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1.
Nat Commun ; 12(1): 4753, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362903

RESUMO

Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer.


Assuntos
Evolução Biológica , Carcinoma/genética , Neoplasias da Vesícula Biliar/genética , Genômica , Neoplasias/genética , Carcinogênese/genética , Carcinoma in Situ/patologia , Feminino , Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/classificação , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Filogenia , Lesões Pré-Cancerosas/genética
2.
Mol Biol (Mosk) ; 55(4): 531-542, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34432772

RESUMO

Small SCP phosphatases CTDSP1, CTDSP2, and CTDSPL specifically dephosphorylate serine and threonine residues in protein molecules. The enzymes are involved in regulating activity of RNA polymerase II at the transition from transcription initiation to elongation, regulating expression of neuron-specific genes, and activating the key cell-cycle protein pRb at the G1/S boundary. In addition, the substrates of SCP phosphatases include SMAD transcription modulators; AKT1 protein kinase, which regulates the cell cycle, apoptosis, and angiogenesis; the TWIST1 and c-MYC transcription factors; Ras family proteins, which are involved in signaling pathways regulating the cell growth and apoptosis; CDCA3, which is associated with cell division; the cyclin-dependent kinase inhibitor p21; and the promyelocytic leukemia protein (PML), which is involved in regulation of the tumor suppressors p53, PTEN, and mTOR. Dysfunction or inactivation of SCP phosphatases leads to various diseases, including cancer. Recently the increase in interest to SCP phosphatases is due to their their tumor growth-inhibiting properties or role in the development of malignant tumors of various etiology and localization. The review discusses the properties of SCP phosphatases and their role in oncogenesis. Understanding the functions of SCP phosphatases and their regulatory mechanisms can be useful in searching for efficient targets for tumor therapy.


Assuntos
Carcinogênese , Neoplasias , Carcinogênese/genética , Ciclo Celular , Proteínas de Ciclo Celular , Transformação Celular Neoplásica/genética , Humanos , Neoplasias/genética , Fosfoproteínas Fosfatases/genética
3.
Adv Exp Med Biol ; 1288: 69-93, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453732

RESUMO

Cancer/testis (CT) antigens are proteins aberrantly overexpressed in various tumorigenic cells, but they can also be normally expressed in the mammalian germline. Most CT antigens are highly immunogenic and known to be involved in cancer cell proliferation and tumor metastasis. A recent genome-wide analysis systematically identified CT antigen expression in 19 cancer types, significantly expanding the repertoire of CT antigens by 5-fold, from over 200 to approximately 1000. However, their function and regulation in tumorigenesis remain poorly understood. The shared functional characteristics between germ cells and cancer cells, if methodically defined, offer a unique gateway to understanding the regulation of CT antigens in cancers by studying gametogenesis. Nonetheless, such studies also provide insightful information on the role of CT antigens in spermatogenesis. Herein, we analyzed publicly available next generation sequencing datasets generated from normal adult testes in rodents, primordial germ cells and cancer samples across a series of published studies and databases. Based on these analyses, we report that a subset of CT antigens belonged to the core fitness gene family. Furthermore, super-enhancers both in normal testes and various cancers controlled specific CT antigens. We found that DNA methylation of CT antigens, such as TEX101 and TAF7L, was inversely correlated with their expression in both normal primordial germ cells and various cancers, which was mediated at least partly by DNA methyltransferase1 (DNMT1). By analyzing data from a testis knockout model, we showed that TAF7L could further influence the expression of additional CT antigens, which also held true in tumors. These findings not only confirmed the previous notion that CT antigens regulate cancer dynamics, but also showed that understanding the regulation of CT antigens during gametogenesis can offer new insights for cancer research.


Assuntos
Antígenos de Neoplasias , Testículo , Animais , Antígenos de Neoplasias/genética , Carcinogênese/genética , Células Germinativas , Masculino , Roedores
4.
Mol Cell ; 81(16): 3339-3355.e8, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352206

RESUMO

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.


Assuntos
Colangiocarcinoma/genética , Proteínas de Ligação ao GTP/genética , Metiltransferases/genética , Biossíntese de Proteínas , Animais , Carcinogênese/genética , Colangiocarcinoma/patologia , Progressão da Doença , Receptores ErbB/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Camundongos , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
5.
Mol Cell ; 81(16): 3323-3338.e14, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352207

RESUMO

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m7G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m7G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m7G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.


Assuntos
Carcinogênese/genética , Metiltransferases/genética , Neoplasias/genética , tRNA Metiltransferases/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Metilação , Neoplasias/patologia , Oncogenes/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
6.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361081

RESUMO

Cancer cachexia is a common deleterious paraneoplastic syndrome that represents an area of unmet clinical need, partly due to its poorly understood aetiology and complex multifactorial nature. We have interrogated multiple genetically defined larval Drosophila models of tumourigenesis against key features of human cancer cachexia. Our results indicate that cachectic tissue wasting is dependent on the genetic characteristics of the tumour and demonstrate that host malnutrition or tumour burden are not sufficient to drive wasting. We show that JAK/STAT and TNF-α/Egr signalling are elevated in cachectic muscle and promote tissue wasting. Furthermore, we introduce a dual driver system that allows independent genetic manipulation of tumour and host skeletal muscle. Overall, we present a novel Drosophila larval paradigm to study tumour/host tissue crosstalk in vivo, which may contribute to future research in cancer cachexia and impact the design of therapeutic approaches for this pathology.


Assuntos
Caquexia/patologia , Carcinogênese/patologia , Modelos Animais de Doenças , Larva/crescimento & desenvolvimento , Neoplasias/complicações , Animais , Caquexia/etiologia , Caquexia/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Drosophila , Perfilação da Expressão Gênica , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Larva/genética , Larva/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
7.
Mol Biol (Mosk) ; 55(4): 598-605, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34432777

RESUMO

Recently, a wealth of data have been accumulating on the role of long non-coding RNAs (lncRNAs) in the fine-tuning of mRNA expression. Four new lncRNAs, namely, TMEM92-AS1, FAM222A-AS, TXLNB, and lnc-CCL28, were identified as differentially expressed in ovarian tumors using deep machine learning. The levels of lnc-CCL28 transcripts in both tumors and normal tissue samples were sufficient for further analysis by RT-PCR. In addition, the promising ovarian cancer biomarkers, lncRNAs LINC00152, NEAT 1 and SNHG17 were added to RT-PCR analysis. For the first time, an increase in the level of lnc-CCL28 and SNHG 17 lncRNAs was found in ovarian tumors, and the overexpression of LINC00152 and NEAT1 was confirmed. It seems that lnc-CCL28 is involved in carcinogenesis and, in particular, in ovarian cancer progression. Overexpression of LINC00152 and lnc-CCL28 was significantly associated with the later stages and metastasis.


Assuntos
Neoplasias Ovarianas , RNA Longo não Codificante , Carcinogênese/genética , Feminino , Humanos , Neoplasias Ovarianas/genética , RNA Longo não Codificante/genética
8.
Adv Exp Med Biol ; 1330: 125-137, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34339034

RESUMO

OBJECTIVES: We tested if METCAM/MUC18 overexpression also plays a suppressor role in another human ovarian cancer cell line, BG-1, in addition to the SK-OV3 cell line. METHODS: Human ovarian cancer BG-1 cells were transfected with METCAM/MUC18 cDNA and G418-resistant clones expressing different levels of METCAM/MUC18 were isolated. These clones were used to test the effects of enforced expression of METCAM/MUC18 on in vitro motility, invasiveness, and anchorage-independent colony formation (in vitro tumorigenesis), and in vivo tumorigenesis after SC injection and after IP injection in female athymic nude mice. RESULTS: Overexpression of METCAM/MUC18 reduced in vitro motility and invasiveness of BG-1 cells and anchorage-independent colony formation (in vitro tumor formation). Higher expression of METCAM/MUC18 in BG-1 cells significantly reduced in vivo tumor proliferation of the BG-1 cells after IP injection (orthotopic route) of the clones in female nude mice, though it did not significantly affect in vivo tumor proliferation after SC injection (non-orthotopic route). CONCLUSION: Similar to SK-OV3 cells, METCAM/MUC18 also plays a suppressor role in the progression of BG-1 cells in a xenograft mouse model.


Assuntos
Carcinogênese , Neoplasias Ovarianas , Animais , Antígeno CD146 , Carcinogênese/genética , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica , Neoplasias Ovarianas/genética
9.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361004

RESUMO

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.


Assuntos
Acetilcisteína/farmacologia , Carcinogênese/efeitos dos fármacos , Estradiol/farmacologia , Estrona/farmacologia , Quinonas/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Carcinogênese/genética , Adutos de DNA , Estradiol/toxicidade , Estrogênios/farmacologia , Estrogênios/toxicidade , Estrona/toxicidade , Humanos , Quinonas/toxicidade
10.
Nat Commun ; 12(1): 5056, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417458

RESUMO

Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a-/- melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.


Assuntos
Epigênese Genética , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fator de Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos Nus , Camundongos Transgênicos , Invasividade Neoplásica , Micrometástase de Neoplasia , Ligação Proteica , Carga Tumoral
11.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201893

RESUMO

Lynch syndrome is a hereditary cancer-predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow-up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR-proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEUROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma formation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR-deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient's carcinogenesis subtype.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Carcinogênese/genética , Neoplasias Colorretais Hereditárias sem Polipose/etiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Modelos Biológicos , Fenótipo , Fatores de Risco
12.
Anticancer Res ; 41(7): 3349-3361, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230131

RESUMO

BACKGROUND/AIM: The present study investigated the oncogenic functions of TACC3 in the progression of gastric cancer (GC). MATERIALS AND METHODS: We analysed TACC3 in relation to cell growth, invasion capability, expression of epithelial-mesenchymal transition (EMT)-related markers, and ERK/Akt/cyclin D1 signaling factors. The correlation between the immunohistochemically confirmed expression of TACC3 and clinical factors was also analyzed. RESULTS: The increased proliferation and invasion of TACC3-over-expressing GC cells was accompanied by altered regulation of EMT-associated markers and activation of ERK/Akt/cyclin D1 signaling. Immunohistochemical analysis of TACC3 in human GC tissues revealed that its expression is correlated with aggressive characteristics and poor prognosis of intestinal-type GC. CONCLUSION: TACC3 contributes to gastric tumorigenesis by promoting EMT via the ERK/Akt/cyclin D1 signaling pathway. The correlation between TACC3 expression and multiple clinicopathological variables implies that its effective therapeutic targeting in GC will depend on the tumor subtype.


Assuntos
Carcinogênese/genética , Ciclina D1/genética , Transição Epitelial-Mesenquimal/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Gástricas/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Transdução de Sinais/genética , Estômago/patologia , Neoplasias Gástricas/patologia
13.
World J Surg Oncol ; 19(1): 207, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253194

RESUMO

BACKGROUND: Mounting evidence in the cancer literature suggests that microRNAs (miRNAs) influence the progression of human cancer cells by targeting protein-coding genes. How insulin-like growth factor 1(IGF1) and miR-186-3p contribute to the development of cervical cancer (CC) remains unclear. This study examined the regulatory roles of miR-186-3p and IGF1 in CC development. METHODS: Gene expression levels were determined by qRT-PCR. Proliferation, migration, and apoptosis of CC and normal cells were determined by MTT, Transwell, and caspase-3 activity assays, respectively. Dual-luciferase reporter activity and RNA pull-down assays were performed to identify the target gene of miR-186-3p. RESULTS: IGF1 was the target of miR-186-3p. The expression of miR-186-3p inhibited cell proliferation and migration abilities of CC cell lines, but induced the apoptosis rate of CC cells. IGF1 could restore the inhibitory effects of miR-186-3p on the proliferation, migration, and apoptosis abilities of CC cells. Experimental results revealed that miR-186-3p could inhibit IGF1 expression, thereby reducing the viability of CC cells. CONCLUSIONS: The data suggest that targeting of IGF1 by miR-186-3p could be crucial in regulating the progression of CC.


Assuntos
MicroRNAs , Neoplasias do Colo do Útero , Apoptose , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator de Crescimento Insulin-Like I/genética , MicroRNAs/genética , Prognóstico , Neoplasias do Colo do Útero/genética
14.
Nat Commun ; 12(1): 4457, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294701

RESUMO

The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Idoso , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Código das Histonas/genética , Humanos , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Oncogenes , Fatores de Transcrição/genética
15.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299381

RESUMO

The MYC oncoprotein and its family members N-MYC and L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that MYC has a bi-directional relationship with the molecular clock in cancer. The molecular clock is responsible for circadian (~24 h) rhythms in most eukaryotic cells and organisms, as a mechanism to adapt to light/dark cycles. Disruption of human circadian rhythms, such as through shift work, may serve as a risk factor for cancer, but connections with oncogenic drivers such as MYC were previously not well understood. In this review, we examine recent evidence that MYC in cancer cells can disrupt the molecular clock; and conversely, that molecular clock disruption in cancer can deregulate and elevate MYC. Since MYC and the molecular clock control many of the same processes, we then consider competition between MYC and the molecular clock in several select aspects of tumor biology, including chromatin state, global transcriptional profile, metabolic rewiring, and immune infiltrate in the tumor. Finally, we discuss how the molecular clock can be monitored or diagnosed in human tumors, and how MYC inhibition could potentially restore molecular clock function. Further study of the relationship between the molecular clock and MYC in cancer may reveal previously unsuspected vulnerabilities which could lead to new treatment strategies.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Carcinogênese/genética , Cromatina/genética , Humanos , Proteínas Circadianas Period/genética , Transcrição Genética/genética
16.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298992

RESUMO

Non-Hodgkin B-cell lymphomas (NHL) are a heterogeneous group of lymphoid neoplasms with complex etiopathology, rich symptomatology, and a variety of clinical courses, therefore requiring different therapeutic approaches. The hypothesis that an infectious agent may initiate chronic inflammation and facilitate B lymphocyte transformation and lymphogenesis has been raised in recent years. Viruses, like EBV, HTLV-1, HIV, HCV and parasites, like Plasmodium falciparum, have been linked to the development of lymphomas. The association of chronic Helicobacter pylori (H. pylori) infection with mucosa-associated lymphoid tissue (MALT) lymphoma, Borrelia burgdorferi with cutaneous MALT lymphoma and Chlamydophila psittaci with ocular adnexal MALT lymphoma is well documented. Recent studies have indicated that other infectious agents may also be relevant in B-cell lymphogenesis such as Coxiella burnettii, Campylobacter jejuni, Achromobacter xylosoxidans, and Escherichia coli. The aim of the present review is to provide a summary of the current literature on infectious bacterial agents associated with B-cell NHL and to discuss its role in lymphogenesis, taking into account the interaction between infectious agents, host factors, and the tumor environment.


Assuntos
Infecções Bacterianas/complicações , Linfoma de Burkitt/microbiologia , Infecções por Helicobacter/microbiologia , Interações Hospedeiro-Patógeno , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma Difuso de Grandes Células B/microbiologia , Infecções Bacterianas/imunologia , Linfoma de Burkitt/complicações , Linfoma de Burkitt/patologia , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
17.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298996

RESUMO

Regulator of Chromatin Condensation 1 (RCC1) is the only known guanine nucleotide exchange factor that acts on the Ras-like G protein Ran and plays a key role in cell cycle regulation. Although there is growing evidence to support the relationship between RCC1 and cancer, detailed pancancer analyses have not yet been performed. In this genome database study, based on The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases, the potential role of RCC1 in 33 tumors' entities was explored. The results show that RCC1 is highly expressed in most human malignant neoplasms in contrast to healthy tissues. RCC1 expression is closely related to the prognosis of a broad variety of tumor patients. Enrichment analysis showed that some tumor-related pathways such as "cell cycle" and "RNA transport" were involved in the functional mechanism of RCC1. In particular, the conducted analysis reveals the relation of RCC1 to multiple immune checkpoint genes and suggests that the regulation of RCC1 is closely related to tumor infiltration of cancer-associated fibroblasts and CD8+ T cells. Coherent data demonstrate the association of RCC1 with the tumor mutation burden and microsatellite instability in various tumors. These findings provide new insights into the role of RCC1 in oncogenesis and tumor immunology in various tumors and indicate its potential as marker for therapy prognosis and targeted treatment strategies.


Assuntos
Proteínas de Ciclo Celular/genética , Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Neoplasias/metabolismo , Proteínas Nucleares/genética , Big Data , Linfócitos T CD8-Positivos/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinogênese/genética , Carcinogênese/imunologia , Ciclo Celular/genética , Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Cromatina/genética , Metilação de DNA , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica/imunologia , Ontologia Genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Proteínas de Checkpoint Imunológico/genética , Estimativa de Kaplan-Meier , Instabilidade de Microssatélites , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Proteínas Nucleares/metabolismo , Fosforilação , Prognóstico , Mapas de Interação de Proteínas , Transcriptoma
18.
Life Sci ; 282: 119817, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273374

RESUMO

R-spondins 2 (RSPO2) protein is a member of RSPO family which plays an essential role in stem cell survival, development and tumorigenicity. There has several evidence suggested that RSPO2 involved in breast, gastric, liver and colorectal cancer. However, the specific function and mechanism of RSPO2 in nasopharyngeal carcinoma (NPC) remain unknown. In the present study, we first observed that RSPO2 expression was elevated in NPC cell lines SUNE-6-10B, SUNE-5-8F, and CNE-1 compared with the normal laryngeal epithelia cell line NP69. Knockdown of RSPO2 significantly inhibits SUNE-6-10B and CNE-1 cell survival and proliferation by using CCK-8 assay and Edu assay, respectively. Further studies verified that RSPO2 silence suppressed migration and invasion of SUNE-6-10B and CNE-1 cells. Further studies suggested that RSPO2 silence suppressed epithelial-to-mesenchymal transition (EMT) related protein E-cadherin expression and promoted Vimentin and N-cadherin expression both in SUNE-6-10B and CNE-1 cells. Molecular mechanism explorations showed that RSPO2 deletion increased ZNRF3 expression and inhibited Gli1 expression. Additionally, knockdown ZNRF3 expression or overexpression Gli1 both reversed the effects of RSPO2 silence on NPC growth and metastasis. Finally, RSPO2 depletion was impaired NPC tumor growth in vivo animal experiments. In conclusion, the present study confirmed that RSPO2 silence inhibits the tumorigenesis of NPC via ZNRF3/Hedgehog-Gli1 signal pathway.


Assuntos
Carcinogênese/metabolismo , Inativação Gênica , Proteínas Hedgehog/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Proteínas Hedgehog/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Ubiquitina-Proteína Ligases/genética , Proteína GLI1 em Dedos de Zinco/genética
19.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199293

RESUMO

Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis.


Assuntos
Carcinogênese/genética , Síndrome Metabólica/genética , MicroRNAs/metabolismo , Animais , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , MicroRNAs/genética , Transdução de Sinais/genética
20.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199457

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are chemical compounds comprised of carbon and hydrogen molecules in a cyclic arrangement. PAHs are associated with risks to human health, especially carcinogenesis. One form of exposure to these compounds is through ingestion of contaminated food, which can occur during preparation and processing involving high temperatures (e.g., grilling, smoking, toasting, roasting, and frying) as well as through PAHs present in the soil, air, and water (i.e., environmental pollution). Differently from changes caused by microbiological characteristics and lipid oxidation, consumers cannot sensorially perceive PAH contamination in food products, thereby hindering their ability to reject these foods. Herein, the occurrence and biological effects of PAHs were comprehensively explored, as well as analytical methods to monitor their levels, legislations, and strategies to reduce their generation in food products. This review updates the current knowledge and addresses recent regulation changes concerning the widespread PAHs contamination in several types of food, often surpassing the concentration limits deemed acceptable by current legislations. Therefore, effective measures involving different food processing strategies are needed to prevent and reduce PAHs contamination, thereby decreasing human exposure and detrimental health effects. Furthermore, gaps in literature have been addressed to provide a basis for future studies.


Assuntos
Carcinogênese/efeitos dos fármacos , Poluição Ambiental/efeitos adversos , Alimentos/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Benzopirenos/efeitos adversos , Carcinogênese/genética , Carvão Vegetal/efeitos adversos , Culinária , Adutos de DNA/efeitos adversos , Análise de Alimentos , Manipulação de Alimentos , Humanos
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