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1.
Mol Cell ; 80(1): 87-101.e5, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931746

RESUMO

Studies in three mouse models of breast cancer identified profound discrepancies between cell-autonomous and systemic Akt1- or Akt2-inducible deletion on breast cancer tumorigenesis and metastasis. Although systemic Akt1 deletion inhibits metastasis, cell-autonomous Akt1 deletion does not. Single-cell mRNA sequencing revealed that systemic Akt1 deletion maintains the pro-metastatic cluster within primary tumors but ablates pro-metastatic neutrophils. Systemic Akt1 deletion inhibits metastasis by impairing survival and mobilization of tumor-associated neutrophils. Importantly, either systemic or neutrophil-specific Akt1 deletion is sufficient to inhibit metastasis of Akt-proficient tumors. Thus, Akt1-specific inhibition could be therapeutic for breast cancer metastasis regardless of primary tumor origin. Systemic Akt2 deletion does not inhibit and exacerbates mammary tumorigenesis and metastasis, but cell-autonomous Akt2 deletion prevents breast cancer tumorigenesis by ErbB2. Elevated circulating insulin level induced by Akt2 systemic deletion hyperactivates tumor Akt, exacerbating ErbB2-mediated tumorigenesis, curbed by pharmacological reduction of the elevated insulin.


Assuntos
Neoplasias Mamárias Animais/enzimologia , Neoplasias Mamárias Animais/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Carcinogênese/patologia , Feminino , Deleção de Genes , Humanos , Insulina/metabolismo , Isoenzimas/metabolismo , Metástase Neoplásica , Neutrófilos/metabolismo , Receptor ErbB-2/metabolismo
2.
Life Sci ; 258: 118186, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768586

RESUMO

Antioxidants are essential in preventing the formation and suppressing the activities of reactive nitrogen and oxygen species. The aim of this study was to review the role of antioxidants in cancer development or prevention. Antioxidants are believed to prevent and treat various types of malignancies. Currently, natural antioxidant compounds have been generally consumed to prevent and treat cancers. Certainly, phenolic compounds extracted from medicinal plants have opened a new prospect with respect to the prevention and treatment of cancers due to having antioxidant characteristics. However, some recently published studies have revealed that antioxidant compounds do not indicate absolute anti-tumor properties. Some antioxidants are helpful in cancer initiation and progression. Taken together, antioxidants demonstrate a two-faced nature toward cancer. However, it is required to conduct further cell culture and in vivo studies to confirm the exact role of antioxidants and then use them for efficient cancer treatments.


Assuntos
Antioxidantes/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Metástase Neoplásica , Neoplasias/patologia
3.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(5): 516-520, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32842435

RESUMO

Colorectal cancer is one of the most common malignant tumors of digestive tract. There are a large number of microorganisms in the digestive tract. Under normal physiological conditions, intestinal microorganisms can help with digestion and absorption, resist pathogen invasion and regulate the proliferation of intestinal mucosal cells. However, intestinal microflora imbalance will affect the intestinal microenvironment and intestinal cell function, and is closely related to the incidence and progression of colorectal cancer. Firstly, this paper introduces the changes of intestinal flora in patients with colorectal cancer, and then summarizes the mode of intestinal flora participating in the occurrence of colorectal cancer from the macro level. Then, we elaborate the involvement of intestinal flora in colorectal cancer from the aspects of cytokine-dependent chronic inflammation, DNA damage of intestinal epithelial cells, carcinogenic metabolites of intestinal flora and cellular enzymes, and changes of intestinal immune system. The pathogenesis of colorectal cancer provides a reference for further study of the pathogenesis of colorectal cancer. Finally, from the perspective of intestinal flora and colorectal cancer treatment, we analyze the significance of probiotics and bacterial flora transplantation for the treatment of colorectal cancer, and provide some new treatment ideas and methods that may be useful for the treatment of colorectal cancer.


Assuntos
Carcinogênese , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/fisiologia , Intestinos/microbiologia , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/fisiopatologia , Neoplasias Colorretais/terapia , Transplante de Microbiota Fecal , Humanos , Intestinos/patologia , Intestinos/fisiopatologia , Probióticos/uso terapêutico , Microambiente Tumoral/fisiologia
4.
Int J Nanomedicine ; 15: 4063-4078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606664

RESUMO

Background: Among various theories for the origin of cancer, the "stemness phenotype model" suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-ßcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-ßcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs. Materials and Methods: We prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-ßcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay. Results: We found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction. Conclusion: Our study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.


Assuntos
Neoplasias da Mama/patologia , Carcinogênese/patologia , Ouro/química , Nanopartículas Metálicas/química , Células-Tronco Neoplásicas/patologia , Coroa de Proteína/química , Vorinostat/farmacologia , Proteínas Wnt/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Células MCF-7 , Nanosferas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Espectrofotometria Ultravioleta , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
5.
Nat Commun ; 11(1): 3431, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647202

RESUMO

Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Although they are generally considered as the most primitive breast malignancies, their histogenesis remains elusive. Here we show that this molecular subtype of breast cancers exhibits a significant diversity, comprising three main subgroups that emerge from unique evolutionary processes. Genetic, gene methylation and gene expression analyses reveal that two of the subgroups relate, respectively, to luminal breast cancers and basal-like breast cancers through the activation of an EMT process over the course of tumor progression. The third subgroup is closely related to normal human mammary stem cells. This unique subgroup of breast cancers shows a paucity of genomic aberrations and a low frequency of TP53 mutations, supporting the emerging notion that the intrinsic properties of the cell-of-origin constitute a major determinant of the genetic history of tumorigenesis.


Assuntos
Neoplasias da Mama/metabolismo , Claudinas/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinogênese/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Genoma Humano , Humanos , Ploidias , Transdução de Sinais/genética
7.
Life Sci ; 258: 118110, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32698074

RESUMO

Incapacitated immune system is a characteristic hallmark of solid tumors. Immune system within a tumor undergoes an imbalance in cellular dispersion and functionality. Effector cells are precluded from the invasive margin of tumor; instead, immune suppressor cells are present at high fractions. Conditions in the tumor microenvironment (TME) like altered metabolism, chronic hypoxia and chronic inflammation are the known predisposing factors, implicated in the immune malfunctioning. Deficiency of innate immune sensing mediated by checkpoint receptors including programmed death-1 receptor (PD-1), CTL-associated antigen-4 (CTLA-4) hijacked by tumor cells takes a major part of the blame, requiring a need for appropriate strategies in order to bring back the balance in the immune system. Immune checkpoint inhibitor (ICI) therapy has been in the eye of the current research rendering promising results. The story is not, however, that easy in which it is not so effective for Cold tumors, it may cause severe adverse effects, and that patients may acquire resistance to such therapy; this requires for updating the current knowledge about the immune ecosystem, using tumor type dependent dose calculation and exploiting proper adjuvants in order for evolving desired responses.


Assuntos
Evasão da Resposta Imune , Neoplasias/imunologia , Animais , Antígeno B7-H1/metabolismo , Carcinogênese/patologia , Humanos , Imunoterapia , Neoplasias/terapia , Microambiente Tumoral/imunologia
8.
Life Sci ; 258: 118128, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32710947

RESUMO

Although breast cancer is one of the leading troublesome cancers, the available therapeutic options have not fulfilled the desired outcomes. Immune-based therapy has gained special attention for breast cancer treatment. Although this approach is highly tolerable, its low response rate has rendered it as an undesirable approach. This review aims to describe the essential oncogenic pathways involved in breast cancer, elucidate the immunosuppression and oncogenic effect of Mucin1, and introduce myeloid-derived suppressor cells, which are the main culprits of anti-tumoral immune response attenuation. The various auto-inductive loops between Mucin1 and myeloid-derived suppressor cells are focal in the suppression of anti-tumoral immune responses in patients with breast cancer. These cross-talks between the Mucin1 and myeloid-derived suppressor cells can be the underlying causes of immunotherapy's impotence for patients with breast cancer. This approach can pave the road for the development of a potent vaccine for patients with breast cancer and is translated into clinical settings.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Mucina-1/metabolismo , Células Supressoras Mieloides/metabolismo , Vacinação , Animais , Neoplasias da Mama/imunologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos
9.
Cancer Immunol Immunother ; 69(9): 1673-1697, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32500231

RESUMO

The tumor microenvironment (TME) not only facilitates cancer progression from the early formation to distant metastasis, but also it differs itself from time to time alongside the tumor evolution. Tumor-associated macrophages (TAMs), whether as pre-existing tissue-resident macrophages or recruited monocytes, are an inseparable part of this microenvironment. As their parents are broadly classified into a dichotomic, simplistic M1 and M2 subtypes, TAMs also exert paradoxical and diverse phenotypes as they are settled in different regions of TME and receive different microenvironmental signals. Briefly, M1 macrophages induce an inflammatory precancerous niche and flame the early oncogenic mutations, whereas their M2 counterparts are reprogrammed to release various growth factors and providing an immunosuppressive state in TME as long as abetting hypoxic cancer cells to set up a new vasculature. Further, they mediate stromal micro-invasion and co-migrate with invasive cancer cells to invade the vascular wall and neural sheath, while another subtype of TAMs prepares suitable niches much earlier than metastatic cells arrive at the target tissues. Accordingly, at the neoplastic transformation, during the benign-to-malignant transition and through the metastatic cascade, macrophages are involved in shaping the primary, micro-invasive and pre-metastatic TMEs. Whether their behavioral plasticity is derived from distinct genotypes or is fueled by microenvironmental cues, it could define these cells as remarkably interesting therapeutic targets.


Assuntos
Carcinogênese/patologia , Macrófagos/patologia , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Neoplasias/patologia , Animais , Humanos , Microambiente Tumoral/fisiologia
10.
Life Sci ; 256: 117936, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32531376

RESUMO

AIMS: The regulation of the Ras-ERK pathway is the crucial point in pancreatic carcinogenesis, and the Ras kinase is an essential regulatory upstream signal molecule of the ERK1/2 pathway. H3K9ac is a vital histone modification, but its specific role in pancreatic cancer remains unclear. This research aims to study whether the modification level of H3K9ac can regulate the characteristic phenotype of the pancreatic cancer cells by affecting the downstream expression, proliferation, migration, and other related genes. MAIN METHODS: The RasG12V/T35S were used to transfect pancreatic cancer cells, and the levels of phosphorylated ERK1/2 and H3K9ac were detected by western blotting. The colony formation assay, transwell assay, and chromatin immunoprecipitation assay were used to study cell viability, migration, and the downstream genes of the ERK1/2 pathway. KEY FINDINGS: The results showed that Ras ERK1/2 reduced H3K9ac expression in ASPC-1 cells, and H3K9ac significantly repressed the viability of cells, colony formation, and ASPC-1 cell movement induced by Ras ERK1/2. Besides, HDAC1 silencing increased H3K9ac expression, and changed the effect of Ras ERK1/2 on ASPC-1 cells proliferation, its movement, and mRNAs of ERK1/2 downstream genes. Moreover, Ras ERK1/2 inhibited H3K9ac expression by the degradation of PCAF via MDM2. SIGNIFICANCE: Ras ERK1/2 promotes pancreatic carcinogenesis cell movement, through down-regulating H3K9ac via MDM2 mediated PCAF degradation.


Assuntos
Carcinogênese/patologia , Histonas/metabolismo , Lisina/metabolismo , Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fatores de Transcrição de p300-CBP/metabolismo , Proteínas ras/metabolismo , Acetilação , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Histona Desacetilase 1/metabolismo , Humanos , Neoplasias Pancreáticas/genética , Fenótipo , Proteólise , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Transcrição Genética
11.
Nat Commun ; 11(1): 3256, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591500

RESUMO

BRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease.


Assuntos
Proteína BRCA1/deficiência , Carcinogênese/patologia , Receptor Notch1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Alelos , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína BRCA1/metabolismo , Morte Celular , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Elementos de DNA Transponíveis/genética , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Knockout , Mitose , Mutação/genética , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética
12.
Proc Natl Acad Sci U S A ; 117(25): 14231-14242, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513687

RESUMO

Transforming growth factor ß-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1 ΔHEP mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation in Tak1 ΔHEP mice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatócitos/metabolismo , Inflamação/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Biomarcadores Tumorais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/genética , Morte Celular , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Hepatócitos/patologia , Inflamação/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/genética , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores CCR2/metabolismo
13.
Nat Commun ; 11(1): 3084, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555153

RESUMO

Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.


Assuntos
Proteínas Ativadoras de GTPase/metabolismo , Células-Tronco Neoplásicas/citologia , Receptor Notch1/metabolismo , Adulto , Idoso , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Hepacivirus , Hepatócitos/citologia , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fosforilação , Receptores Notch/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
14.
Arch Biochem Biophys ; 689: 108434, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32473899

RESUMO

BACKGROUND: Circular RNA (circRNA) has been proposed to be involved in carcinogenesis. Here, we explored the functional significance and regulatory role of circ-FARSA in colorectal cancer (CRC). METHODS: Gene expression was determined using quantitative reverse transcriptase polymerase chain reaction and Western blot. We determined the effect of circFARSA on CRC progression using cell count kit-8, colony formation assay, wound-healing assay, transwell invasion assay, luciferase reporter assay and in vivo assay. RESULT: circ-FARSA was upregulated in CRC tissues and cell lines, and its expression had a significant association with the overall survival of CRC patients. Knockdown of circ-FARSA inhibited the proliferation, migration, and invasion of CRC cells in vitro. Moreover, circ-FARSA functioned as a sponge of miR-330-5p, and its upregulation mitigated the inhibitory effects of miR-330-5p on CRC cell proliferation and metastasis. In addition, circ-FARSA regulated the expression of LIM and SH3 protein 1 (LASP1) by sponging miR-330-5p. Besides, inhibition of circ-FARSA repressed the growth of CRC in vivo. CONCLUSION: Silencing of circ-FARSA restricted the growth of CRC through regulating the miR-330-5p/LASP1 axis, providing a novel regulatory mechanism for CRC tumorigenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais/genética , Proteínas do Citoesqueleto/genética , Regulação Neoplásica da Expressão Gênica , Proteínas com Domínio LIM/genética , MicroRNAs/genética , RNA Circular/genética , Animais , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Regulação para Cima
15.
Life Sci ; 256: 117925, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522570

RESUMO

AIMS: This study aims to explore the effect and underlying mechanism of zoledronic acid (ZA) on the incidence of thyroid cancer (TC) tumorigenesis. MATERIALS AND METHODS: Human mononuclear cells THP-1 were differentiated into M2-like tumor associated macrophages (TAMs) by incubation with PMA followed by additional incubation of IL-4 and IL-13. TC cells TPC-1 and IHH4 were co-cultured with M2-like TAMs. Identification of M2-like TAMs markers were determined by immunohistochemistry or flow cytometry. Cell proliferation, stemness and migration/invasion ability were measured by colony, sphere formation assay and transwell assay, respectively. The expression levels of cell stemness, EMT and Wnt/ß-catenin pathway-related factors were verified by qRT-PCR, Western blotting, and immunofluorescence. A subcutaneous tumor model was established in nude mice to examine the in vivo effects of ZA. KEY FINDINGS: M2-like TAMs were enriched in TC tissues, and they promoted the colony/sphere formation, accompanied with a down-regulated expression in E-cadherin and an up-regulated expression in N-cadherin, Vimentin and other stemness-associated markers (CD133, Oct4, c-Myc) in TC cells. The effects were suppressed when ZA co-treatment was given, because ZA inhibited the polarization of M2-like TAMs and ß-catenin entry into the nucleus. Moreover, in agreement with in vitro data, ZA also limited subcutaneous tumor formation and macrophage enrichment in nude mice. SIGNIFICANCE: ZA suppressed M2-like TAMs induced TC cell proliferation, stemness and metastasis through inhibiting M2-like TAMs polarization and Wnt/ß-catenin pathway, which sheds light on the mechanisms of TC and provides avenues for the development of clinical therapy to TC.


Assuntos
Macrófagos/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Ácido Zoledrônico/farmacologia , beta Catenina/metabolismo , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Carcinogênese/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Transdução de Sinais , Células THP-1/metabolismo , Microambiente Tumoral , Via de Sinalização Wnt
16.
Anticancer Res ; 40(5): 2687-2694, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366413

RESUMO

BACKGROUND/AIM: Transforming growth factor-ß (TGF-ß) plays dual suppressive and oncogenic roles in mammary carcinogenesis. MATERIALS AND METHODS: To analyze whether TGF-ß exerts suppressive or oncogenic actions on mammary carcinogenesis, transgenic mice overexpressing a dominant-negative mutant type II TGF-ß receptor (TßRII-DNR) driven by the mouse mammary tumor virus (MMTV) promoter were treated with a low dose of urethane, a carcinogen present in fermented food products and alcoholic beverages. RESULTS: Lobular proliferative lesions, showing high ß-casein expression, developed in the mammary glands of TßRII-DNR+/+ mice aged >61 weeks. Compared with wild-type mice, TßRII-DNR+/+ mice administered with urethane showed significant increases in dysplastic hyperplasias and adenocarcinomas of the mammary glands. CONCLUSION: The functional decline of TGF-ß signaling in mammary glands led to a high susceptibility to urethane-induced mammary carcinogenesis. TGF-ß signaling may act as a tumor suppressor during mammary tumor development.


Assuntos
Carcinogênese/patologia , Genes Dominantes , Neoplasias Mamárias Animais/genética , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Neoplasias Pulmonares/patologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/induzido quimicamente , Neoplasias Mamárias Animais/patologia , Camundongos Transgênicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Transgenes , Uretana
17.
Future Oncol ; 16(20): 1463-1474, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32456461

RESUMO

As cancer patients are clinically known to be predisposed to COVID-19 infection, a corollary question of whether COVID-19 infection predisposes to cancer is explored. This article seeks to establish an association between novel coronavirus sequelae and cancer. A literature review on COVID-19 mechanisms of action, molecular responses it elicits upon infection and tumorigenesis pathways is conducted to establish this association. Major signaling pathways implicated in aberrant cellular growth are activated, the ensuing cytokine storm weakens the immune system response to tumors, and patients may develop cancer as a result of superimposed mutagenic and/or carcinogenic events. Future work needs to be performed to support this hypothesis, both in in vitro models and preclinical studies. COVID-19 patients may need to be monitored post-infection for developing cancer.


Assuntos
Infecções por Coronavirus/etiologia , Infecções por Coronavirus/patologia , Neoplasias/complicações , Neoplasias/epidemiologia , Pneumonia Viral/etiologia , Pneumonia Viral/patologia , Betacoronavirus , Carcinogênese/patologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Suscetibilidade a Doenças/imunologia , Humanos , Neoplasias/patologia , Pandemias
18.
Nat Commun ; 11(1): 2333, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393735

RESUMO

Missense-type mutant p53 plays a tumor-promoting role through gain-of-function (GOF) mechanism. In addition, the loss of wild-type TP53 through loss of heterozygosity (LOH) is widely found in cancer cells. However, malignant progression induced by cooperation of TP53 GOF mutation and LOH remains poorly understood. Here, we show that mouse intestinal tumors carrying Trp53 GOF mutation with LOH (AKTPM/LOH) are enriched in metastatic lesions when heterozygous Trp53 mutant cells (AKTP+/M) are transplanted. We show that Trp53 LOH is required for dormant cell survival and clonal expansion of cancer cells. Moreover, AKTPM/LOH cells show an increased in vivo tumor-initiating ability compared with AKTPNull and AKTP+/M cells. RNAseq analyses reveal that inflammatory and growth factor/MAPK pathways are specifically activated in AKTPM/LOH cells, while the stem cell signature is upregulated in both AKTPM/LOH and AKTPNull cells. These results indicate that TP53/Trp53 LOH promotes TP53/Trp53 GOF mutation-driven metastasis through the activation of distinct pathway combination.


Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Neoplasias Hepáticas/secundário , Mutação/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Células Clonais , Análise por Conglomerados , Feminino , Mutação com Ganho de Função , Humanos , Inflamação/patologia , Neoplasias Intestinais/patologia , Perda de Heterozigosidade , Sistema de Sinalização das MAP Quinases , Camundongos , Organoides/patologia
19.
Nat Cell Biol ; 22(6): 728-739, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32367049

RESUMO

The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.


Assuntos
Carcinogênese/patologia , Proliferação de Células , Senescência Celular , Frutose-Bifosfatase/fisiologia , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/patologia , Neoplasias Hepáticas/patologia , Animais , Carcinogênese/metabolismo , Feminino , Células Estreladas do Fígado/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Yonsei Med J ; 61(6): 460-470, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32469170

RESUMO

PURPOSE: MicroRNAs play key regulatory roles in the tumorigenesis of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). This study aimed to explore the regulatory effects of microRNA-98-5p (miR-98-5p) on the proliferation, migration, invasion, and apoptosis of HBV-HCC cells, as well as the underlying mechanisms involving nuclear factor-κB-inducing kinase (NIK). MATERIALS AND METHODS: The expressions of miR-98-5p and NIK in HBV-HCC tissues and cells, and the level of HBV DNA in HBV-HCC cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration, invasion, and apoptosis of HBV-HCC cells were analyzed by cell counting kit-8, wound healing, transwell, and flow cytometry assay, respectively. The targeting relationship between miR-98-5p and NIK was predicted by StarBase3.0 and verified by dual-luciferase reporter assay. HBV-HCC xenograft tumor model was constructed in mice to observe the tumor growth in vivo. RESULTS: The expression of miR-98-5p was declined in HBV-HCC tissues and cells. Overexpression of miR-98-5p markedly reduced the level of HBV DNA; inhibited the proliferation, migration, and invasion; and promoted the apoptosis of HBV-HCC cells. NIK was a target of miR-98-5p. Overexpression of miR-98-5p markedly decreased the protein expression of NIK in MHCC97H-HBV cells. NIK reversed the tumor-suppressing effect of miR-98-5p on HBV-HCC cells. Furthermore, overexpression of miR-98-5p significantly inhibited the xenograft tumor growth and decreased the expression of NIK in mice. CONCLUSION: MiR-98-5p inhibits the secretion of HBV, proliferation, migration, and invasion of HBV-HCC cells by targeting NIK.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Apoptose/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Tela Subcutânea/patologia
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