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3.
Wei Sheng Yan Jiu ; 49(5): 711-723, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070810

RESUMO

OBJECTIVE: To investigate the expression and biological significance of LINC00310 in the malignant transformation of human bronchial epithelial cells(16 HBE) induced by glycidyl methacrylate(GMA). METHODS: The 16 HBE cells recovered successfully used 1 µg/mL dimethyl sulfoxide(DMSO) as the solvent control group, and the final concentration was 8 µg/mL GMA as the treatment group, and were subcultured after repeated exposure 3 times for 72 hours each time. The 10 th, 20 th and 30 th generation cells of the GMA treatment group and corresponding DMSO control group were collected. The LncRNA microarrays was used to analyze the expression changes of LINC00310 in different periods, and the target gene and function prediction was performed by NCBI and cBioPortal bioinformatics database, and real-time quantification PCR(qPCR) was used to detect the relative expression levels of LINC00310 and predicted target genes. RESULTS: The result of the microarray showed that LINC00310 in the GMA-treated group was down-regulated by 2. 02-fold, up-regulated by 6. 17-fold, and up-regulated by 2. 03-fold in the pre-transformation, mid-term, and late, respectively. The result of qPCR confirmed that the expression of LINC00310 relative expression level of 10 th, 20 th and 30 th generation cells was consistent with the microarray result, which were down-regulated by 2. 76-fold, up-regulated by 2. 68-fold, and up-regulated by 3. 09-fold. Consistently, the relative expression of the target gene C-Myc was statistically significant in 20 th and 30 th generation cells. CONCLUSION: LINC00310 induced low expression in the early stage of malignant transformation of 16 HBE cells induced by GMA, and was highly expressed in the middle and late stages. It indicated that LINC00310 may play a cancer-promoting role in the process of cell malignant transformation through C-Myc.


Assuntos
Compostos de Epóxi , Metacrilatos , Transformação Celular Neoplásica/genética , Células Epiteliais , Compostos de Epóxi/toxicidade , Humanos , Metacrilatos/toxicidade , RNA Longo não Codificante
4.
Nat Commun ; 11(1): 5120, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037194

RESUMO

Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients.


Assuntos
Matriz Extracelular/patologia , Neoplasias/patologia , Animais , Transformação Celular Neoplásica/patologia , Humanos , Microambiente Tumoral
5.
Am J Clin Oncol ; 43(9): 670-675, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889839

RESUMO

During the course of therapy, patients with small cell lung cancer have been noted to develop transformation to non-small cell lung cancer and conversely, patients with non-small cell lung cancer have had transformation to small cell lung cancer or other non-small cell histologies. Transformation may occur after prior tyrosine kinase inhibitors, chemotherapy, immunotherapy or radiation therapy. These changes reflect on the overlapping biology of these cell types and the clinical need for re-biopsy at times of disease progression. The optimum therapy after transformation will depend upon prior therapies received, the functional capacity of the patient, and further research to define the best therapy options.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Transformação Celular Neoplásica , Receptores ErbB/genética , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapia
6.
Adv Exp Med Biol ; 1268: 211-226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918221

RESUMO

Tumor development is the result of genetic derangement and the inability to prevent unfettered proliferation. Genetic derangements leading to tumorigenesis are variable, but the immune system plays a critical role in tumor development, prevention, and production. In this chapter, we will discuss the importance of the immune system as it relates to the development of skin cancer-both melanoma and non-melanoma skin cancers (NMSC).


Assuntos
Transformação Celular Neoplásica/imunologia , Sistema Imunitário , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Humanos
7.
Adv Exp Med Biol ; 1268: 227-253, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918222

RESUMO

Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds.


Assuntos
Calcitriol/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Vitamina D/farmacologia , Animais , Calcitriol/química , Calcitriol/metabolismo , Humanos , Vitamina D/química , Vitamina D/metabolismo , Vitaminas/química , Vitaminas/metabolismo , Vitaminas/farmacologia
8.
Dermatol Online J ; 26(7)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898403

RESUMO

Poorly controlled and long-standing hidradenitis suppurativa (HS) increases the risk of squamous cell carcinoma (SCC). We report a 54-year-old woman with an over 20-year history of HS, who had previously undergone wide perineal excision with secondary intention healing and presented with a painful verrucous vulvar plaque and proximal non-healing perineal wound. The patient had four perineal scouting biopsies performed and excisional biopsy with no evidence of high-grade dysplasia or carcinoma on histology. Chromogenic in situ hybridization was negative for HPV 16 and 18 mRNA; the patient's HIV and HSV PCR were also negative. Our patient was treated with interferon alfa-2b with notable clinical improvement. There is currently no standardized stepwise approach to monitoring verrucous lesions in HS patients with significant risk factors for SCC. Our report highlights a vigilant approach to monitoring. If scouting biopsies are negative, complete testing for high risk HPV strains (HPV 16 and 18) is warranted. If negative, we recommend follow up every 6 months with no further biopsies except if overt clinical changes are observed. We also recommend treatment of verrucous changes to decrease risk of possible malignant conversion. Interferon alfa-2b was effective in decreasing the verrucous lesion burden in our patient and may be considered.


Assuntos
Hidradenite Supurativa/complicações , Interferon alfa-2/uso terapêutico , Verrugas/tratamento farmacológico , Biópsia , Carcinoma de Células Escamosas/prevenção & controle , Transformação Celular Neoplásica , Condiloma Acuminado/patologia , Diagnóstico Diferencial , Feminino , Hidradenite Supurativa/cirurgia , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/isolamento & purificação , Humanos , Pessoa de Meia-Idade , Períneo/patologia , RNA Viral/análise , Falha de Tratamento , Vulva/patologia , Verrugas/etiologia , Cicatrização
9.
Anticancer Res ; 40(9): 5081-5090, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878796

RESUMO

BACKGROUND/AIM: Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with limited targets for chemotherapy. This study evaluated the inhibitory effects of novel imidazo[2,1-b]oxazole-based rapidly accelerated fibrosarcoma (RAF) inhibitors, KIST0215-1 and KIST0215-2, on epithelial cell transformation and TNBC tumorigenesis. MATERIALS AND METHODS: Immunoblotting, BrdU incorporation assay, reporter gene assay, and soft agar assay analyses were performed. In vivo effects were studied using the BALB/c mouse xenograft model. RESULTS: KIST0215-1 and KIST0215-2 inhibited the RAFs-MEK1/2-ERK1/2 signalling pathway induced by EGF in MDA-MB-231 cells, which inhibited c-fos transcriptional activity and activator protein-1 transactivation activity. KIST0215-1 and KIST0215-2 also prevented neoplastic transformation of JB6 C141 mouse epidermal cells induced by EGF and consistently suppressed the growth of tumours formed by 4T1 cells in BALB/c mice. CONCLUSION: Inhibition of RAF kinases using KIST0215-1 and KIST0215-2 is a promising chemotherapeutic strategy to treat TNBC.


Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Imidazóis/farmacologia , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Genes Reporter , Humanos , Imidazóis/química , Camundongos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Protoc ; 15(9): 3105-3128, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32826993

RESUMO

Zebrafish are an ideal cell transplantation model. They are highly fecund, optically clear and an excellent platform for preclinical drug discovery studies. Traditionally, xenotransplantation has been carried out using larval zebrafish that have not yet developed adaptive immunity. Larval engraftment is a powerful short-term transplant platform amenable to high-throughput drug screening studies, yet animals eventually reject tumors and cannot be raised at 37 °C. To address these limitations, we have recently developed adult casper-strain prkdc-/-, il2rgα-/- immunocompromised zebrafish that robustly engraft human cancer cells for in excess of 28 d. Because the adult zebrafish can be administered drugs by oral gavage or i.p. injection, our model is suitable for achieving accurate, preclinical drug dosing. Our platform also allows facile visualization of drug effects in vivo at single-cell resolution over days. Here, we describe the procedures for xenograft cell transplantation into the prkdc-/-, il2rgα-/- model, including refined husbandry protocols for optimal growth and rearing of immunosuppressed zebrafish at 37 °C; optimized intraperitoneal and periocular muscle cell transplantation; and epifluorescence and confocal imaging approaches to visualize the effects of administering clinically relevant drug dosing at single-cell resolution in vivo. After identification of adult homozygous animals, this procedure takes 35 d to complete. 7 days are required to acclimate adult fish to 37 °C, and 28 d are required for engraftment studies. Our protocol provides a comprehensive guide for using immunocompromised zebrafish for xenograft cell transplantation and credentials the model as a new preclinical drug discovery platform.


Assuntos
Transformação Celular Neoplásica , Imagem Molecular/métodos , Análise de Célula Única/métodos , Peixe-Zebra/imunologia , Animais , Linhagem Celular Tumoral , Humanos
11.
Nat Commun ; 11(1): 4012, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782388

RESUMO

Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca2+ channel-like protein, is highly up-regulated in several cancer types. Here, we show that TMBIM6 is closely associated with survival in patients with cervical, breast, lung, and prostate cancer. TMBIM6 deletion or knockdown suppresses primary tumor growth. Further, mTORC2 activation is up-regulated by TMBIM6 and stimulates glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca2+ from TMBIM6, a unique characteristic, is shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identify that the BIA compound, a potentialTMBIM6 antagonist, prevents TMBIM6 binding to mTORC2, decreases mTORC2 activity, and also regulates TMBIM6-leaky Ca2+, further suppressing tumor formation and progression in cancer xenograft models. This previously unknown signaling cascade in which mTORC2 activity is enhanced via the interaction with TMBIM6 provides potential therapeutic targets for various malignancies.


Assuntos
Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Indenos/farmacologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/genética , Neoplasias/patologia , Ligação Proteica , Ribossomos/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
12.
Nat Commun ; 11(1): 4085, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796935

RESUMO

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.


Assuntos
Progressão da Doença , Genômica , Cisto Pancreático/genética , Neoplasias Pancreáticas/genética , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Exoma/genética , Dosagem de Genes , Humanos , Mutação , Cisto Pancreático/patologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Proteína Smad4/genética
13.
Int J Oral Sci ; 12(1): 23, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826859

RESUMO

The integrity of the basal stem cell layer is critical for epithelial homoeostasis. In this paper, we review the expression of oral mucosal stem cell markers (OM-SCMs) in oral submucous fibrosis (OSF), oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) to understand the role of basal cells in potentiating cancer stem cell behaviour in OSF. While the loss of basal cell clonogenicity triggers epithelial atrophy in OSF, the transition of the epithelium from atrophic to hyperplastic and eventually neoplastic involves the reactivation of basal stemness. The vacillating expression patterns of OM-SCMs confirm the role of keratins 5, 14, 19, CD44, ß1-integrin, p63, sex-determining region Y box (SOX2), octamer-binding transcription factor 4 (Oct-4), c-MYC, B-cell-specific Moloney murine leukaemia virus integration site 1 (Bmi-1) and aldehyde dehydrogenase 1 (ALDH1) in OSF, OPMDs and OSCC. The downregulation of OM-SCMs in the atrophic epithelium of OSF and their upregulation during malignant transformation are illustrated with relevant literature in this review.


Assuntos
Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Bucais/patologia , Fibrose Oral Submucosa/patologia , Animais , Camundongos , Mucosa Bucal , Células-Tronco
14.
J Cancer Res Clin Oncol ; 146(11): 2721-2730, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32772231

RESUMO

Activation Induced cytidine Deaminase (AID) is an essential enzyme of the adaptive immune system. Its canonical activity is restricted to B lymphocytes, playing an essential role in the diversification of antibodies by enhancing specificity and changing affinity. This is possible through its DNA deaminase function, leading to mutations in DNA. In the last decade, AID has been assigned an additional function: that of a powerful DNA demethylator. Adverse cellular conditions such as chronic inflammation can lead to its deregulation and overexpression. It is an important driver of B-cell lymphoma due to its natural ability to modify DNA through deamination, leading to mutations and epigenetic changes. However, the deregulation of AID is not restricted to lymphoid cells. Recent findings have provided new insights into the role that this protein plays in the development of non-lymphoid cancers, with some research shedding light on novel AID-driven mechanisms of cellular transformation. In this review, we provide an updated narrative of the normal physiological functions of AID. Additionally, we review and discuss the recent research studies that have implicated AID in carcinogenesis in varying tissue types including lymphoid and non-lymphoid cancers. We review the mechanisms, whereby AID promotes carcinogenesis and highlight important areas of future research.


Assuntos
Imunidade Adaptativa/fisiologia , Citidina Desaminase/fisiologia , Neoplasias/enzimologia , Animais , Transformação Celular Neoplásica/imunologia , Humanos , Neoplasias/imunologia
15.
Hum Cell ; 33(4): 1321-1328, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32815117

RESUMO

Giant cell tumor of bone (GCTB) is a rare osteolytic bone tumor, accounting for approximately 5% of all primary bone tumors. GCTB is characterized by unique giant cells. It is also characterized by recurrent mutations in the histone tail of the histone variant H3.3, H3F3A, on chromosome 1, therapeutic implications of which have not been established yet. There are few effective standardized treatments for GCTB, and a novel therapy has long been required. Patient-derived cancer cells have facilitated the understanding of mechanisms underlying the etiology and progression of multiple cancers. Thus far, only 10 GCTB cell lines have been reported, and none of them are publicly available. The aim of this study was to develop an accessible patient-derived cell line of GCTB, which could be used as a screening tool for drug development. Here, we describe the establishment of a cell line, designated NCC-GCTB1-C1, from the primary tumor tissue of a male patient with GCTB on the right distal radius. NCC-GCTB1-C1 cells were maintained as a monolayer culture for over 23 passages for 7 months. These cells exhibited continuous growth, as well as spheroid formation and invasive ability. Using an oncology agent screen, we tested the effect of anticancer drugs on the proliferation of NCC-GCTB1-C1 cells. The cells displayed a remarkable response to romidepsin and vincristine. Thus, we established a novel GCTB cell line, NCC-GCTB1-C1, which could be a useful tool for studying GCTB tumorigenesis and the efficacy of anticancer drugs.


Assuntos
Neoplasias Ósseas , Técnicas de Cultura de Células/métodos , Tumor de Células Gigantes do Osso , Antineoplásicos/farmacologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica , Desenvolvimento de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Tumor de Células Gigantes do Osso/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica
16.
Nat Commun ; 11(1): 3945, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770028

RESUMO

TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.


Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Complexo de Golgi/patologia , Síndrome de Li-Fraumeni/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Biópsia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Feminino , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Complexo de Golgi/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndrome de Li-Fraumeni/patologia , Camundongos , Microtúbulos/metabolismo , Microtúbulos/patologia , Mutação , Cultura Primária de Células , Vesículas Secretórias/metabolismo , Vesículas Secretórias/patologia , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Gene ; 761: 145028, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32763490

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies and inflicts high mortality worldwide. The effect of tumor microenvironment components on HCC oncogenesis remains unknown. In particular, the nonleukocyte portion of the stromal fraction (SF) is poorly understood. METHODS: We comprehensively evaluated the proportional cell counts and gene expression data from The Cancer Genome Atlas (TCGA) to examine the contributions of cell components to the tumor microenvironment. Single-cell sequencing data from the Gene Expression Omnibus (GEO) were also analyzed to verify the association between the nonleukocyte SF and genes. We classified HCC using a hierarchical clustering method based on diversity of nonleukocyte SF-related gene expression among different components, and we used an appropriate GEO dataset to verify the clusters with a support vector machine (SVM) model. The prognosis of subtypes and their relationship with tumor microenvironmental cell proportions, clinicopathogenesis factors, and other indicators were evaluated. RESULTS: Based on linear regression, 711 genes related to nonleukocyte SF were selected from the TCGA dataset. We classified HCC into three subtypes using genes related to the nonleukocyte SF. Additionally, the GEO single-cell sequencing data confirmed the relationship between genes and the nonleukocyte SF. The tumor microenvironment of Type 2 contained the most significant mutually reinforcing interaction between the nonleukocyte SF and tumor cells. Meanwhile, Type 2 patients had the poorest prognosis and the most severe tumor-node-metastasis (TNM) stages, histological grades, etc. The analysis based on the GEO dataset verified the classification results with an SVM model. Type 2 was associated with worse clinicopathological characteristics, including tumor grading and staging, than the other types. In addition, the pathway analysis revealed that signals related to the SF and cell proliferation were significantly enhanced in Type 2 compared to the other group, which consisted of Types 1 and 3. CONCLUSION: The nonleukocyte SF in the tumor microenvironment contributed greatly to HCC oncogenesis. We can use these HCC classification criteria to stratify patients into subtypes for personalized treatment.


Assuntos
Carcinoma Hepatocelular/genética , Células Estromais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genômica , Humanos , Neoplasias Hepáticas/genética , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral/genética
19.
PLoS Pathog ; 16(8): e1008730, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776977

RESUMO

Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Herpesvirus Humano 8/metabolismo , Fatores Reguladores de Interferon/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Sarcoma de Kaposi/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Virais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Transformação Celular Neoplásica , Herpesvirus Humano 8/genética , Interações Hospedeiro-Patógeno , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/fisiopatologia , Sarcoma de Kaposi/virologia , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas Virais/genética
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