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1.
Nat Commun ; 12(1): 5238, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475389

RESUMO

The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.


Assuntos
Neoplasias da Mama/genética , Perda de Heterozigosidade/genética , Animais , Neoplasias da Mama/patologia , Transformação Celular Neoplásica , Elementos de DNA Transponíveis/genética , Feminino , Genes Supressores de Tumor , Humanos , Camundongos , Mutagênese Insercional , Neoplasias Experimentais , Transdução de Sinais
2.
Nucleic Acids Res ; 49(15): 8714-8731, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34379776

RESUMO

Microhomology-mediated break-induced replication (MMBIR) is a DNA repair pathway initiated by polymerase template switching at microhomology, which can produce templated insertions that initiate chromosomal rearrangements leading to neurological and metabolic diseases, and promote complex genomic rearrangements (CGRs) found in cancer. Yet, how often templated insertions accumulate from processes like MMBIR in genomes is poorly understood due to difficulty in directly identifying these events by whole genome sequencing (WGS). Here, by using our newly developed MMBSearch software, we directly detect such templated insertions (MMB-TIs) in human genomes and report substantial differences in frequency and complexity of MMB-TI events between normal and cancer cells. Through analysis of 71 cancer genomes from The Cancer Genome Atlas (TCGA), we observed that MMB-TIs readily accumulate de novo across several cancer types, with particularly high accumulation in some breast and lung cancers. By contrast, MMB-TIs appear only as germline variants in normal human fibroblast cells, and do not accumulate as de novo somatic mutations. Finally, we performed WGS on a lung adenocarcinoma patient case and confirmed MMB-TI-initiated chromosome fusions that disrupted potential tumor suppressors and induced chromothripsis-like CGRs. Based on our findings we propose that MMB-TIs represent a trigger for widespread genomic instability and tumor evolution.


Assuntos
Reparo do DNA , Neoplasias/genética , Adenocarcinoma de Pulmão/genética , Fibroblastos , Genes Supressores de Tumor , Genoma Humano , Instabilidade Genômica , Humanos , Neoplasias Pulmonares/genética , Mutagênese Insercional , Pele/citologia , Software
3.
Tumour Biol ; 43(1): 159-176, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34420994

RESUMO

The human TMPRSS2 gene is pathogenetically implicated in both coronaviral lung infection and prostate cancer, suggesting its potential as a drug target in both contexts. SARS-COV-2 spike polypeptides are primed by the host transmembrane TMPRSS2 protease, triggering virus fusion with epithelial cell membranes followed by an endocytotic internalisation process that bypasses normal endosomal activation of cathepsin-mediated innate immunity; viral co-opting of TMPRSS2 thus favors microbial survivability by attenuating host inflammatory responses. In contrast, most early hormone-dependent prostate cancers express TMPRSS2:ERG fusion genes arising from deletions that eliminate the TMPRSS2 coding region while juxtaposing its androgen-inducible promoter and the open reading frame of ERG, upregulating pro-inflammatory ERG while functionally disabling TMPRSS2. Moreover, inflammatory oxidative DNA damage selects for TMPRSS2:ERG-fused cancers, whereas patients treated with antiinflammatory drugs develop fewer of these fusion-dependent tumors. These findings imply that TMPRSS2 protects the prostate by enabling endosomal bypass of pathogens which could otherwise trigger inflammation-induced DNA damage that predisposes to TMPRSS2:ERG fusions. Hence, the high oncogenic selectability of TMPRSS2:ERG fusions may reflect a unique pro-inflammatory synergy between androgenic ERG gain-of-function and fusogenic TMPRSS2 loss-of-function, cautioning against the use of TMPRSS2-inhibitory drugs to prevent or treat early prostate cancer.


Assuntos
COVID-19/patologia , Fertilidade , Genes Supressores de Tumor , Inflamação/patologia , Neoplasias da Próstata/prevenção & controle , Serina Endopeptidases/metabolismo , COVID-19/genética , COVID-19/virologia , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , SARS-CoV-2/isolamento & purificação , Serina Endopeptidases/genética
4.
Theranostics ; 11(16): 7715-7734, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335960

RESUMO

Rationale: Emerging evidence indicates that the growth of blood vessels and osteogenesis is tightly coordinated during bone development. However, the molecular regulators of intercellular communication in the bone microenvironment are not well studied. Therefore, we aim to investigate whether BMMSC-Exo promotes osteogenesis and angiogenesis via transporting lnc-H19 in the CBS- heterozygous mouse model. Methods: Using RT2 lncRNA PCR array screening, we identify a bone-specific, long noncoding RNA-H19 (lncRNA-H19/lnc-H19) in exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exo) during osteogenesis. Using bioinformatics analysis, we further discovered the seed sequence of miR-106a that could bind to lnc-H19. A luciferase reporter assay was performed to demonstrate the direct binding of miR-106a to the target gene angiopoietin 1 (Angpt1). We employed an immunocompromised Nude mouse model, to evaluate the effects of BMMSC-Exo on angiogenesis in vivo. Using a micro-CT scan, we monitored microstructural changes of bone in the experimental mice. Results: BMMSC-Exo possessed exosomal characteristics including exosome size, and typical markers including CD63, CD9, and TSD101. In vitro, BMMSC-Exo significantly promoted endothelial angiogenesis and osteogenesis. Mechanistic studies have shown that exosomal lnc-H19 acts as "sponges" to absorb miR-106 and regulate the expression of angiogenic factor, Angpt1 that activates lnc-H19/Tie2-NO signaling in mesenchymal and endothelial cells. Both of these effects on osteogenesis and angiogenesis are inhibited by antagonizing Tie2 signaling. Treatment of BMMSC-Exo also restored the bone formation and mechanical quality in vivo. Conclusion: These findings provide a novel insight into how the extracellular role of exosomal lnc-H19 affects osteogenesis and angiogenesis through competing endogenous RNA networks.


Assuntos
MicroRNAs/genética , Osteogênese/genética , RNA Longo não Codificante/genética , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Angiopoietina-1/fisiologia , Animais , Osso e Ossos/metabolismo , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Exossomos/genética , Genes Supressores de Tumor , Células-Tronco Mesenquimais/metabolismo , Camundongos , Neovascularização Patológica/genética , Óxido Nítrico/metabolismo , RNA Longo não Codificante/metabolismo , Receptor TIE-2/metabolismo , Receptor TIE-2/fisiologia , Transdução de Sinais/genética
5.
Theranostics ; 11(16): 8112-8128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335983

RESUMO

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas/genética , Humanos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
6.
Nucleic Acids Res ; 49(13): 7437-7456, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34197623

RESUMO

Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7's role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genes Supressores de Tumor , Fatores de Transcrição de Fator Regulador X/metabolismo , Estresse Fisiológico/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose , Diferenciação Celular/genética , Linhagem Celular Tumoral , DNA/metabolismo , Doxorrubicina/farmacologia , Humanos , Camundongos , Neoplasias/genética , Neoplasias/mortalidade , Prognóstico , Regiões Promotoras Genéticas , Fatores de Transcrição de Fator Regulador X/fisiologia , Transdução de Sinais , Transativadores/metabolismo , Transcriptoma
7.
Cancer Sci ; 112(9): 3856-3870, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288281

RESUMO

Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and epidermal growth factor receptor (EGFR) inhibitors. To identify microRNAs (miRNAs) that can improve the efficacy of BRAF inhibitor dabrafenib (DAB) and MEK inhibitor trametinib (TRA), we screened 240 miRNAs in BRAF-mutated CRC cells and identified five candidate miRNAs. Overexpression of miR-193a-3p, one of the five screened miRNAs, in CRC cells inhibited cell proliferation by inducing apoptosis. Reverse-phase protein array analysis revealed that proteins with altered phosphorylation induced by miR-193a-3p were involved in several oncogenic pathways including MAPK-related pathways. Furthermore, overexpression of miR-193a-3p in BRAF-mutated cells enhanced the efficacy of DAB and TRA through inhibiting reactivation of MAPK signaling and inducing inhibition of Mcl1. Inhibition of Mcl1 by siRNA or by Mcl1 inhibitor increased the antiproliferative effect of combination therapy with DAB, TRA, and anti-EGFR antibody cetuximab. Collectively, our study demonstrated the possibility that miR-193a-3p acts as a tumor suppressor through regulating multiple proteins involved in oncogenesis and affects cellular sensitivity to MAPK-related pathway inhibitors such as BRAF inhibitors, MEK inhibitors, and/or anti-EGFR antibodies. Addition of miR-193a-3p and/or modulation of proteins involved in the miR-193a-3p-mediated pathway, such as Mcl1, to EGFR/BRAF/MEK inhibition may be a potential therapeutic strategy against BRAF-mutated CRC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Genes Supressores de Tumor , Imidazóis/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Oximas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/farmacologia , Pirimidinonas/farmacologia , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Cetuximab/farmacologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Quimioterapia Combinada/métodos , Receptores ErbB/antagonistas & inibidores , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transfecção
8.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298978

RESUMO

microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions.


Assuntos
Regulação da Expressão Gênica , Doenças dos Genitais Femininos/genética , MicroRNAs/genética , Envelhecimento , Animais , Biomarcadores , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Feminino , Fertilidade/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Doenças dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Humanos , Camundongos , MicroRNAs/fisiologia , Terapia de Alvo Molecular , Gravidez , Complicações na Gravidez/genética , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/genética , RNA Neoplásico/fisiologia
9.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201751

RESUMO

Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.


Assuntos
Carcinoma de Células Escamosas/patologia , Enzima Desubiquitinante CYLD/genética , Neoplasias Cutâneas/patologia , Animais , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Enzima Desubiquitinante CYLD/metabolismo , Genes Supressores de Tumor , Imunocompetência , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , NF-kappa B/metabolismo , Neovascularização Patológica/genética , Ésteres de Forbol/toxicidade , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
10.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201353

RESUMO

We identified the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) tissues by RNA sequencing, in which 168 miRNAs were significantly upregulated, including both strands of the miR-31 duplex (miR-31-5p and miR-31-3p). The aims of this study were to identify networks of tumor suppressor genes regulated by miR-31-5p and miR-31-3p in HNSCC cells. Our functional assays showed that inhibition of miR-31-5p and miR-31-3p attenuated cancer cell malignant phenotypes (cell proliferation, migration, and invasion), suggesting that they had oncogenic potential in HNSCC cells. Our in silico analysis revealed 146 genes regulated by miR-31 in HNSCC cells. Among these targets, the low expression of seven genes (miR-31-5p targets: CACNB2 and IL34; miR-31-3p targets: CGNL1, CNTN3, GAS7, HOPX, and PBX1) was closely associated with poor prognosis in HNSCC. According to multivariate Cox regression analyses, the expression levels of five of those genes (CACNB2: p = 0.0189; IL34: p = 0.0425; CGNL1: p = 0.0014; CNTN3: p = 0.0304; and GAS7: p = 0.0412) were independent prognostic factors in patients with HNSCC. Our miRNA signature and miRNA-based approach will provide new insights into the molecular pathogenesis of HNSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias de Cabeça e Pescoço/patologia , MicroRNAs/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Biomarcadores Tumorais/genética , Proliferação de Células , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas
11.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188574, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34062154

RESUMO

Hepatocellular carcinoma (HCC) is one of the lethal and leading types of cancer threatening the globe with a high mortality rate. STAT3 is an oncogenic transcription factor that is aberrantly activated in several human malignancies including HCC. Many STAT3-driven genes control cell proliferation and survival, apoptotic resistance, cell cycle progression, metastasis, and chemotherapeutic resistance. STAT3 signaling is regulated by endogenous modulators such as protein tyrosine phosphatase (PTP), suppressor of cytokine signaling (SOCS), protein inhibitor of activated STAT (PIAS), and various long noncoding RNAs (lncRNAs). Interestingly, lncRNAs have been reported to exhibit oncogenic and tumor suppressor functions, and these effects are mediated through diverse molecular mechanisms including sponging of microRNAs (miRs), transcription activation/inhibition, and epigenetic modifications. In this article, we have discussed the possible role of STAT3 signaling in hepatocarcinogenesis and various mechanisms by which lncRNAs impart their oncogenic or tumor suppressive action by modulating the STAT3 pathway in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Oncogenes , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/genética
12.
Nat Commun ; 12(1): 3707, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140478

RESUMO

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600E PtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.


Assuntos
Carcinogênese/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Proteínas de Homeodomínio/metabolismo , Melanoma/metabolismo , Fatores do Domínio POU/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Estudos de Coortes , Variações do Número de Cópias de DNA , Progressão da Doença , Técnicas de Silenciamento de Genes , Haploinsuficiência , Proteínas de Homeodomínio/genética , Humanos , Imuno-Histoquímica , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise em Microsséries , Fator de Transcrição Associado à Microftalmia/metabolismo , Mutação , Fatores do Domínio POU/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , RNA Interferente Pequeno , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário
13.
Sci Transl Med ; 13(599)2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162754

RESUMO

Increasing clinical evidence has demonstrated that the deletion or mutation of tumor suppressor genes such as the gene-encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in cancer cells may correlate with an immunosuppressive tumor microenvironment (TME) and poor response or resistance to immune checkpoint blockade (ICB) therapy. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor's sensitivity to ICB therapy. Here, we demonstrate that mRNA delivery by polymeric nanoparticles can effectively induce expression of PTEN in Pten-mutated melanoma cells and Pten-null prostate cancer cells, which in turn induces autophagy and triggers cell death-associated immune activation via release of damage-associated molecular patterns. In vivo results illustrated that PTEN mRNA nanoparticles can reverse the immunosuppressive TME by promoting CD8+ T cell infiltration of the tumor tissue, enhancing the expression of proinflammatory cytokines, such as interleukin-12, tumor necrosis factor-α, and interferon-γ, and reducing regulatory T cells and myeloid-derived suppressor cells. The combination of PTEN mRNA nanoparticles with an immune checkpoint inhibitor, anti-programmed death-1 antibody, results in a highly potent antitumor effect in a subcutaneous model of Pten-mutated melanoma and an orthotopic model of Pten-null prostate cancer. Moreover, the combinatorial treatment elicits immunological memory in the Pten-null prostate cancer model.


Assuntos
Melanoma/imunologia , Nanopartículas , PTEN Fosfo-Hidrolase , Neoplasias da Próstata/imunologia , Linhagem Celular Tumoral , Genes Supressores de Tumor , Humanos , Masculino , PTEN Fosfo-Hidrolase/genética , RNA Mensageiro/genética , Microambiente Tumoral
14.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070531

RESUMO

SMAD4, a key regulator of transforming growth factor-ß (TGF-ß) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-ß/SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as p21WAF1 and p15INK4b through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of SMAD4 could be related to tumorigenesis or malignancy progression. However, in some cancer types, SMAD4 is neither mutated nor deleted. In the current study, we demonstrate that TGF-ß signaling with a preserved SMAD4 function can contribute to cancer through associations with negative pathway regulators. We found that nuclear respiratory factor-1 (NRF1) is a novel interaction SMAD4 partner that inhibits TGF-ß/SMAD4-induced p15INK4b mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the SMAD4 promoter, thereby decreasing SMAD4 mRNA expression. On the whole, our data suggest that NRF1 is a negative regulator of SMAD4 and can interfere with TGF-ß/SMAD-induced tumor suppression. Our findings provide a novel perception into the molecular basis of TGF-ß/SMAD4-signaling suppression in tumorigenesis.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Transdução de Sinais/genética , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Inibidor de Quinase Dependente de Ciclina p15/genética , Dimerização , Genes Supressores de Tumor , Humanos , Fator 1 Nuclear Respiratório/genética , Regiões Promotoras Genéticas , Ligação Proteica , Domínios Proteicos , Deleção de Sequência , Proteína Smad4/genética , Fator de Crescimento Transformador beta/farmacologia
15.
J Biochem Mol Toxicol ; 35(8): e22824, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34047431

RESUMO

The pseudogene annexin A2 pseudogene 2 (ANXA2P2) is highly expressed in glioblastoma (GBM). However, its role and mechanism involved in the progression of GBM remain poorly understood. ANXA2P2 messenger RNA expression was measured by quantitative reverse transcription-polymerase chain reaction. The protein levels were detected by Western blot. Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase (LDH) release assays. Cell invasive ability was investigated by the transwell assay and by epithelial-mesenchymal transition (EMT). Cell apoptosis was examined by flow cytometry. The results showed that ANXA2P2 expression was increased in GBM tissues and cells. Silencing of ANXA2P2 inhibited the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) pathway in GBM cells. Knockdown of ANXA2P2 decreased cell viability, promoted LDH release, suppressed cell invasive ability, and EMT, and induced cell apoptosis in GBM cells. The addition of the PI3K/PKB activator 740Y-P abrogated the effects of ANXA2P2 knockdown on cell viability, LDH release, invasive ability, and apoptosis. In conclusion, knockdown of ANXA2P2 inhibited cell viability and invasion but promoted the apoptotic rate by suppressing the PI3K/PKB pathway in GBM cells. ANXA2P2 may represent a new target for the treatment of GBM.


Assuntos
Técnicas de Silenciamento de Genes , Genes Supressores de Tumor , Glioblastoma , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pseudogenes , Linhagem Celular Tumoral , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética
16.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188567, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34015411

RESUMO

Giant obscurins (720-870 kDa), encoded by OBSCN, were originally discovered in striated muscles as cytoskeletal proteins with scaffolding and regulatory roles. Recently though, they have risen to the spotlight as key players in cancer development and progression. Herein, we provide a timely prudent synopsis of the expanse of OBSCN mutations across 16 cancer types. Given the extensive work on OBSCN's role in breast epithelium, we summarize functional studies implicating obscurins as potent tumor suppressors in breast cancer and delve into an in silico analysis of its mutational profile and epigenetic (de)regulation using different dataset platforms and sophisticated computational tools. Lastly, we formally describe the OBSCN-Antisense-RNA-1 gene, which belongs to the long non-coding RNA family and discuss its potential role in modulating OBSCN expression in breast cancer. Collectively, we highlight the escalating involvement of obscurins in cancer biology and outline novel potential mechanisms of OBSCN (de)regulation that warrant further investigation.


Assuntos
Genes Supressores de Tumor , Mutação , Neoplasias/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Metilação de DNA , Epigênese Genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/enzimologia , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/genética , RNA Antissenso/genética , RNA Antissenso/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Transdução de Sinais
17.
Life Sci ; 278: 119573, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33964297

RESUMO

AIMS: Myosin phosphatase targeting protein 1 (MYPT1) was identified to function as a tumor suppressor in several kinds of cancers, but its role and the molecular mechanisms in non-small cell lung cancer (NSCLC) remain undiscovered. Herein, we aimed to reveal MYPT1 expression pattern and role in NSCLC, and investigate the underlying mechanisms. MAIN METHODS: Sixty-eight paired NSCLC tissues and the adjacent normal tissues were included in this study. Western blotting and quantitative reverse transcription-polymerase chain (qPCR) technologies were applied for protein and RNA detection. CCK-8, colony formation, flow cytometry, wound healing, transwell chambers coated with Matrigel and in vivo experiments were applied to detect cell viability, colony formation, apoptosis, migration, invasiveness and tumorigenesis, respectively. KEY FINDINGS: MYPT1 expressed at a lower level in NSCLC tissues as compared with the adjacent normal tissues, which predicted advanced clinic process and poor prognosis. Overexpression of MYPT1 resulted in obvious inhibitions in cell viability, colony formation, migration, invasiveness and tumorigenesis, and induced cell apoptotic rates, as well as decreased the expression levels of ß-catenin and TCF4. Besides, overexpression of ß-catenin weakened the above roles of MYPT1. In addition, the luciferase gene reporter assay verified that MYPT1 was a target of miR-19b-3p. Further experiments showed that miR-19b-3p promoted cell viability, invasiveness and migration and repressed cell apoptosis by targeting MYPT1. SIGNIFICANCE: In conclusion, this study demonstrates that MYPT1, regulated by miR-19b-3p, inhibits the progression of NSCLC via inhibiting the activation of wnt/ß-catenin signaling.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Via de Sinalização Wnt , Células A549 , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica , Pneumonectomia , RNA Longo não Codificante/genética , Reprodutibilidade dos Testes , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
18.
Cancer Sci ; 112(7): 2781-2791, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33960594

RESUMO

The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC-associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient-derived, treatment-related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.


Assuntos
Adenocarcinoma/patologia , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral/patologia , Neoplasias da Próstata/patologia , Animais , Proteínas Reguladoras de Apoptose/genética , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/secundário , Linhagem Celular Tumoral/metabolismo , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Ensaios de Seleção de Medicamentos Antitumorais , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Deleção de Genes , Expressão Gênica , Genes Neoplásicos , Genes do Retinoblastoma , Genes Supressores de Tumor , Genes p53 , Engenharia Genética , Xenoenxertos , Homozigoto , Humanos , Cariotipagem , Perda de Heterozigosidade , Masculino , Camundongos SCID , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Transplante de Neoplasias , PTEN Fosfo-Hidrolase/genética , Neoplasias Penianas/genética , Neoplasias Penianas/secundário , Neoplasias da Próstata/genética , Proteínas de Ligação a RNA/genética , Receptores Androgênicos
19.
DNA Cell Biol ; 40(6): 740-747, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34015233

RESUMO

MicroRNA is a small noncoding RNA that plays a role in regulating gene expression. miR-1271 is a tumor suppressor microRNA, which is related to the biological changes of many cancers. miR-1271 is considered a biomarker with a potential prognosis and high therapeutic value in tumors. Besides, the expression of miR-1271 is also regulated by many factors. In this study, we summarize the role of miR-1271 in tumors, focusing on the molecular mechanisms of the target genes of miR-1271. Our review will provide a comprehensive understanding of miR-1271 in tumors, as well as ideas for subsequent tumor research related to miR-1271.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , MicroRNAs/fisiologia , Neoplasias/metabolismo , Biomarcadores Tumorais/fisiologia , Humanos , Neoplasias/genética , Transdução de Sinais
20.
Comput Biol Med ; 133: 104323, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33934067

RESUMO

Mutations in proto-oncogenes (ONGO) and the loss of regulatory function of tumor suppression genes (TSG) are the common underlying mechanism for uncontrolled tumor growth. While cancer is a heterogeneous complex of distinct diseases, finding the potentiality of the genes related functionality to ONGO or TSG through computational studies can help develop drugs that target the disease. This paper proposes a classification method that starts with a preprocessing stage to extract the feature map sets from the input 3D protein structural information. The next stage is a deep convolutional neural network stage (DCNN) that outputs the probability of functional classification of genes. We explored and tested two approaches: in Approach 1, all filtered and cleaned 3D-protein-structures (PDB) are pooled together, whereas in Approach 2, the primary structures and their corresponding PDBs are separated according to the genes' primary structural information. Following the DCNN stage, a dynamic programming-based method is used to determine the final prediction of the primary structures' functionality. We validated our proposed method using the COSMIC online database. For the ONGO vs TSG classification problem the AUROC of the DCNN stage for Approach 1 and Approach 2 DCNN are 0.978 and 0.765, respectively. The AUROCs of the final genes' primary structure functionality classification for Approach 1 and Approach 2 are 0.989, and 0.879, respectively. For comparison, the current state-of-the-art reported AUROC is 0.924. Our results warrant further study to apply the deep learning models to humans' (GRCh38) genes, for predicting their corresponding probabilities of functionality in the cancer drivers.


Assuntos
Aprendizado Profundo , Bases de Dados Factuais , Genes Supressores de Tumor , Humanos , Redes Neurais de Computação , Oncogenes/genética
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