ultraestrutura , Humanos , Baço/ultraestrutura , Linfócitos T/ultraestruturaRESUMO
Immunohistochemistry is not only the most important tool for pathologists to establish a final diagnosis, but it can also inform decisions regarding optimal treatment methods. However, there is no universal standard notation for expressing immunohistochemical findings. For a diagnosis of malignant lymphoma, it is important to confirm the presence or absence of MYC translocation and communicate these results to a clinical audience. However, the criteria for selecting cases for fluorescence in situ hybridization (FISH) analysis to confirm MYC translocation are ill defined. We therefore devised a notation that we termed proportion of immunoreactivity/expression for immunohistochemistry (PRIME notation) based on the cellular proportion showing different antigen-antibody reactivity in immunohistochemistry (CPAR) and used it to examine the relationship between MYC translocation and the proportion of c-MYC+ lymphoma cells. We reviewed 82 cases diagnosed as diffuse large B-cell lymphoma or diffuse large B-cell lymphoma coexisting with grade 3A to 3B follicular lymphoma. The most common notation was "+/(weak)+/-" (49/82 cases [59.8%]); cases that were CPAR positive, weakly positive, and negative for tumor cells each accounted for about one-third of the total. Unexpectedly, no MYC translocation was observed by FISH in this group. Thus, FISH is not needed even if more than half of cells are c-MYC positive by PRIME notation. This is the first report describing a correspondence between immunohistochemical findings and chromosomal abnormality, reflecting findings at the protein and gene levels, respectively.
Assuntos
Rearranjo Gênico , Linfoma Folicular/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Biomarcadores Tumorais/metabolismo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genéticaRESUMO
Alterations of several microRNA (miRNA) have been linked to cancer development and its biology. To search for unique miRNA that might play a role in the development of anaplastic thyroid carcinoma (ATC), we examined the expression of multiple miRNA and their functional effects on target genes in human thyroid carcinoma cell lines. We quantitatively evaluated the expression of multiple miRNA in 10 ATC and five papillary thyroid carcinoma (PTC) cell lines, as well as primary tumors from 11 thyroid carcinoma patients (three ATC and eight PTC), using the stem-loop-mediated reverse transcription real-time polymerase chain reaction method. We also examined the target gene specificity of unique miRNA that showed differences in expression between ATC and PTC cell lines. One miRNA, miR-138, was significantly downregulated in ATC cell lines in comparison with PTC (P < 0.01). Eleven miRNA (including miR-138) potentially targeting the human telomerase reverse transcriptase (hTERT) gene were totally downregulated in both ATC and PTC cell lines in comparison with normal thyroid tissues. A tendency for an inverse correlation between miR-138 and hTERT protein expression was observed in the thyroid cancer cell lines, although this failed to reach significance (r = -0.392, P = 0.148). We demonstrated that overexpression of miR-138 induced a reduction in hTERT protein expression, and confirmed target specificity between miR-138 and the hTERT 3'-untranslated region by luciferase reporter assay. These results suggest that loss of miR-138 expression may partially contribute to the gain of hTERT protein expression in ATC, and that further multiple miRNA targeting hTERT mRNA might be involved in the development of thyroid carcinoma.
Assuntos
Carcinoma/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Telomerase/genética , Neoplasias da Glândula Tireoide/genética , Carcinoma/metabolismo , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Linhagem Celular Tumoral , Humanos , RNA Mensageiro/metabolismo , Telomerase/metabolismo , Neoplasias da Glândula Tireoide/metabolismoRESUMO
Hodgkin lymphoma (HL) commonly presents superficial lymphadenopathy. In addition, HL cells can arise in various organs including the liver and spleen as an extranodal lymphoma. HL in bone is unusual at the initial diagnosis, although some cases show late-stage localization of lymphoma cells to bone. We report the rare case of a young patient with cranial bone classic HL, presumably originating from the skull without any involvement of lymph nodes. As the main clinical manifestation was only tumor mass in the skull without osteoscopic pain, the tentative diagnosis of Langerhans cell histiocytosis was histologically confirmed by an excisional biopsy. Before the final pathological diagnosis as classic HL, we noticed several small lesions in extranodal regions through systemic surveys, suggesting that the cranial lesion appeared antecedent to those lesions. This is a rare and instructive case of cranial bone HL for which a histological diagnosis has been meticulously made.
Assuntos
Histiocitose de Células de Langerhans/patologia , Doença de Hodgkin/patologia , Linfonodos/patologia , Células de Reed-Sternberg/patologia , Biópsia , Osso e Ossos/patologia , Criança , Feminino , Doença de Hodgkin/diagnóstico , HumanosAssuntos
Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Medula Óssea/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Rituximab/uso terapêutico , Células Estromais/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismoAssuntos
ADP-Ribosil Ciclase 1/metabolismo , Anticorpos Monoclonais , Mieloma Múltiplo , Derrame Pleural , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Derrame Pleural/etiologia , Derrame Pleural/patologiaRESUMO
Several approaches for the detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) have shown the importance of determining the level of MRD precisely. In the present study, we tested a new real-time quantitative polymerase chain reaction (RQ-PCR) strategy with minor groove binder (MGB) technology for immunoglobulin heavy chain gene rearrangements by positioning a MGB probe at the germline JH segments and one of the primers at the downstream introns in combination with an allele-specific oligonucleotide (ASO) primer complementary to the VH-DH or DH-JH junctional region. A MGB probe forms extremely stable duplexes with single-stranded DNA targets, allowing the use of shorter probes for hybridization-based assays. Therefore, it shows positional flexibility. We have designed two novel consensus MGB JH germline probes for analyzing all of the germline rearrangements registered in the V BASE database, and demonstrated that the MRD was detectable with the probes in 17 cases of childhood ALL. The actual copy number for the targets and dynamic changes before and after treatment were almost identical between the JH MGB probe and conventional non-MGB probes in each patient. MGB technology will undoubtedly contribute to MRD-PCR studies of childhood ALL.
Assuntos
Sondas de DNA , Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética , Reação em Cadeia da Polimerase/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Sequência de Bases , Pré-Escolar , Sequência Consenso/genética , Humanos , Dados de Sequência Molecular , Neoplasia Residual , Sondas de Oligonucleotídeos/genética , PrognósticoRESUMO
The anti-arrhythmic agent amiodarone (AD) is associated with numerous adverse effects, but serious liver disease is rare. The improved safety of administration of daily low doses of AD has already been established and this regimen is used for long-term medication. Nevertheless, asymptomatic continuous liver injury by AD may increase the risk of step-wise progression of non-alcoholic fatty liver disease. We present an autopsy case of AD-induced liver cirrhosis in a patient who had been treated with a low dose of AD (200 mg/d) daily for 84 mo. The patient was a 85-year-old male with a history of ischemic heart disease. Seven years after initiation of treatment with AD, he was admitted with cardiac congestion. The total dose of AD was 528 g. Mild elevation of serum aminotransferase and hepatomegaly were present. Liver biopsy specimens revealed cirrhosis, and under electron microscopy numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis were observed. Initially, withdrawal of AD led to a slight improvement of serum aminotransferase levels, but unfortunately his general condition deteriorated and he died from complications of pneumonia and renal failure. Long-term administration of daily low doses of AD carries the risk of progression to irreversible liver injury. Therefore, periodic examination of liver function and/or liver biopsy is required for the management of patients receiving long-term treatment with AD.
Assuntos
Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Cirrose Hepática/induzido quimicamente , Isquemia Miocárdica/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Humanos , Cirrose Hepática/patologia , MasculinoRESUMO
Progressive transformation of germinal center (PTGC) represents an asymptomatic persistent form of lymphadenopathy. We present a case of classical Hodgkin lymphoma occurring in association with PTGC. The patient was a 60-year-old woman who had noted swelling of the submandibular lymph nodes. Histopathologically, the enlarged lymph nodes appeared as multiple nodules with ill-defined and irregularly expanded germinal centers. Immunohistochemical studies indicated that the germinal center cells comprised B cells that were positive for CD10 and CD20, and negative for bcl-2. Enlarged vascular endothelial cells were present in the interfollicular areas. CD30-positive Hodgkin & Reed-Sternberg cells were seen between the interfollicular area and the mantle zone, and were surrounded by CD3-positive T-cells. In situ hybridization studies demonstrated no expression of Epstein-Barr virus-encoded small RNA in the Hodgkin & Reed-Sternberg cells. A diagnosis of classical Hodgkin lymphoma complicated by PTGC was made from the lymph node specimen.
Assuntos
Transformação Celular Neoplásica/patologia , Centro Germinativo/patologia , Doença de Hodgkin/patologia , Linfoma/patologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Small and large non-coding RNAs (ncRNAs) contribute to the acquisition of aggressive tumor behavior in diverse human malignancies. Two types of ncRNAs, miRNA10b (miR-10b) and homemobox (HOX) transcript antisense RNA (HOTAIR), can suppress the translation of the HOXD10 gene, an mRNA encoding a transcriptional repressor that inhibits the expression of cell migration/invasion-associated genes. Using epithelial ovarian cancer cell lines and primary tumors, we investigated whether miR10b and/or HOTAIR can regulate the expression of HOXD10, and whether it permits gain of prometastatic gene products, matrix metallopeptidase 14 (MMP14) and ras homolog family member C (RHOC). Overexpression of miR-10b induced a decrease in HOXD10 protein expression, and upregulated the migration and invasion abilities in ovarian cancer cell lines (P<0.05). In these cells, a significant increase of MMP14 and RHOC protein was observed. No significant upregulation of the HOXD10 protein was observed in cells with the treatment of HOTAIR-siRNA. Positive signals for HOXD10 and MMP14 proteins were observed in 47 (69%) and 25 (37%) of 68 patients with epithelial ovarian cancers. An inverse correlation between HOXD10 and MMP14 immunoreactivities was observed (P<0.05), and miR-10b expression was also inversely correlated with HOXD10 protein expression (P<0.05). These results suggested that downregulation of HOXD10 expression by miR-10b overexpression may induce an increase of pro-metastatic gene products, such as MMP14 and RHOC, and contribute to the acquisition of metastatic phenotypes in epithelial ovarian cancer cells.