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1.
Anticancer Res ; 41(7): 3683-3688, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230167

RESUMO

BACKGROUND/AIM: There are no clinically significant cutoff values of serum vitamin D levels and time points to predict the prognosis of colon cancer, particularly in patients who underwent curative surgical resection. PATIENTS AND METHODS: We retrospectively analyzed serum vitamin D levels in 795 patients with stages I to III colon cancer who underwent curative surgical resection. RESULTS: Patients with vitamin D levels below 12 ng/ml at one year after surgical resection demonstrated a significantly reduced disease-free survival (DFS) than those who did not have vitamin D deficiency (p=0.01). In the multivariate analysis, an age of 70 years or older [hazard ratio (HR)=1.992; p=0.001], pathologic stage (HR=3.739; p<0.001), and vitamin D deficiency (less than 12 ng/ml) at one year after surgery (HR=0.563; p=0.020) were factors unfavorably influencing DFS. CONCLUSION: In patients with stages I to III of colon cancer, vitamin D deficiency at one year after surgical resection was associated with increased disease relapse.


Assuntos
Neoplasias do Colo/patologia , Recidiva Local de Neoplasia/patologia , Deficiência de Vitamina D/patologia , Vitamina D/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias/métodos , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Deficiência de Vitamina D/metabolismo , Adulto Jovem
2.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202689

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide. One of its subtypes is associated with defective mismatch repair (dMMR) genes. Saffron has many potentially protective roles against colon malignancy. However, these roles in the context of dMMR tumors have not been explored. In this study, we aimed to investigate the effects of saffron and its constituents in CRC cell lines with dMMR. METHODS: Saffron crude extracts and specific compounds (safranal and crocin) were used in the human colorectal cancer cell lines HCT116, HCT116+3 (inserted MLH1), HCT116+5 (inserted MSH3), and HCT116+3+5 (inserted MLH1 and MSH3). CDC25b, p-H2AX, TPDP1, and GAPDH were analyzed by Western blot. Proliferation and cytotoxicity were analyzed by MTT. The scratch wound assay was also performed. RESULTS: Saffron crude extracts restricted (up to 70%) the proliferation in colon cells with deficient MMR (HCT116) compared to proficient MMR. The wound healing assay indicates that deficient MMR cells are doing better (up to 90%) than proficient MMR cells when treated with saffron. CDC25b and TDP1 downregulated (up to 20-fold) in proficient MMR cells compared to deficient MMR cells, while p.H2AX was significantly upregulated in both cell types, particularly at >10 mg/mL saffron in a concentration-dependent manner. The reduction in cellular proliferation was accompanied with upregulation of caspase 3 and 7. The major active saffron compounds, safranal and crocin reproduced most of the saffron crude extracts' effects. CONCLUSIONS: Saffron's anti-proliferative effect is significant in cells with deficient MMR. This novel effect may have therapeutic implications and benefits for MSI CRC patients who are generally not recommended for the 5-fluorouracil-based treatment.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Crocus/química , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Instabilidade de Microssatélites/efeitos dos fármacos , Extratos Vegetais/farmacologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Extratos Vegetais/química
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206240

RESUMO

The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM+ cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos , Fosfolipídeos/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Idoso , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Células Epiteliais/enzimologia , Células Epiteliais/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Humanos , Lipidômica , Lipogênese , Masculino , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
4.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063570

RESUMO

Understanding the global metabolic changes during the senescence of tumor cells can have implications for developing effective anti-cancer treatment strategies. Ionizing radiation (IR) was used to induce senescence in a human colon cancer cell line HCT-116 to examine secretome and metabolome profiles. Control proliferating and senescent cancer cells (SCC) exhibited distinct morphological differences and expression of senescent markers. Enhanced secretion of pro-inflammatory chemokines and IL-1, anti-inflammatory IL-27, and TGF-ß1 was observed in SCC. Significantly reduced levels of VEGF-A indicated anti-angiogenic activities of SCC. Elevated levels of tissue inhibitors of matrix metalloproteinases from SCC support the maintenance of the extracellular matrix. Adenylate and guanylate energy charge levels and redox components NAD and NADP and glutathione were maintained at near optimal levels indicating the viability of SCC. Significant accumulation of pyruvate, lactate, and suppression of the TCA cycle in SCC indicated aerobic glycolysis as the predominant energy source for SCC. Levels of several key amino acids decreased significantly, suggesting augmented utilization for protein synthesis and for use as intermediates for energy metabolism in SCC. These observations may provide a better understanding of cellular senescence basic mechanisms in tumor tissues and provide opportunities to improve cancer treatment.


Assuntos
Senescência Celular/genética , Neoplasias do Colo/genética , Redes e Vias Metabólicas/genética , Metaboloma/genética , Senescência Celular/efeitos da radiação , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Interleucina-1/genética , Interleucina-27/genética , Redes e Vias Metabólicas/efeitos da radiação , Metaboloma/efeitos da radiação , Radiação Ionizante , Fator de Crescimento Transformador beta1/genética , Fator A de Crescimento do Endotélio Vascular/genética
5.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070303

RESUMO

Colorectal cancer (CRC) is the third leading malignant tumor in the world, which has high morbidity and mortality. In this study we found that trichodermic acid (TDA), a secondary metabolite isolated from the plant endophytic fungus Penicillium ochrochloronthe with a variety of biological and pharmacological activities, exhibited the antitumor effects on colorectal cancer cells in vitro and in vivo. Our results showed that TDA inhibited the proliferation of colon cancer cells in a dose-dependent manner. TDA induces sustained endoplasmic reticulum stress, which triggers apoptosis through IRE1α/XBP1 and PERK/ATF4/CHOP pathways. In addition, we found that TDA mediated endoplasmic reticulum stress also induces autophagy as a protective mechanism. Moreover, combined treatment of TDA with autophagy inhibitors significantly enhanced its anticancer effect. In conclusion, our results indicated that TDA can induce ER stress and autophagy mediated apoptosis, suggesting that targeting ER stress and autophagy may be an effective strategy for the treatment of CRC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias do Colo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Animais , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073365

RESUMO

Ferroptosis is a new type of programmed cell death, which occurs with iron dependence. Previous studies have showed that ferroptosis plays an important regulatory role in the occurrence and development of tumors. Colon cancer is one of the major morbidities and causes of mortality in the world. This study used RNA-seq and colon cancer clinical data to explore the relationship between ferroptosis-related genes and colon cancer. Based on the fifteen prognostic ferroptosis-related genes, two molecular subgroups of colon cancer were identified. Surprisingly, we also found cluster2 was characterized by lower mutation burden and expression of checkpoint genes, better survival, and higher expression of NOX1. Moreover, cluster2 has fewer BRAF mutations. We also found the expression of NOX1 is related to the status of BRAF. Finally, using 15 ferroptosis-related genes from The Cancer Genome Atlas cohort, we constructed a prognosis model, and this model may be used to predict the prognosis of patients in clinics.


Assuntos
Neoplasias do Colo/metabolismo , Bases de Dados de Ácidos Nucleicos , Ferroptose , Regulação Neoplásica da Expressão Gênica , Modelos Biológicos , NADPH Oxidase 1/biossíntese , Proteínas Proto-Oncogênicas B-raf/biossíntese , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Humanos , NADPH Oxidase 1/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , RNA-Seq
7.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062897

RESUMO

Cancer is a phenomenon broadly related to ageing in various ways such as cell cycle deregulation, metabolic defects or telomerases dysfunction as principal processes. Although the tumor cell is the main actor in cancer progression, it is not the only element of the disease. Cells and the matrix surrounding the tumor, called the tumor microenvironment (TME), play key roles in cancer progression. Phenotypic changes of the TME are indispensable for disease progression and a few of these transformations are produced by epigenetic changes including miRNA dysregulation. In this study, we found that a specific group of miRNAs in the liver TME produced by colon cancer called geromiRs, which are miRNAs related to the ageing process, are significantly downregulated. The three principal cell types involved in the liver TME, namely, liver sinusoidal endothelial cells, hepatic stellate (Ito) cells and Kupffer cells, were isolated from a murine hepatic metastasis model, and the miRNA and gene expression profiles were studied. From the 115 geromiRs and their associated hallmarks of aging, which we compiled from the literature, 75 were represented in the used microarrays, 26 out of them were downregulated in the TME cells during colon cancer colonization of the liver, and none of them were upregulated. The histone modification hallmark of the downregulated geromiRs is significantly enriched with the geromiRs miR-15a, miR-16, miR-26a, miR-29a, miR-29b and miR-29c. We built a network of all of the geromiRs downregulated in the TME cells and their gene targets from the MirTarBase database, and we analyzed the expression of these geromiR gene targets in the TME. We found that Cercam and Spsb4, identified as prognostic markers in a few cancer types, are associated with downregulated geromiRs and are upregulated in the TME cells.


Assuntos
Neoplasias do Colo/genética , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , MicroRNAs/genética , Animais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/genética , Células Estreladas do Fígado/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/patologia , Fígado/patologia , Camundongos , MicroRNAs/classificação
8.
J Cancer Res Clin Oncol ; 147(8): 2199-2207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34115239

RESUMO

Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.


Assuntos
Carcinoma/prevenção & controle , Transformação Celular Neoplásica , Neoplasias do Colo/prevenção & controle , Pólipos do Colo/terapia , Terapia de Alvo Molecular/métodos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adenoma/prevenção & controle , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/prevenção & controle , Antineoplásicos/uso terapêutico , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Genes de Troca/efeitos dos fármacos , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
9.
FASEB J ; 35(7): e21677, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34125978

RESUMO

Meprin ß is a zinc-dependent metalloprotease exhibiting a unique cleavage specificity with strong preference for acidic amino acids at the cleavage site. Proteomic studies revealed a diverse substrate pool of meprin ß including the interleukin-6 receptor (IL-6R) and the amyloid precursor protein (APP). Dysregulation of meprin ß is often associated with pathological conditions such as chronic inflammation, fibrosis, or Alzheimer's disease (AD). The extracellular regulation of meprin ß including interactors, sheddases, and activators has been intensively investigated while intracellular regulation has been barely addressed in the literature. This study aimed to analyze C-terminal phosphorylation of meprin ß with regard to cell surface expression and proteolytic activity. By immunoprecipitation of endogenous meprin ß from the colon cancer cell line Colo320 and subsequent LC-MS analysis, we identified several phosphorylation sites in its C-terminal region. Here, T694 in the C-terminus of meprin ß was the most preferred residue after phorbol 12-myristate 13-acetate (PMA) stimulation. We further demonstrated the role of protein kinase C (PKC) isoforms for meprin ß phosphorylation and identified the involvement of PKC-α and PKC-ß. As a result of phosphorylation, the meprin ß activity at the cell surface is reduced and, consequently, the extent of substrate cleavage is diminished. Our data indicate that this decrease of the surface activity is caused by the internalization and degradation of meprin ß.


Assuntos
Membrana Celular/metabolismo , Neoplasias do Colo/patologia , Espaço Extracelular/metabolismo , Metaloendopeptidases/metabolismo , Proteína Quinase C beta/metabolismo , Proteína Quinase C-alfa/metabolismo , Proteólise , Neoplasias do Colo/metabolismo , Regulação da Expressão Gênica , Humanos , Metaloendopeptidases/genética , Fosforilação , Proteína Quinase C beta/genética , Proteína Quinase C-alfa/genética , Células Tumorais Cultivadas
10.
Int J Mol Sci ; 22(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065633

RESUMO

The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial-mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial-mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Neoplasias do Colo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Antígenos CD/metabolismo , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Bases de Dados Genéticas , Molécula de Adesão da Célula Epitelial/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Técnicas de Silenciamento de Genes , Humanos , Queratina-20/metabolismo , Invasividade Neoplásica/genética , Oxaliplatina/farmacologia , Transporte Proteico , Vimentina/metabolismo , beta Catenina/metabolismo
11.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069111

RESUMO

In colon cancer, wingless (Wnt)/ß-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/ß-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and ß-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/ß-catenin/glycogen synthase kinase-3ß (GSK-3ß) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/ß-catenin/GSK-3ß signaling.


Assuntos
Antiparasitários/farmacologia , Neoplasias do Colo/tratamento farmacológico , Nitrocompostos/farmacologia , Tiazóis/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Antiparasitários/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HCT116 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Nitrocompostos/química , Antígeno Nuclear de Célula em Proliferação/imunologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Tiazóis/química , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
12.
Nat Commun ; 12(1): 3464, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103493

RESUMO

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFß signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFß-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFß-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.


Assuntos
Carcinogênese/metabolismo , Neoplasias do Colo/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinogênese/patologia , Diferenciação Celular , Sobrevivência Celular , Colo/patologia , Neoplasias do Colo/genética , Células Epiteliais/metabolismo , Feto/patologia , Inflamação/patologia , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt
13.
Ann Clin Lab Sci ; 51(2): 271-276, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941570

RESUMO

Here we present the case of a 73-year-old male with rectal adenocarcinoma with heterotopic ossification (HO). Cancer-associated HO in the digestive system is rare. Thus, the precise mechanism and clinicopathological significance of HO have not yet been defined. To clarify the molecular mechanisms of HO, we analyzed the expression levels of signaling molecules related to epithelial-mesenchymal transition (EMT) that lead to ossification in the tumor cells discriminating the ossified area (HO-area) and non-ossified area (non-HO area). Expression levels of BMP4 were elevated in both areas, whereas BMP2 was specifically increased in the HO-area by qPCR. EMT-related molecules such as Snail and Slug were especially higher in the HO-area. By immunohistochemistry, the expression of Smad4, nuclear staining of ß-catenin, and the phosphorylated form of GSK-3ß were detectable in both areas, and GSK-3ß was highly phosphorylated in the HO-area. The tumor growth rate was extremely high, with the Ki-67 labeling index at 90%. In the HO-area, osteoblasts with alkaline phosphatase expression were distributed surrounding the tumor cells. This is the first demonstration of the involvement of EMT in HO of colon cancer through BMP/SMAD and WNT/ß-catenin signaling pathways, which are especially prominent in the HO-area leading to the osteogenic property.


Assuntos
Proteína Morfogenética Óssea 2/genética , Transição Epitelial-Mesenquimal/fisiologia , Ossificação Heterotópica/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Idoso , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/fisiopatologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Osteoblastos/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
14.
Cell Mol Life Sci ; 78(12): 5179-5195, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33974094

RESUMO

Despite new advances on the functions of ER chaperones at the cell surface, the translocation mechanisms whereby these chaperones can escape from the ER to the cell surface are just emerging. Previously we reported that in many cancer types, upon ER stress, IRE1α binds to and triggers SRC activation resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. In this study, using a combination of molecular, biochemical, and imaging approaches, we discovered that in colon and lung cancer, upon ER stress, ER chaperones, such as GRP78 bypass the Golgi and unconventionally traffic to the cell surface via endosomal transport mediated by Rab GTPases (Rab4, 11 and 15). Such unconventional transport is driven by membrane fusion between ER-derived vesicles and endosomes requiring the v-SNARE BET1 and t-SNARE Syntaxin 13. Furthermore, GRP78 loading into ER-derived vesicles requires the co-chaperone DNAJC3 that is regulated by ER-stress induced PERK-AKT-mTOR signaling.


Assuntos
Membrana Celular/metabolismo , Neoplasias do Colo/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Choque Térmico/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteínas de Choque Térmico/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutagênese Sítio-Dirigida , Mutação , Transporte Proteico , Transdução de Sinais , Células Tumorais Cultivadas
15.
Methods Mol Biol ; 2255: 119-134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34033099

RESUMO

The study of necroptosis is a rapidly growing field in current research of cell death mechanisms and cancer treatment strategies. While apoptotic cells can be reliably identified via annexin V assay, necroptosis is not associated with exposure of easily detectable markers. The most reliable way to identify necroptotic events is immunochemical detection of active phosphorylated RIPK1, RIPK3, and MLKL proteins facilitating necroptosis execution. This chapter describes a detailed protocol on necroptosis induction in human colon adenocarcinoma HT-29 cells, preparation of various positive and negative controls, detection of necroptosis mediator proteins via Western Blot analysis, and interpretation of results. This protocol allows reliable and specific detection of necroptosis in cell culture or tissue samples, and it provides a well-established model suitable for detailed studies of necroptosis molecular mechanisms in vitro.


Assuntos
Adenocarcinoma/patologia , Western Blotting/métodos , Neoplasias do Colo/patologia , Necroptose , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Humanos , Indóis/farmacologia , Fosforilação , Células Tumorais Cultivadas
16.
Methods Mol Biol ; 2255: 159-169, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34033102

RESUMO

Cytotoxic T cell-induced cell death is well documented. Cytotoxic T cell releases various cytolytic proteins. The cytolytic proteins induce target cell death. T cell-induced cell death can be measured by the lytic assay. One of the well-known lytic assays uses radioactive tracer, Chromium-51 (51Cr), and detects the amount of 51Cr released from target cells. This assay can detect cell death and the efficiency of the T cell-induced cell death by coculture effector cells (T cells) and target cells. This assay can determine the kinetics of the cell lysis. The issue of this approach is the use of radioactive material. This chapter describes measuring T cell-induced cell death by determining the epigenetic remodeling and the release of cytolytic proteins. Determine the efficiency of T cell-induced cell death by using a flow cytometry-based detection method.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Radioisótopos de Cromo/análise , Neoplasias do Colo/patologia , Testes Imunológicos de Citotoxicidade/métodos , Citometria de Fluxo/métodos , Linfoma de Células B/patologia , Linfócitos T Citotóxicos/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Morte Celular , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Camundongos , Células Tumorais Cultivadas
17.
Nat Commun ; 12(1): 2809, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990575

RESUMO

The paradoxical roles of transforming growth factor-ß (TGFß) signaling and nuclear receptor Nur77 in colon cancer development are known but the underlying mechanisms remain obscure. Inhibitor of differentiation 1 (ID1) is a target gene of TGFß and a key promoter for colon cancer progression. Here, we show that Nur77 enhances TGFß/Smad3-induced ID1 mRNA expression through hindering Smurf2-mediated Smad3 mono-ubiquitylation, resulting in ID1 upregulation. In the absence of TGFß, however, Nur77 destabilizes ID1 protein by promoting Smurf2-mediated ID1 poly-ubiquitylation, resulting in ID1 downregulation. Interestingly, TGFß stabilizes ID1 protein by switching Nur77 interaction partners to inhibit ID1 ubiquitylation. This also endows TGFß with an active pro-tumorigenic action in Smad4-deficient colon cancers. Thus, TGFß converts Nur77's role from destabilizing ID1 protein and cancer inhibition to inducing ID1 mRNA expression and cancer promotion, which is highly relevant to colon cancer stemness, metastasis and oxaliplatin resistance. Our data therefore define the integrated duality of Nur77 and TGFß signaling in regulating ID1 expression and provide mechanistic insights into the paradoxical roles of TGFß and Nur77 in colon cancer progression.


Assuntos
Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Proteína 1 Inibidora de Diferenciação/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Carcinogênese , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Modelos Biológicos , Estabilidade Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteína Smad3/metabolismo , Proteína Smad4/deficiência , Proteína Smad4/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
18.
Aging (Albany NY) ; 13(7): 10354-10368, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33819920

RESUMO

Colon cancer is the third most common malignant tumor and its mortality rate ranks fourth among all malignant tumor types. Bioinformatics analysis has shown that GSPT1 is dysregulated in colon cancer and is associated with tumor progression. However, the underlying mechanism remains unclear. To address this research gap, we examined the impact of GSPT1 on cell proliferation, apoptosis, migration, and invasion in vitro as well as tumor growth in vivo in colon cancer by using a Cell Counting Kit-8 assay, flow cytometry, transwell migration assay, transwell invasion assay, and tumor xenograft model-based analysis, respectively. GSPT1 was significantly up-regulated in colon cancer tissues and cell lines. High GSPT1 expression was correlated with a larger tumor size. Depletion of GSPT1 suppressed cell proliferation, migration, and invasion-induced colon cancer cell apoptosis in vitro and restrained tumorigenicity in vivo in HCT116 colon cancer cells. Taken together, our findings suggest that the GSPT1/GSK pathway exerts tumor-promoting actions in colon cancer oncogenesis and progression. The GSPT1/GSK pathway may thus be an effective target for controlling colon cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/patologia , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Fatores de Terminação de Peptídeos/metabolismo , Adulto , Idoso , Animais , Neoplasias do Colo/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Células HCT116 , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Transdução de Sinais/fisiologia
19.
FASEB J ; 35(5): e21432, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33794029

RESUMO

While failure in resolution of inflammation is considered to increase the risk of tumorigenesis, there is paucity of experimental as well as clinical evidence supporting this association. Resolvin D1 (RvD1) is a representative pro-resolving lipid mediator that is endogenously generated from docosahexaenoic acid for the resolution of inflammation. Here, we report a decreased level of RvD1 in the blood from colorectal cancer patients and mice having inflammation-induced colon cancer, suggesting plasma RvD1 as a potential biomarker for monitoring colorectal cancer. Administration of RvD1 attenuated dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colorectal carcinogenesis by suppressing the production of interleukin-6 (IL-6) and IL-6-mediated chromosomal instability. The protective effect of RvD1 against chromosomal instability is associated with downregulation of IL-6-induced Cyclin D1 expression, which appears to be mediated by blocking the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) axis. RvD1 inhibited the STAT3 signaling pathway by interfering with the binding of IL-6 to its receptor (IL-6R), suggesting the novel function of RvD1 as a putative IL-6R antagonist. Together, our findings suggest that RvD1-mediated blockade of IL-6 signal transmission may contribute to inhibition of chromosomal instability and tumorigenesis.


Assuntos
Carcinogênese/patologia , Colite/complicações , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-6/farmacologia , Fuso Acromático/efeitos dos fármacos , Animais , Carcinogênese/metabolismo , Estudos de Casos e Controles , Colite/induzido quimicamente , Colite/patologia , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fuso Acromático/patologia
20.
Nutrients ; 13(4)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916690

RESUMO

Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.


Assuntos
Carcinogênese/metabolismo , Neoplasias do Colo/terapia , Microbioma Gastrointestinal/efeitos dos fármacos , Triptofano/metabolismo , Evasão Tumoral/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Colo/microbiologia , Colo/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/microbiologia , Terapia Combinada/métodos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indóis/administração & dosagem , Indóis/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Cinurenina/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/imunologia , Probióticos/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/metabolismo , Simbiose/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
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