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1.
Anticancer Res ; 39(9): 4787-4794, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519580

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate the effects of the macrophage colony-stimulating factor (M-CSF) receptor antagonist on hepatic carcinogenesis in mice. MATERIALS AND METHODS: Mice were injected with diethylnitrosamine (DEN) and treated with M-CSF receptor antagonist GW2580 (GW) or a saline vehicle just after (early treated group) or 2 weeks after (late treated group) DEN injection. Animals were sacrificed after 28 weeks and incidence of tumor was assessed. Isolated Kupffer cells were co-cultured with M-CSF in the presence or absence of GW, and the concentration of VEGF was measured. RESULTS: The incidence of tumors was significantly blunted both in the early- and the late-treated groups. In addition, angiogenesis within the tumor was also suppressed in both groups. The concentration of VEGF increased in Kupffer cells treated with M-CSF compared to those cultured without M-CSF. This increase was blunted by GW. CONCLUSION: M-CSF and its receptor could be novel molecular targets for hepatocellular carcinoma.


Assuntos
Anisóis/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Pirimidinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Imuno-Histoquímica , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Carga Tumoral/efeitos dos fármacos
2.
Molecules ; 24(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974882

RESUMO

Hepatocellular carcinoma (HCC) is one of the most deadly genetic diseases, but surprisingly chemotherapeutic approaches against HCC are only limited to a few targets. In particular, considering the difficulty of a chemotherapeutic drug development in terms of cost and time enforces searching for surrogates to minimize effort and maximize efficiency in anti-cancer therapy. In spite of the report that approximately one thousand lichen-derived metabolites have been isolated, the knowledge about their functions and consequences in cancer development is relatively limited. Moreover, one of the major second metabolites from lichens, Atranorin has never been studied in HCC. Regarding this, we comprehensively analyze the effect of Atranorin by employing representative HCC cell lines and experimental approaches. Cell proliferation and cell cycle analysis using the compound consistently show the inhibitory effects of Atranorin. Moreover, cell death determination using Annexin-V and (Propidium Iodide) PI staining suggests that it induces cell death through necrosis. Lastly, the metastatic potential of HCC cell lines is significantly inhibited by the drug. Taken these together, we claim a novel functional finding that Atranorin comprehensively suppresses HCC tumorigenesis and metastatic potential, which could provide an important basis for anti-cancer therapeutics.


Assuntos
Carcinoma Hepatocelular , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica , Hidroxibenzoatos , Líquens/química , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/isolamento & purificação , Hidroxibenzoatos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia
3.
Molecules ; 24(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999681

RESUMO

Skin cancer has always been and remains the leader among all tumors in terms of occurrence. One of the main factors responsible for skin cancer, natural and artificial UV radiation, causes the mutations that transform healthy cells into cancer cells. These mutations inactivate apoptosis, an event required to avoid the malignant transformation of healthy cells. Among these deadliest of cancers, melanoma and its 'younger sister', Merkel cell carcinoma, are the most lethal. The heavy toll of skin cancers stems from their rapid progression and the fact that they metastasize easily. Added to this is the difficulty in determining reliable margins when excising tumors and the lack of effective chemotherapy. Possibly the biggest problem posed by skin cancer is reliably detecting the extent to which cancer cells have spread throughout the body. The initial tumor is visible and can be removed, whereas metastases are invisible to the naked eye and much harder to eliminate. In our opinion, antisense oligonucleotides, which can be used in the form of targeted ointments, provide real hope as a treatment that will eliminate cancer cells near the tumor focus both before and after surgery.


Assuntos
Antineoplásicos/uso terapêutico , Melanoma , Mutação , Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Cutâneas , Raios Ultravioleta/efeitos adversos , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos da radiação , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
4.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013830

RESUMO

Breast cancer is the most common malignancy in women worldwide and can be categorized into several subtypes according to histopathological parameters or genomic signatures. Such heterogeneity of breast cancer can arise from the reactivation of mammary stem cells in situ during tumorigenesis. Moreover, different breast cancer subtypes exhibit varieties of cancer incidence, therapeutic response, and patient prognosis, suggesting that a specific therapeutic protocol is required for each breast cancer subtype. Recent studies using molecular and cellular assays identified a link between specific genetic/epigenetic alterations and distinct cells of origin of breast cancer subtypes. These alterations include oncogenes, tumor suppressor genes, and cell-lineage determinants, which can induce cell reprogramming (dedifferentiation and transdifferentiation) among two lineage-committed mammary epithelial cells, namely basal and luminal cells. The interconversion of cell states through cell reprogramming into the intermediates of mammary stem cells can give rise to heterogeneous breast cancers that complicate effective therapies of breast cancer. A better understanding of mechanisms underlying cell reprogramming in breast cancer can help in not only elucidating tumorigenesis but also developing therapeutics for breast cancer. This review introduces recent findings on cancer gene-mediated cell reprogramming in breast cancer and discusses the therapeutic potential of targeting cell reprogramming.


Assuntos
Neoplasias da Mama/etiologia , Transformação Celular Neoplásica , Reprogramação Celular , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem da Célula/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Epigênese Genética/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Terapia de Alvo Molecular , Células-Tronco/metabolismo , Células-Tronco/patologia
5.
Environ Toxicol ; 34(7): 869-877, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033183

RESUMO

As a human carcinogen, coal tar pitch (CTP) can significantly increase the risk of lung cancer. However, the mechanism underlying CTP-induced lung carcinogenesis has not been well understood. This study aims to explore the role of the LncRNA-ENST00000501520 in the proliferation of malignant-transformed human bronchial epithelial cells (BAES-2B) induced by CTP extract for the first time. BEAS-2B cells were stimulated with 2.4 µg/mL CTP extract, and then passaged for three times, which were named passage 1 and then passaged until passage 30 (named as CTP group). The ENST000001520 of cells in CTP group was interfered using siRNA. The results showed that ENST000001520 located in cell nucleus (>80%) had no or weak ability of protein encoding. After interference of ENST000001520, the migration and proliferation of cells in CTP group were inhibited, and the cell cycle was arrested in the G0/G1 phase; however, the apoptosis of cells in CTP group was promoted. The target genes (SKB1, CLTB, TAP2, PIPK2, and SOCS3) of ENST000001520 were screened out, and the mRNA and protein expression of SBK1 and SOCS3 was significantly decreased after ENST000001520 interference. SBK1 and SOCS3 may play a promoting role in occurrence and development of cancers. The study suggests that LncRNA-ENST00000501520 could promote the proliferation in malignant-transformed BEAS-2B cells induced with CTP extract which may be mediated by target genes. This study may provide a new target for prevention and treatment of lung cancer.


Assuntos
Brônquios/efeitos dos fármacos , Proliferação de Células , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Alcatrão/toxicidade , RNA Longo não Codificante/fisiologia , Mucosa Respiratória/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mucosa Respiratória/metabolismo
6.
Proc Natl Acad Sci U S A ; 116(12): 5223-5232, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30819896

RESUMO

Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.


Assuntos
Carcinogênese/metabolismo , Prolactina/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais/fisiologia , Células Estromais/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Celecoxib/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Receptores X Retinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
7.
Neoplasia ; 21(4): 376-388, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30875566

RESUMO

The anticancer activity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol) has been widely reported in preclinical models. However, systematic investigation into the chemopreventive potential of calcitriol against the spectrum of oral carcinogenesis has not been performed. To address this gap in knowledge, we conducted a preclinical prevention trial of calcitriol in the 4-nitroquinoline-1-oxide (4NQO) oral carcinogenesis model. C57BL/6 mice were exposed to the carcinogen 4NQO in drinking water for 16 weeks and randomized to control (4NQO only) or calcitriol arms. Calcitriol (0.1 µg i.p, Monday, Wednesday, and Friday) was administered for (i) 16 weeks concurrently with 4NQO exposure, (ii) 10 weeks post completion of 4NQO exposure, and, (iii) a period of 26 weeks concurrent with and following 4NQO exposure. Longitudinal magnetic resonance imaging (MRI) was performed to monitor disease progression until end point (week 26). Correlative histopathology of tongue sections was performed to determine incidence and multiplicity of oral dysplastic lesions and squamous cell carcinomas (SCC). Vitamin D metabolites and calcium were measured in the serum using liquid chromatography-mass spectrometry (LC-MS/MS) and colorimetric assay, respectively. Renal CYP24A1 (24-hydroxylase) and CYP27B1 (1α-hydroxylase) expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunostaining of tongue sections for vitamin D receptor (VDR), CYP24A1, and Ki67 was also performed. Non-invasive MRI enabled longitudinal assessment of lesions in the oral cavity. Calcitriol administered concurrently with 4NQO for 16 weeks significantly (P < .001) decreased the number of premalignant lesions by 57% compared to 4NQO only controls. Mice treated with calcitriol for 26 weeks showed highest renal CYP24A1, lowest serum 1,25(OH)2D3 levels and highest incidence of invasive SCC. Immunohistochemistry revealed increased VDR, CYP24A1 and Ki67 staining in dysplastic epithelia compared to normal epithelium, in all four groups. Collectively, our results show that the effects of calcitriol on oral carcinogenesis are critically influenced by the stage of intervention and duration of exposure and provide the basis for exploring the potential of calcitriol for prevention of OSCC in the clinical setting.


Assuntos
Calcitriol/farmacologia , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Neoplasias Bucais/prevenção & controle , Animais , Biomarcadores , Calcitriol/administração & dosagem , Hormônios e Agentes Reguladores de Cálcio/administração & dosagem , Modelos Animais de Doenças , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Imuno-Histoquímica , Imagem por Ressonância Magnética , Camundongos , Neoplasias Bucais/diagnóstico por imagem , Neoplasias Bucais/etiologia , Neoplasias Bucais/patologia , Fenótipo
8.
Environ Toxicol Pharmacol ; 68: 141-147, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30897525

RESUMO

Increasing evidence showed that Cadmium (Cd) can accumulate in the body and damage cells, resulting in cancerigenesis of the prostate with complex mechanisms. In the present study, we aimed to explore the possible key genes, pathways and therapeutic drugs using bioinformatics methods. Microarray-based data were retrieved and analyzed to screen differentially expressed genes (DEGs) between Cd-treated prostate cells and controls. Then, functions of the DEGs were annotated and hub genes were screened. Next, key genes were selected from the hub genes via validation in a prostate cancer cohort from The Cancer Genome Atlas (TCGA). Afterward, potential drugs were further predicted. Consequently, a gene expression profile, GSE9951, was retrieved. Then, 361 up-regulated and 30 down-regulated DEGs were screened out, which were enriched in various pathways. Among the DEGs, seven hub genes (HSPA5, HSP90AB1, RHOA, HSPD1, MAD2L1, SKP2, and CCT2) were dysregulated in prostate cancer compared to normal controls, and two of them (HSPD1 and CCT2) might influence the prostate cancer prognosis. Lastly, ionomycin was predicted to be a potential agent reversing Cd-induced prostate cell malignant transformation. In summary, the present study provided novel evidence regarding the mechanisms of Cd-induced prostate cell malignant transformation, and identified ionomycin as a potential small molecule against Cd toxicity.


Assuntos
Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata/genética , Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Mineração de Dados , Humanos , Masculino , Análise em Microsséries , Neoplasias da Próstata/tratamento farmacológico
9.
Cancer Sci ; 110(4): 1293-1305, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30724425

RESUMO

Colorectal cancer (CRC) is caused by genetic alterations, and comprehensive sequence analyses have revealed the mutation landscapes. In addition to somatic changes, genetic variations are considered important factors contributing to tumor development; however, our knowledge on this subject is limited. Familial adenomatous polyposis coli (FAP) is an autosomal-dominant inherited disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP patients are classified into two major groups based on clinical manifestations: classical FAP (CFAP) and attenuated FAP (AFAP). In this study, we established 42 organoids from three CFAP patients and two AFAP patients. Comprehensive gene expression analysis demonstrated a close association between IFN/STAT signaling and the phenotypic features of FAP patients. Genetic disruption of Stat1 in the mouse model of FAP reduced tumor formation, demonstrating that the IFN/STAT pathway is causally associated with the tumor-forming potential of APC-deficient tumors. Mechanistically, STAT1 is downstream target of KRAS and is phosphorylated by its activating mutations. We found that enhanced IFN/STAT signaling in CFAP conferred resistance to MEK inhibitors. These findings reveal the crosstalk between RAS signaling and IFN/STAT signaling, which contributes to the tumor-forming potential and drug response. These results offer a rationale for targeting of IFN/STAT signaling and for the stratification of CRC patients.


Assuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Interferons/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos , Modelos Biológicos , Organoides , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nature ; 566(7743): 249-253, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700914

RESUMO

Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Colo/citologia , Interleucinas/farmacologia , Mutagênicos/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Neoplasias do Colo/genética , Neoplasias do Colo/prevenção & controle , Dano ao DNA , Dieta/efeitos adversos , Glucosinolatos/administração & dosagem , Glucosinolatos/farmacologia , Imunidade Inata , Interleucinas/biossíntese , Mucosa Intestinal/citologia , Ligantes , Camundongos , Mutagênicos/administração & dosagem , Mutação/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Interleucina/metabolismo , Células-Tronco/citologia , Linfócitos T/metabolismo
11.
Nat Commun ; 10(1): 296, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655532

RESUMO

Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotate the regulated kinases. As an example, we identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. An integrated siRNA screen identifies nine kinases, including SGK1, as being essential for Src-induced transformation. Accordingly, we find that Src positively regulates SGK1 expression in triple negative breast cancer cells, which exhibit a prominent signalling network governed by Src family kinases. Furthermore, combined inhibition of Src and SGK1 reduces colony formation and xenograft growth more effectively than either treatment alone. Therefore, this approach not only provides mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.


Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Imediatamente Precoces/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Quinases da Família src/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Proteínas Imediatamente Precoces/antagonistas & inibidores , Espectrometria de Massas/métodos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes/genética , Mapeamento de Interação de Proteínas/métodos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteômica/métodos , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/antagonistas & inibidores
12.
J Zhejiang Univ Sci B ; 20(1): 39-48, 2019 Jan..
Artigo em Inglês | MEDLINE | ID: mdl-30614229

RESUMO

Interferon-γ (IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.


Assuntos
Histona Desacetilase 2/metabolismo , Interferon gama/metabolismo , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Proteínas Proto-Oncogênicas c-abl/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Bovinos , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/genética , Mesilato de Imatinib/farmacologia , Interferon gama/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Transdução de Sinais , Ácido Valproico/farmacologia
13.
J Int Med Res ; 47(2): 1064-1071, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30616420

RESUMO

Primary myelofibrosis (PMF) is a type of cloned myeloproliferative neoplasm stemming from haematopoietic stem cells, and tends to transform to acute myeloid leukaemia (AML) in approximately 10-20% of cases over a 10-year period. The transformation into AML has a poor prognosis, with a median overall survival of only 2.6 months in patients receiving supportive treatment. To date, treatment of AML transformation remains poor. The case of a 58-year-old female patient with AML transformed from PMF, who was treated with decitabine combined with all-trans retinoic acid, is reported. The patient had complete remission and a 17-month overall survival from initial diagnosis of transformed AML, with tolerated haematologic toxicity during the treatment period.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transformação Celular Neoplásica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Transformação Celular Neoplásica/patologia , Decitabina/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Mielofibrose Primária/complicações , Mielofibrose Primária/patologia , Prognóstico , Tretinoína/administração & dosagem
14.
J Exp Clin Cancer Res ; 38(1): 39, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691509

RESUMO

BACKGROUND: Tobacco smoke (TS) critically contributes to the development of hepatocellular carcinoma. Cancer stem cells (CSCs) induced by TS is an early event in the initiation of carcinogenesis. Tumor specific microenvironment including inflammatory factors is key mediator for maintaining the stemness of CSCs through various pathways such as p38 MAPK. However, the mechanisms of inflammatory factors in TS-induced acquisition of liver CSCs properties remain undefined. The aim of this study was to investigate the role of IL-33/p38 axis in long term TS-induced acquisition of hepatic CSCs properties in mouse liver tissues and human liver cells. METHODS: BALB/c mice were exposed to TS for 12 weeks, along with or without 1 mg/kg SB203580 (p38 inhibitors) treatment. Histopathological analysis, alterations in the levels of IL-33, liver CSCs markers, EMT-like changes and p38 MAPK activation in liver tissues of mice were analyzed by immunohistochemical staining, immunofluorescence assay and Western blot analysis. Moreover, LO2 immortalized human liver cells were exposed to cigarette smoke extract (CSE) and the tumorsphere formation ability was determined. LO2 cells were further treated with IL-33 or CSE and the expression of phosphorylated p38, liver CSCs markers and EMT-related proteins was examined. RESULTS: Long term TS exposure increased the levels of CSCs markers, induced epithelial-to mesenchymal transition (EMT) and inflammatory factor IL-33 expression. Moreover, we showed that p38 MAPK modulated TS-stimulated hepatic CSC-like properties, as evidenced by the findings that long term TS exposure activated p38, and that TS-induced stemness was abolished by p38 inhibition. In addition, data from in vitro model showed that similar to cigarette smoke extract (CSE), IL-33 treatment promoted the activation of p38, increased the levels of liver CSCs markers expression and EMT-like changes. CONCLUSIONS: Collectively, these data suggested that IL-33/p38 axis plays an important role in long term TS exposure-induced acquisition of hepatic CSC-like properties.


Assuntos
Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal , Interleucina-33/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Células-Tronco Neoplásicas/patologia , Tabaco/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Proliferação de Células , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Humanos , Interleucina-33/genética , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Fosforilação , Transdução de Sinais , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por Mitógeno/genética
15.
Environ Toxicol ; 34(5): 585-593, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30698909

RESUMO

Inflammatory microenvironment has been found as a new characteristic of cancer; however, the mechanisms of inflammation-related lung cancer remain unclear. To explore the role of NLRP3 inflammsome activation in inflammation-related lung carcinogenesis, a cell model was set up. Human bronchial epithelial cells (BEAS-2B) were stimulated with 1 µg/mL lipopolysaccharide (LPS) for 24 hours, and then treated with 2.4 µg/mL coal tar pitch extract (CTPE) for 24 hours, after removal of LPS and CTPE, the cells were numbered passage 1 and were passaged and treated in this way until passage 30, which was called LPS + CTPE group. DMSO and Saline were used as vehicle controls. Malignant transformation of cells in passage 30 was evaluated by morphological change, platelet clone formation assay, and tumor formation in nude mice. The mRNA levels of NLRP3 and IL-1ß were detected by real time-PCR. The combination of NLRP3 and caspase-1 were determined using immunofluorescence and confocal. The protein expression of NLRP3, cleaved caspase-1(p10), and cleaved IL-1ß was detected using Western blot. It was shown that CTPE, LPS + CTPE-stimulated BEAS-2B cells of passage 30 changed a lot morphologically. The clone formation rates, the rates of positive cells of NLRP3 and caspase-1 combination, the mRNA levels of NLRP3 and IL-1ß, the protein expression of NLRP3, cleaved caspase-1(p10) and cleaved IL-1ß of cells exposed with CTPE and LPS + CTPE at passage 30 were significantly increased compared to vehicle controls. Furthermore, the ability of tumor formation in nude mice, the rates of clone formation and positive cells, mRNA and protein levels of NLRP3 inflammasome activation-related factors in LPS + CTPE-induced cells were all higher than those in cells stimulated with CTPE alone. In conclusion, the cell model of inflammation-related lung cancer is set up successfully, and NLRP3 inflammasome activation may be involved in the malignant transformation of BEAS-2B cells which induced by CTPE alone or LPS combined with CTPE.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Alcatrão/toxicidade , Células Epiteliais/efeitos dos fármacos , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Linhagem Celular , Transformação Celular Neoplásica/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Inflamassomos/imunologia , Inflamação , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus
16.
Toxicol Appl Pharmacol ; 365: 51-60, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30625338

RESUMO

Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. Metformin, a first-line oral agent used in the treatment of type 2 diabetes, exhibits efficacy in metabolic reprogramming fueling changes in cell growth and proliferation for multiple cancer types, including HCC. However, the molecular mechanism by which metformin delays hepatocarcinogenesis in individuals with hepatic steatosis remains rare. Here, we investigate the preventive efficacy of metformin in a rapid AKT/c-Met-triggered HCC mouse model featuring excessive levels of steatosis. Hematoxylin and eosin staining, Oil Red O staining and immunoblotting were applied for mechanistic investigations. Pharmacological and biochemical strategies were employed to illuminate molecular evidence for HCC cell lines. The results show that metformin obstructs the malignant transformation of hepatocytes in AKT/c-Met mice. Mechanistically, metformin reduces the expression of phospho-ERK (Thr202/Tyr204) and two forms of proto-oncogenes, Cyclin D1 and c-Myc, in AKT/c-Met mice. Moreover, metformin ameliorates FASN-mediated aberrant lipogenesis and HK2/PKM2-driven ATP generation in vivo. Furthermore, metformin represses the expression of FASN and HK-2 by targeting c-Myc in an AMPK-dependent manner in vitro. In addition, metformin is effective at inhibiting PKM2 expression in the presence of an AMPK inhibitor compound C, suggesting that its functioning in PKM2 is AMPK-independent. Our study experimentally validates a novel molecular mechanism by which metformin alleviates enhanced lipogenesis and high energy metabolism during hepatocarcinogenesis, indicating that metformin may serve as an agent for the prevention of HCC in patients with nonalcoholic fatty liver diseases.


Assuntos
Trifosfato de Adenosina/metabolismo , Anticarcinógenos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Transformação Celular Neoplásica/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Metformina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Hexoquinase/metabolismo , Humanos , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-met/genética , Piruvato Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Biomed Pharmacother ; 111: 178-187, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30583225

RESUMO

The structural integrity and excellent immune system of the skin makes it a protective covering, inspite of its exposure to hazardous compounds. In the present study, the chemopreventive efficacy of D-carvone was studied in 7, 12-dimethylbenz[a]anthracene (DMBA) induced skin carcinogenesis. DMBA (25 µg in 0.1 m L-1acetone) was used to induce skin cancer in Swiss albino mice. Animals were randomly divided into six groups of six animals in each. Different concentrations of D-carvone (10, 20, 30 mg/kg body weight) were used to assess its anticancer effect. Tumor incidence, tumor volume, tumor burden, histological examination and levels of phase I and phase II detoxification agents were analyzed in experimental animals. Further, expression of p53 and various apoptotic proteins including- Bcl-2, Bax was analyzed using immunohistochemistry and enzymatic expression of apoptotic proteins caspase-3 and caspase-9 was carried out by using ELISA. We observed 100% tumor incidence in DMBA-painted animals and our results showed that D-carvone at 20 mg dose significantly prevents skin carcinogenesis. Our results also showed decreased levels of phase I enzymes (Cyt P450 and-Cyt b5) with increased levels of phase II enzymes (GR, GST and GSH) and increased expression of Bax, caspase-3 and caspase-9 with decreased expression of mutated p53 and Bcl-2 in animals treated with DMBA and D-carvone at 20 mg dose. The results of the present study suggest that D-carvone can be used as a chemopreventive agent against skin cancer, as it induces apoptosis in cancer. However, further studies are warranted to check chemopreventive efficacy of D-carvone on cell proliferation, angiogenesis, and metastasis before going to human trial.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Monoterpenos/uso terapêutico , Neoplasias Cutâneas/prevenção & controle , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/fisiologia , Carcinogênese/induzido quimicamente , Carcinogênese/patologia , Carcinógenos/toxicidade , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Monoterpenos/farmacologia , Distribuição Aleatória , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Xenobióticos/metabolismo
18.
Immunity ; 49(6): 1132-1147.e7, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30552022

RESUMO

Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15%-30% of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C ζ (PKCζ) and PKCλ/ι was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKCλ/ι deficiency led to immunogenic cell death and the infiltration of CD8+ T cells, which repressed tumor initiation, PKCζ loss impaired interferon and CD8+ T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-ß receptor inhibitor plus anti-PD-L1 checkpoint blockade showed synergistic curative activity. Analysis of human samples supported the relevance of these kinases in the immunosurveillance defects of human serrated CRC. These findings provide insight into avenues for the detection and treatment of this poor-prognosis subtype of CRC.


Assuntos
Mucosa Intestinal/imunologia , Neoplasias Intestinais/imunologia , Isoenzimas/imunologia , Proteína Quinase C/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Vigilância Imunológica/genética , Vigilância Imunológica/imunologia , Mucosa Intestinal/enzimologia , Mucosa Intestinal/patologia , Neoplasias Intestinais/enzimologia , Neoplasias Intestinais/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo
19.
World J Gastroenterol ; 24(33): 3695-3708, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30197476

RESUMO

Hepatocellular carcinoma (HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition receptor (c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microRNAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
20.
J Pharmacol Sci ; 137(4): 324-332, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30150145

RESUMO

Glycyrrhiza Uralensis Polysaccharide (GCP), as a macromolecular polysaccharide extracted from the Traditional Chinese Medicine (TCM) - Licorice has been proved to inhibit tumor growth in vitro and in vivo; however, the specific anti-tumor mechanism of GCP needs to be further investigated. In this study, we explore the anti-tumor mechanism of GCP from the angle of gut microbiota. Colon carcinoma cells (CT-26) were used to set up a tumor-bearing mouse model. After 14 days of GCP treatment, the weights of tumors were significantly reduced. In addition, HE staining of tissue sections reflected that GCP could effectively inhibit tumor metastasis. 16SrRNA high-throughput sequencing of fecal samples showed a significant change between the model group and GCP group in the composition of gut microbiota. Subsequently, gut microbiota depletion and fecal transplantation experiments further confirmed the relationship between the anti-tumor effects of GCP and gut microbiota. Following depletion of gut microbiota, GCP cannot inhibit tumor growth. Fecal transplantation experiments found that transplanting the feces of GCP-treated mice, to a certain extent, could inhibit tumor growth and metastasis. These results indicate that Glycyrrhiza Polysaccharides exert anti-tumor effects by affecting gut microbiota composition.


Assuntos
Antineoplásicos Fitogênicos , Transformação Celular Neoplásica/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Glycyrrhiza uralensis/química , Fitoterapia , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Masculino , Camundongos Endogâmicos BALB C
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