RESUMO
ALK-rearranged renal cell carcinoma (ALK-RCC) is rare, molecularly defined RCC subtype in the recently published fifth edition of World Health Organization classification of tumors. In this study, we described 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were 6 male and 3 female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for 8 patients and on biopsy specimen for 1. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6 of 9 patients (6-36 months); 5 had no tumor recurrence or metastasis and 1 developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib-targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n = 1), and pale foamy cytoplasm (n = 1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included psammomatous microcalcifications (n = 5), rhabdoid cells (n = 4), prominent intracytoplasmic vacuoles (n = 4), prominent chronic inflammatory infiltrate (n = 3), signet ring cell morphology (n = 2), and pleomorphic cells (n = 2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4 of 8 tested cases showed reactivity for TFE3 protein. By fluorescence in situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n = 2), STRN (n = 1), TPM3 (n = 1), KIF5B (n = 1), HOOK1 (n = 1), SLIT1 (n = 1), and TPM1(3' UTR) (n = 1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.
Assuntos
Quinase do Linfoma Anaplásico , Carcinoma de Células Renais , Rearranjo Gênico , Neoplasias Renais , Receptores Proteína Tirosina Quinases , Humanos , Masculino , Quinase do Linfoma Anaplásico/genética , Pessoa de Meia-Idade , Feminino , Neoplasias Renais/genética , Neoplasias Renais/patologia , Adulto , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Adolescente , Adulto Jovem , Receptores Proteína Tirosina Quinases/genética , Imuno-Histoquímica , Biomarcadores Tumorais/genética , Hibridização in Situ Fluorescente , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genéticaRESUMO
BACKGROUND: Minimally invasive modifications of inguinal lymphadenectomy (IL), including laparoscopic IL (LIL) and robotic-assisted IL (RAIL), have been utilized for penile cancer. Comparative study is necessary to guide the decision about which minimally invasive technique to select for IL. Therefore we compared RAIL with LIL performed via an antegrade approach in terms of perioperative outcomes. METHODS: We conducted a retrospective study of 43 patients who underwent RAIL (n = 20) or LIL (n = 23) for penile cancer from 2016 to 2020. The key surgical procedures and techniques are described. Complications were graded by the Clavien-Dindo classification, and operative time, estimated blood loss (EBL), lymph nodal yield, nodal positivity, postoperative drain duration, and disease recurrence during follow-up were assessed. Categorical variables were compared using chi-squared whereas continuous variables were compared by t-tests. RESULTS: The operative time for RAIL was significantly shorter than that of LIL (median 83 vs 95 min). Significantly less blood loss was reported with RAIL than with LIL (median 10 vs 35 ml). Lymph node yield, pathological positive nodes, the hospital stay, postoperative drain duration, postoperative complications and recurrence were similar for RAIL and LIL. CONCLUSIONS: For patients with penile cancer, perioperative outcomes of RAIL and LIL were similar, but there was less blood loss, a shorter operative time for robotic cases.
Assuntos
Laparoscopia , Neoplasias Penianas , Procedimentos Cirúrgicos Robóticos , Masculino , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Neoplasias Penianas/cirurgia , Estudos Retrospectivos , Recidiva Local de Neoplasia/cirurgia , Excisão de Linfonodo/métodos , Laparoscopia/métodosRESUMO
UNLABELLED: Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs), which participate in tumor invasion, therapeutic resistance, and tumor relapse leading to poor outcome and limited therapeutic options. Histone deacetylatase sirtuin 1 (SIRT1) has been shown to be up-regulated in human cancers; however, its role in liver CSCs is unknown. In this study, we explored the biological functions of SIRT1 in liver CSCs. Our data show that SIRT1 is highly expressed in liver CSCs and decreases during differentiation. In addition, high levels of SIRT1 predict a decreased probability of survival in patients with HCC. SIRT1 is responsible for the maintenance of self-renewal and tumorigenicity of liver CSCs, and overexpression of exogenous SIRT1 can restore self-renewal of non-CSCs. We demonstrated that SOX2 is a main downstream regulator of SIRT1-mediated self-renewal and tumorigenicity potential of liver CSCs. Mechanistically, SIRT1 regulates transcription of the SOX2 gene by way of chromatin-based epigenetic changes, which are dependent on DNA methylation. This effect is achieved by alternation of histone modification and interaction with DNA methyltransferase 3A, resulting in hypermethylation of SOX2 promoter. Furthermore, we demonstrated that insulin growth factor signaling plays an important role in maintaining SIRT1 expression through increased SIRT1 protein stability. CONCLUSIONS: These findings highlight the importance of SIRT1 in the biology of liver CSCs and suggest that SIRT1 may serve as a molecular target for HCC therapy. (Hepatology 2016;64:814-827).
Assuntos
Carcinoma Hepatocelular/metabolismo , Autorrenovação Celular , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Sirtuína 1/metabolismo , Animais , DNA Metiltransferase 3A , Epigênese Genética , Feminino , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Somatomedinas/metabolismoRESUMO
Triggering receptor expressed on myeloid cells 1(TREM-1) is a newly identified member of the immunoglobulin superfamily and is extensively involved in the regulation of innate immunity. To determine the role of TREM-1 in innate antiviral immunity, we investigated TREM-1 expression and its downstream signaling effect in the murine bone marrow-derived macrophages or RAW264.7 macrophage-like mouse cell line by double-stranded RNA (dsRNA) stimulation. The level of TREM-1 expression was low at the baseline and could up-regulate markedly in dose- and time-dependent manners upon stimulation by dsRNA/poly IC. Inhibitor studies disclosed mitogen-activated protein kinase (MAPK) p38 and PI3K pathways were involved in dsRNA-induced up-regulation of TREM-1. Compared with lipopolysaccharide (LPS), the peak response of poly IC-induced TREM-1 expression is delayed, and cells pretreated with scrambled RNA presented higher expression of TREM-1 upon LPS challenge. After ligation with the agonist antibody, TREM-1 can potentiate type I interferon (IFN) production and antiviral inflammation induced by dsRNA, which is ralated to the enhanced phosphorylation of MAPKs and expression of RLRs and TLRs by TREM-1 ligation. This study is the first to show the regulatory role of TREM-1 in RLRs and TLRs expression, and these findings might enrich the understanding of the up-regulation mechanism and the function of TREM-1.
Assuntos
Antivirais/farmacologia , Imunidade Inata/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , RNA de Cadeia Dupla/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/metabolismo , Receptores Toll-Like/metabolismo , Animais , Células da Medula Óssea/citologia , Citocinas/metabolismo , Inflamação/patologia , Interferon Tipo I/farmacologia , Lentivirus/metabolismo , Lipossomos/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Poli I-C/farmacologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , Receptor Gatilho 1 Expresso em Células Mieloides , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: The present study was designed to observe the effects of the bacterial component flagellin on anti-sepsis protection through TLR-5, VCAN and IL-1RN. METHODS: A clinically relevant model of sepsis was induced by cecal ligation and puncture (CLP). An in vitro culture of endothelial cells was analyzed. RESULTS: Flagellin induced anti-sepsis protection through inhibition of inflammation and induction of endothelial proliferation by down-regulating the expression of TLR 3, TLR 4, and IL-1RN and promoting the expression of VCAN in mice 24 h post-CLP. In vitro, flagellin promoted the proliferation of endothelial cells. These effects could be inhibited by transfection of endothelial cells with VCAN siRNA or IL-1RN over-expression constructs. VCAN expression decreased after transfection of the cells with an IL-1RN over-expression construct and increased after transfection of the cells with an IL-1RN siRNA construct. IL-1RN expression remained unchanged after transfection of the cells with VCAN over-expression or siRNA constructs. CONCLUSIONS: These data suggest that flagellin pretreatment promoted anti-sepsis protection through the TLR-5, IL-1RN and VCAN pathway. This pathway is necessary to mediate endothelial repair and thereby promote survival following sepsis challenge.
Assuntos
Anti-Inflamatórios/uso terapêutico , Flagelina/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Sepse/tratamento farmacológico , Receptor 5 Toll-Like/imunologia , Versicanas/imunologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/análise , Proteína Antagonista do Receptor de Interleucina 1/genética , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Sepse/genética , Sepse/imunologia , Sepse/microbiologia , Receptor 5 Toll-Like/análise , Receptor 5 Toll-Like/genética , Versicanas/análise , Versicanas/genéticaRESUMO
The response to epidermal growth factor receptor (EGFR)-targeted therapy in metastatic colorectal cancer (mCRC) is variable because of intra-tumor heterogeneity at the genetic level, and consequently, it is important to develop sensitive and selective assays to predict patient responses to therapy. Low-abundance BRAF V600E mutations are associated with poor response to treatment with EGFR inhibitors. We developed a method for the detection of BRAF V600E mutations in mCRC using real-time wild-type blocking PCR (WTB-PCR), in which a chimera composed of locked nucleic acids and DNA is incorporated to amplify the mutant allele at high efficiency while simultaneously inhibiting the amplification of wild-type alleles. Mixing experiments showed that this method is exquisitely sensitive, with detection of the mutated allele at a mutant/wild-type ratio of 1:10,000. To demonstrate the applicability of this approach for mCRC patients, we assessed the V600E mutations in 50 clinical cases of mCRC by real-time WTB-PCR. The percentage of patients with V600E mutation as determined by WTB-PCR (16%, 8/50) was higher than by traditional PCR (10%, 5/50), suggesting an increased sensitivity for WTB-PCR. By calculating the ΔC q for real-time traditional PCR, which amplifies all BRAF alleles, versus WTB-PCR, which selectively amplifies mutant BRAF, we demonstrated that among the V600E-positive mCRC patient samples, the percentage of BRAF DNA with the V600E mutation ranged from 0.05 to 52.32%. In conclusion, WTB-PCR provides a rapid, simple, and low-cost method to detect trace amounts of mutated BRAF V600E gene.
Assuntos
Neoplasias Colorretais/enzimologia , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Alelos , Sequência de Bases , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , DNA/química , DNA/genética , Humanos , Dados de Sequência Molecular , Ácidos Nucleicos/química , Ácidos Nucleicos/genética , Reação em Cadeia da Polimerase/instrumentaçãoRESUMO
Infiltration and activation of intratumoral T lymphocytes are critical for immune checkpoint blockade (ICB) therapy. Unfortunately, the low tumor immunogenicity and immunosuppressive tumor microenvironment (TME) induced by tumor metabolic reprogramming cooperatively hinder the ICB efficacy. Herein, we engineered a lactate-depleting MOF-based catalytic nanoplatform (LOX@ZIF-8@MPN), encapsulating lactate oxidase (LOX) within zeolitic imidazolate framework-8 (ZIF-8) coupled with a coating of metal polyphenol network (MPN) to reinforce T cell response based on a "two birds with one stone" strategy. LOX could catalyze the degradation of the immunosuppressive lactate to promote vascular normalization, facilitating T cell infiltration. On the other hand, hydrogen peroxide (H2O2) produced during lactate depletion can be transformed into anti-tumor hydroxyl radical (â¢OH) by the autocatalytic MPN-based Fenton nanosystem to trigger immunogenic cell death (ICD), which largely improved the tumor immunogenicity. The combination of ICD and vascular normalization presents a better synergistic immunopotentiation with anti-PD1, inducing robust anti-tumor immunity in primary tumors and recurrent malignancies. Collectively, our results demonstrate that the concurrent depletion of lactate to reverse the immunosuppressive TME and utilization of the by-product from lactate degradation via cascade catalysis promotes T cell response and thus improves the effectiveness of ICB therapy.
Assuntos
Estruturas Metalorgânicas , Neoplasias , Humanos , Ácido Láctico/farmacologia , Estruturas Metalorgânicas/farmacologia , Peróxido de Hidrogênio/farmacologia , Linfócitos T , Imunoterapia , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
cGAS-STING signaling plays a critical role in radiotherapy (RT)-mediated immunomodulation. However, RT alone is insufficient to sustain STING activation in tumors under a safe X-ray dose. Here, we propose a radiosensitization cooperated with cGAS stimulation strategy by engineering a core-shell structured nanosized radiosensitizer-based cGAS-STING agonist, which is constituted with the hafnium oxide (HfO2) core and the manganese oxide (MnO2) shell. HfO2-mediated radiosensitization enhances immunogenic cell death to afford tumor associated antigens and adequate cytosolic dsDNA, while the GSH-degradable MnO2 sustainably releases Mn2+ in tumors to improve the recognition sensitization of cGAS. The synchronization of sustained Mn2+ supply with cumulative cytosolic dsDNA damage synergistically augments the cGAS-STING activation in irradiated tumors, thereby enhancing RT-triggered local and system effects when combined with an immune checkpoint inhibitor. Therefore, the synchronous radiosensitization with sustained STING activation is demonstrated as a potent immunostimulation strategy to optimize cancer radio-immuotherapy.
Assuntos
Háfnio , Compostos de Manganês , Neoplasias , Humanos , Compostos de Manganês/farmacologia , Óxidos/farmacologia , Óxidos/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , NucleotidiltransferasesRESUMO
UNLABELLED: Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cell-related genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog-positive cells. We demonstrate that Nanog-positive cells exhibited enhanced ability of self-renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). Nanog(Pos) CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that Nanog(Pos) CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock-down expression of Nanog in Nanog(Pos) CSCs could decrease self-renewal accompanied with decreased expression of stem-cell-related genes and increased expression of mature hepatocyte-related genes. Overexpression of Nanog in Nanog(Neg) cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (IGF1R) were up-regulated in Nanog(Pos) CSCs. Knock-down expression of Nanog in Nanog(Pos) CSCs inhibited the expression of IGF1R, and overexpression of Nanog in Nanog(Neg) cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self-renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog-mediated self-renewal. CONCLUSION: These data indicate that Nanog could be a novel biomarker for CSCs in HCC, and that Nanog could play a crucial role in maintaining the self-renewal of CSCs through the IGF1R-signaling pathway.
Assuntos
Carcinoma Hepatocelular/patologia , Proteínas de Homeodomínio/fisiologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/fisiologia , Receptor IGF Tipo 1/fisiologia , Proteínas de Homeodomínio/biossíntese , Humanos , Proteína Homeobox Nanog , Transdução de SinaisRESUMO
Radiotherapy (RT) is one of the important clinical treatments for local control of triple-negative breast cancer (TNBC), but radioresistance still exists. Ferroptosis has been recognized as a natural barrier for cancer progression and represents a significant role of RT-mediated anticancer effects, while the simultaneous activation of ferroptosis defensive system during RT limits the synergistic effect between RT and ferroptosis. Herein, we engineered a tumor microenvironment (TME) degradable nanohybrid with a dual radiosensitization manner to combine ferroptosis induction and high-Z effect based on metal-organic frameworks for ferroptosis-augmented RT of TNBC. The encapsulated l-buthionine-sulfoximine (BSO) could inhibit glutathione (GSH) biosynthesis for glutathione peroxidase 4 (GPX4) inactivation to break down the ferroptosis defensive system, and the delivered ferrous ions could act as a powerful ferroptosis executor via triggering the Fenton reaction; the combination of them induces potent ferroptosis, which could synergize with the surface decorated Gold (Au) NPs-mediated radiosensitization to improve RT efficacy. In vivo antitumor results revealed that the nanohybrid could significantly improve the therapeutic efficacy and antimetastasis efficiency based on the combinational mechanism between ferroptosis and RT. This work thus demonstrated that combining RT with efficient ferroptosis induction through nanotechnology was a feasible and promising strategy for TNBC treatment.
Assuntos
Ferroptose , Neoplasias de Mama Triplo Negativas , Humanos , Anestésicos Locais , Butionina Sulfoximina , Fibrinolíticos , Glutationa , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Primary pulmonary hyalinizing clear cell carcinoma (HCCC) is a rare salivary gland-type tumor newly recognized in recent years, with approximately 21 cases reported to date in the English literature, which constitutes a challenge in pathology diagnosis, particularly in small biopsy specimens. Here, we present a case of pulmonary HCCC diagnosed by computed tomography-guided percutaneous lung biopsy in a 70-year-old man's right lower lung. Although the morphology and immunophenotype of the tumor suggested the diagnosis of mucoepidermoid carcinoma, fluorescence in situ hybridization failed to reveal the rearrangement of MAML2 gene, which is characteristic of mucoepidermoid carcinoma. Instead, further molecular genetic testing showed that the tumor harbored a rare EWSR1::CREM fusion combined with a previously unreported IRF2::NTRK3 fusion. Pulmonary HCCC is commonly regarded as a low-grade malignant tumor with an indolent course, but this case has a different biological behavior, presenting extensive dissemination and metastases at the time of diagnosis, which expands our understanding of the prognosis of this tumor. The patient has had five cycles of combination chemotherapy and has been alive with the tumor for eight months.
RESUMO
Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.
Assuntos
Glioma , Inibidores de Checkpoint Imunológico , Interleucina-8 , Animais , Camundongos , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/patologia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Interleucina-8/metabolismo , Linfócitos T , Microambiente TumoralRESUMO
Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.
RESUMO
OBJECTIVES: To review the clinicopathologic features of perivascular epithelioid cell tumor (PEComa) of the urinary bladder. METHODS: Seven cases of bladder PEComa were studied by light microscopy, immunohistochemistry, and fluorescence in situ hybridization (FISH). RESULTS: In our 7 cases, 5 patients were female and 2 were male, with ages between 26 and 78 years. Patients presented with hematuria and recurrent abdominal discomfort as the main clinical symptoms. Microscopically, the epithelioid and spindle-shaped tumor cells with clear to granular eosinophilic cytoplasm were arranged in fascicular, acinar, or nested patterns. The tumor cells were positive for HMB45, melan-A, and SMA, but no TFE3 gene rearrangement was detected in any of the 7 samples by FISH. The analysis of all 35 cases from the literature and ours showed a patient age range from 16 to 78 years (mean age, 39 years), a male-to-female ratio of 1:1.3, maximal tumor diameters from 0.6 to 18.8 cm (mean, 4.5 cm). With a mean follow-up of 27 months, the recurrence, metastasis, and mortality rates were 10.7%, 10.7%, and 7.1%, respectively. CONCLUSIONS: Bladder PEComa is extremely rare, remains a diagnostic challenge, and needs more attention. Strengthening the understanding of this tumor will improve diagnostic accuracy.
Assuntos
Neoplasias de Células Epitelioides Perivasculares/patologia , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The NAD-dependent deacetylase sirtuin 1 (SIRT1), a member of the mammalian sirtuin family, plays a pivotal role in deacetylating histone and nonhistone proteins. Recently, it has been reported that SIRT1 is upregulated in various kinds of tumors and is associated with cell growth and metastasis. However, the factors and molecular mechanism regulating its cellular levels remain to be clarified. Here, we reported that the E3 ubiquitin ligase SMURF2 interacts with SIRT1 and mediates its ubiquitination and degradation. Depletion of SMURF2 leads to SIRT1 upregulation and induces the tumor formation and growth of colorectal cancer in vitro and in vivo. Furthermore, we show a negative correlation between SIRT1 and SMURF2 expression in human colorectal cancer. Thus, we propose a novel mechanism of colorectal tumorigenesis via SIRT1 regulation by SMURF2, which could potentially give rise to a new strategy for the treatment of colorectal cancer.
Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Proteínas de Neoplasias/metabolismo , Sirtuína 1/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Animais , Divisão Celular , Movimento Celular , Neoplasias Colorretais/metabolismo , Xenoenxertos , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Proteínas Recombinantes/metabolismo , Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
The NAD-dependent histone deacetylase sirtuin 2 (SIRT2) plays critical roles in mitosis and cell cycle progression and recently was shown to suppress tumor growth and to be downregulated in several types of cancers. However, the underlying mechanism of SIRT2 downregulation remains unknown. In this study, using bioinformatics, gene expression profiling, protein overexpression approaches, and cell migration assays, we showed that E3 ubiquitin ligase 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase degradation 1 (HRD1) interacts with SIRT2 and promotes its ubiquitination and degradation. Furthermore, we found that HRD1 deficiency induces SIRT2 upregulation and inhibits the growth and tumor formation of lung cancer cells both in vitro and in vivo Of note, we observed that SIRT2 expression is downregulated in human lung cancer and also negatively correlates with HRD1 expression in these cancers. Additionally, we found that patients with lung adenocarcinoma having lower HRD1 or higher SIRT2 expression levels tend to survive longer. On the basis of these results, we propose a mechanism of lung tumorigenesis that involves HRD1-mediated downregulation of SIRT2 and suggest that interventions targeting HRD1 activity could be a potential therapeutic strategy to treat patients with lung cancer.
Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinogênese/genética , Neoplasias Pulmonares/patologia , Sirtuína 2/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Transplante Heterólogo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/fisiologia , Regulação para Cima/genéticaRESUMO
BACKGROUND AND AIMS: Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present. METHODS: 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG. RESULTS: The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS. CONCLUSIONS: SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirurgia , Humanos , Microvasos , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
It was hypothesized that in the WTB-PCR system, the greater number of cycles, associated with the thermodynamic driving force of DNA polymerase resulted in artificial introduction of mutant nucleotides in amplicons. In the current study, universal WTB-PCR was developed to overcome these limitations, in which two strategies were used: phosphorothioate modifications were made at the 5'-termini bases of the WTB oligonucleotides, and amplification of referenced internal positive controller (RIPC) fragments was performed. The results showed that universal WTB-PCR could detect single-copy KRAS mutant alleles with higher selectivity (i.e., 0.01%), and with greater ability to eliminate non-specific amplification of KRAS wild-type alleles in amounts up to 200â¯ng. Moreover, the introduction of referenced internal positive controller (RIPC) fragments prevented false-negative results caused by inadequate amounts of input sample DNA, and allowed for quantitative analysis of the mutation levels in each FFPE sample. In clinical application in 50 samples of FFPE tissue sections from mCRC patients, 70% (35/50) showed various mutations at codons 12 and 13 of KRAS genes; 30% (15/50) could be detected by traditional PCR without WTB oligonucleotides. In conclusion, universal WTB-PCR is a rapid, simple and low-cost method for detection of low-abundance KRAS mutations in mCRC patients.
Assuntos
Códon/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise Mutacional de DNA , Humanos , Reação em Cadeia da Polimerase , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare malignancy. In addition to the classical histopathologic features, it has also some special morphological variants that can present a challenge in the diagnosis of this disease. CASE PRESENTATION: A 45-year-old male who presented with a left supraclavicular mass was given a final diagnosis of FDCS after lymph node biopsy. The specimen obtained during radical resection revealed five different morphologies, including the classical histological appearance and atypical areas resembling desmoplastic infiltrative carcinoma, anaplastic large cell lymphoma (ALCL), hemangiopericytoma and classical Hodgkin's lymphoma (CHL). Immunohistochemistry was notable for positive CD21 and CD23 expression across all morphologies. Given the atypical appearance and location, the specimen was initially misdiagnosed as a metastatic carcinoma based on histology alone at an outside institution. The patient eventually underwent surgical resection followed by adjuvant chemotherapy and radiation. Despite treatment, the disease progressed, and the patient passed away 36 months after surgery. CONCLUSIONS: This unusual case of FDCS contains four types of atypical histomorphologies within a single tumor specimen, including those resembling ALCL and hemangiopericytoma which are described here for the first time. Our report further expands the histopathologic spectrum of FDCS and may help assist in the diagnosis of other such challenging cases.
Assuntos
Biomarcadores Tumorais/análise , Sarcoma de Células Dendríticas Foliculares/patologia , Doença de Hodgkin/patologia , Biópsia , Sarcoma de Células Dendríticas Foliculares/diagnóstico , Diagnóstico Diferencial , Erros de Diagnóstico , Doença de Hodgkin/diagnóstico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Upregulation of special AT-rich sequence-binding protein-1 (SATB1) has been suggested to promote tumor growth and metastasis. However, the factors governing its cellular levels remain unclear. Here, we report that ubiquitin-specific peptidase 47 (USP47), a member of the deubiquitinating enzymes family, interacts with SATB1 and mediates its deubiquitination and stability. USP47 deficiency impairs transcriptional activity of SATB1 target genes and inhibits colon cancer cell proliferation, migration, and tumorigenesis in a mouse model of colon cancer. Furthermore, we identified SMURF2 as an E3 ubiquitin ligase that promotes SATB1 degradation by upregulating its ubiquitination, and its deficiency promotes colon cancer cell proliferation and SATB1 target gene transcription. SMURF2 is negatively regulated by USP47, and USP47 depletion sensitizes colon cancer cells to 5-FU treatment-induced apoptosis. Taken together, our findings provide a ubiquitination-related mechanistic link to USP47, SMURF2, and SATB1 and suggest that USP47 might be targeted for colon cancer treatment when SATB1 is overexpressed.