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1.
Biomed Khim ; 66(1): 95-99, 2020 Jan.
Artículo en Ruso | MEDLINE | ID: mdl-32116232

RESUMEN

Using flow cytometry GD2 ganglioside expression was evaluated both on colorectal adenocarcinoma cell lines and on tumor tissue samples from colorectal cancer patients. The marker was found on EpCAM-positive tumor cells in 6 of 12 patients' samples but not on the HT29 and CaCo-2 cell lines. GD2 expression was not an exceptional feature of cancer stem cells, since its expression level was similar on CD133-positive and CD133-negative tumor cells. Thus, the presence of GD2 ganglioside was revealed on colorectal adenocarcinoma cells for the first time. This finding makes it possible to use targeted therapy to treat this disease.


Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias Colorrectales/metabolismo , Gangliósidos/metabolismo , Células CACO-2 , Células HT29 , Humanos
2.
Anticancer Res ; 40(2): 767-777, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014919

RESUMEN

BACKGROUND/AIM: Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays an important role in cancer. We examined the effect of COUP-TFII overexpression on the proliferation and invasion of the human colorectal cancer SNU-C4 cells. MATERIALS AND METHODS: SNU-C4 cells were stably transfected with COUP-TFII expression plasmid to overexpress COUP-TFII (COUP-TFII-SNU-C4 cells). Cell proliferation, colony-forming ability and transwell invasion assays were performed. To elucidate the underlying molecular mechanism of COUP-TFII action, western blot analysis, p53 shRNA transfection, and Myr-Akt transfection were performed. RESULTS: Cell proliferation and colony-forming ability were significantly inhibited in COUP-TFII-SNU-C4 cells. Western blot analyses demonstrated that while the expression of p53 and PTEN was increased, the p-Akt levels were decreased in COUP-TFII-SNU-C4 cells. Knockdown of p53 partially restored the cell proliferation, but did not reverse the inhibition of invasion. Constitutive activation of Akt via Myr-Akt transfection reversed the inhibited cell proliferation and invasion by COUP-TFII. CONCLUSION: p53 is required for the inhibition of cell proliferation, and decreased phosphorylation of Akt may mediate the inhibition of cell proliferation and invasion by COUP-TFII.


Asunto(s)
Factor de Transcripción COUP II/biosíntesis , Neoplasias Colorrectales/metabolismo , Fosfohidrolasa PTEN/biosíntesis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína p53 Supresora de Tumor/biosíntesis , Factor de Transcripción COUP II/metabolismo , Proliferación Celular/fisiología , Neoplasias Colorrectales/patología , Humanos , Fosfohidrolasa PTEN/metabolismo , Fosforilación , Transfección , Proteína p53 Supresora de Tumor/metabolismo
3.
Anticancer Res ; 40(2): 653-664, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014906

RESUMEN

BACKGROUND/AIM: Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of mitochondrial biogenesis and metabolism. We investigated the effect of PGC-1α knockdown in the human colorectal cancer cell line SW620, which highly expresses PGC-1α. MATERIALS AND METHODS: We established the PGC-1α shRNA-silenced SW620 stable cell line (PGC-1α shRNA-SW620 cells) and examined cell proliferation by cell counts and carboxyfluorescein succinimidyl ester (CFSE) staining, migration by wound-healing and transwell migration assay, and invasion by transwell assays. RESULTS: PGC-1α knockdown inhibited cell proliferation, migration, and invasion in SW620 cells. Western blot analysis showed that p-AKT, p-GSK-3ß, ß-catenin, N-cadherin and vimentin expression were all reduced, but E-cadherin had increased expression in PGC-1α shRNA-SW620 cells. We also examined cell proliferation, migration, invasion and the expression of p-AKT, p-GSK-3ß, ß-catenin, N-cadherin, vimentin, and E-cadherin in PGC-1α overexpressing SW480 cells (a low PGC-1α expressing line). We observed a complete reversal of the results seen in the knockdown. CONCLUSION: PGC-1α might regulate cell proliferation and invasion via AKT/GSK-3ß/ß-catenin pathway in SW620 and SW480 cells.


Asunto(s)
Glucógeno Sintasa Quinasa 3 beta/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , beta Catenina/metabolismo , Línea Celular Tumoral , Proliferación Celular/fisiología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Técnicas de Silenciamiento del Gen , Humanos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/biosíntesis , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Transducción de Señal , Transfección
4.
Adv Exp Med Biol ; 1226: 1-22, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32030672

RESUMEN

The tumour microenvironment (TME) of intestinal tumours is highly complex and comprises a network of stromal cells, tumour cells, immune cells and fibroblasts, as well as microorganisms. The tumour location, environmental factors and the tumour cells themselves influence the cells within the TME. Immune cells can destroy tumour cells and are associated with better patient prognosis and response to therapy; however, immune cells are highly plastic and easily influenced to instead promote tumour growth. The interaction between local immune cells and the microbiome can lead to progression or regression of intestinal tumours. In this chapter, we will discuss how tumour development and progression can influence, and be influenced by, the microenvironment surrounding it, focusing on immune and fibroblastic cells, and the intestinal microbiota, particularly in the context of colorectal cancer.


Asunto(s)
Neoplasias Intestinales , Microambiente Tumoral , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Humanos , Neoplasias Intestinales/inmunología , Neoplasias Intestinales/metabolismo , Neoplasias Intestinales/patología
5.
Life Sci ; 245: 117354, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-31987874

RESUMEN

Hepatitis B X-interacting protein (HBXIP) is highly expressed in many cancers, but the correlation between the expression of HBXIP and the clinical significance and underlying molecular mechanisms in colorectal cancer (CRC) is still unclear. We selected 186 specimens from CRC patients for analyzing the relationship between the expression of HBXIP and the clinical-pathological features by immunohistochemistry. Migration and invasion experiments were performed to examine the effect of HBXIP on CRC cell metastasis. Besides, we also explored the possible molecular mechanism of HBXIP regulation of CRC cell metastasis by Western blot. Our data indicated that the HBXIP was overexpressed in CRC tissues. High HBXIP expression was correlated with metastasis and shorter survival times in patients with CRC and served as an independent factor for poor prognosis. Moreover, HBXIP promotes CRC metastasis by enhancing the epithelial-mesenchymal transition (EMT) process. Our findings provide the first evidence that HBXIP induces EMT to promote metastasis and predicts the poor prognosis of CRC. Therefore, HBXIP may become a new target for CRC treatment.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias Colorrectales/diagnóstico , Transición Epitelial-Mesenquimal , Proteínas Adaptadoras Transductoras de Señales/análisis , Anciano , Biomarcadores de Tumor , Western Blotting , Línea Celular Tumoral , Neoplasias Colorrectales/química , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/fisiología , Femenino , Células HCT116 , Humanos , Masculino , Invasividad Neoplásica , Pronóstico , Análisis de Supervivencia
6.
Chemistry ; 26(9): 1947-1952, 2020 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-31909511

RESUMEN

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N')PtIV compounds derived from amine-imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Resistencia a Antineoplásicos , Platino (Metal)/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Complejos de Coordinación/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Conformación Molecular , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Espectrometría de Fluorescencia
7.
Gene ; 730: 144323, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-31917230

RESUMEN

The subjection of DNA to numerous lethal damages is threatening for the stability and integrity of the whole body genome. DNA damage response (DDR) is a critical phosphorylation-based signaling pathway developed for the maintaining of the genome against these threatens. Recent studies showed that various targets of DDR are involved in the activation of autophagy, as one of the important effectors of this signaling. The interplay between DDR and autophagy may have a critical role in the pathogenesis of various malignancies such as colorectal cancer, which can be a basement for the designing novel therapeutic strategies for combating this cancer type. On the other hand, autophagy is also demonstrated to be contributed to the regulation of DDR components. Therefore, in this review article, we will discuss the crosstalk between DDR and autophagy and their exact function in the pathogenesis of various human cancer types, with special attention on colorectal cancer.


Asunto(s)
Autofagia/genética , Neoplasias Colorrectales/metabolismo , Reparación del ADN/fisiología , Neoplasias del Colon/genética , Neoplasias Colorrectales/genética , Daño del ADN/fisiología , Inestabilidad Genómica/genética , Humanos , Transducción de Señal/genética
8.
Anticancer Res ; 40(1): 101-107, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892558

RESUMEN

BACKGROUND: Mitochondria are energy-producing organelles, and dysfunction in these organelles causes various types of disease. Although several studies have identified mutations in nuclear DNA that are associated with the etiology of ulcerative colitis (UC), information regarding mitochondrial DNA (mtDNA) in UC is limited. This study aimed to investigate the mitochondrial DNA polymorphism underlying the etiology of UC and UC-associated colorectal cancer. MATERIALS AND METHODS: Next-generation sequencing was performed to assess mitochondrial DNA mutations in 12 patients with UC-associated cancer. The mtDNA mutations in the non-neoplastic mucosa, tumor tissues, and healthy controls were compared. RESULTS: The incidence of mutations of nicotinamide adenine dinucleotide phosphate ubiquinone oxidase subunit, ATP synthetase, and tRNA was higher in non-neoplastic mucosa in those with UC compared with the healthy controls. However, no statistically significant differences were observed in mutations between the tumor tissues and non-neoplastic mucosa in UC. CONCLUSION: Significant mutations in mtDNA were observed in the non-neoplastic mucosa of patients with UC-associated cancer.


Asunto(s)
Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/genética , Neoplasias Colorrectales/etiología , Genes Mitocondriales , Polimorfismo Genético , Transformación Celular Neoplásica/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Susceptibilidad a Enfermedades , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Mutación
9.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892565

RESUMEN

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Asunto(s)
Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Biomarcadores , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Fluorouracilo/farmacología , Xenoinjertos , Humanos , Receptores de Hialuranos/genética , Ratones
10.
Anticancer Res ; 40(1): 177-190, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892566

RESUMEN

BACKGROUND/AIM: The chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) regulates cancer cell proliferation and invasion via complex molecular mechanisms. We aimed to investigate whether COUP-TFII modulates proliferation and invasion of the colorectal adenocarcinoma cell line HT-29. MATERIALS AND METHODS: HT-29 cells were stably tranfected with COUP-TFII shRNA plasmid to knock-down COUP-TFII (COUP-TFII shRNA-HT-29 cells). Cell proliferation, colony formation assay, invasion assay, microarray assays and western blot analyses were performed. RESULTS: Cell proliferation and invasion were significantly enhanced in COUP-TFII shRNA-HT-29 cells. The protein levels of forkhead box C1 (FOXC1), p-Akt, p-glycogen synthase kinase-3ß (p-GSK-3ß), and ß-catenin, which are known to be involved in cell proliferation and invasion, were significantly increased in COUP-TFII shRNA-HT-29 cells. Akt inhibitor IV and dominant negative (DN)-Akt expression vector transfection reversed the increased proliferation and invasion, which was accompanied by decreased protein levels of p-Akt, p-GSK-3ß, ß-catenin and FOXC1. CONCLUSION: COUP-TFII knock-down promoted proliferation and invasion via activation of Akt/GSK-3ß/ß-catenin and up-regulation of FOXC1. Further studies on the molecular mechanism of interaction between ß-catenin and FOXC1 expression may reveal novel target molecules for metastatic colorectal cancer therapy.


Asunto(s)
Factor de Transcripción COUP II/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor de Transcripción COUP II/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/patología , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , ARN Interferente Pequeño/genética
11.
Life Sci ; 244: 117300, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31953162

RESUMEN

MiR-346-5p is overexpressed in several cancers, including colorectal cancer (CRC). However, the effects of miR-346-5p on CRC progression have not yet been clarified. In our study, miR-346-5p levels in four CRC cell lines and normal human colon epithelial cells were determined by real-time PCR. SW620 and HCT116 cells were selected and then transfected with miR-346-5p mimic, miR-346-5p inhibitor, or specific siRNAs targeting F-box/LRR-repeat protein 2 (FBXL2). Cell proliferation, cell cycle distribution and cell cycle regulators were examined by CCK-8 assay, flow cytometry, and western blot. The binding of miR-346-5p on 3' untranslated region (UTR) of FBXL2 were verified by dual-luciferase reporter assay. CRC cells were co-transfected with miR-346-5p inhibitor and siFBXL2 to investigate the involvement of FBXL2. Interaction of FBXL2 with forkhead box M1 (FoxM1) was examined by co-immunoprecipitation (Co-IP) assay. The effect of miR-346-5p knockdown on CRC tumorigenesis in vivo was investigated. Here, we found that miR-346-5p overexpression promoted, while miR-346-5p knockdown inhibited cell proliferation and G1-S transition. Inhibition of FBXL2 showed similar effects as miR-346-5p overexpression. Moreover, we verified that FBXL2 was a direct target of miR-346-5p. FBXL2 interacted with FoxM1, and then negatively regulated both FoxM1 and nuclear ß-catenin levels. Additionally, FBXL2 knockdown reversed the effects of miR-346-5p inhibitor. In xenograft models, miR-346-5p knockdown significantly inhibited tumor growth, increased FBXL2 expression, and downregulated the levels of FoxM1 and nuclear ß-catenin. In conclusion, miR-346-5p may promote CRC growth by targeting FBXL2 and activating the ß-catenin signaling pathway. MiR-346-5p may be a novel target in cancer therapy.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Proteínas F-Box/metabolismo , MicroARNs/genética , Animales , Apoptosis/genética , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Proteínas F-Box/genética , Proteína Forkhead Box M1/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , Transducción de Señal/genética , Vía de Señalización Wnt/genética , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismo
12.
Chem Biol Interact ; 315: 108886, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31682804

RESUMEN

Colorectal cancer (CRC) is one of the most common malignancies, and multidrug resistance (MDR) reduces the efficiency of anticancer drugs. Therefore, the development of novel anticancer drugs that are highly active against CRC with MDR is urgently needed. Our previous study showed that 5-(3,4,5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) is not a P-glycoprotein (P-gp) substrate and has a potent anticancer effect against paclitaxel -sensitive or -resistant non-small-cell lung cancer (NSCLC) in vitro and in vivo. In the present study, we found that BZML exhibited strong anticancer activity not only in sensitive CRC cells (SW480 and HCT-116 cells) but also in intrinsically drug-resistant CRC cells (Caco2 cells). In addition, by targeting the colchicine binding site, BZML inhibited tubulin polymerization, which induced G2/M phase arrest, and it caused DNA damage by directly targeting DNA or producing ROS. Further, BZML induced apoptosis through the time-dependent ROS-mediated mitochondrial apoptotic pathway in the CRC cells. Additionally, BZML inhibited P-gp-mediated drug efflux and enhanced the inhibition of the cell growth that had been induced by paclitaxel or doxorubicin in Caco2 cells. In summary, BZML is a multi-targeted anticancer drug that targets tubulin and DNA, and the mechanisms underlying its potent anticancer activity involve disrupting microtubule assembly, causing DNA damage, inducing cell cycle arrest and eventually activating the ROS-mediated mitochondrial apoptotic pathway in SW480, HCT-116 and Caco2 cells. Therefore, the novel compound BZML is a promising anticancer drug that has tremendous potential for CRC treatment, especially for the treatment of drug-resistant CRC.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , ADN/metabolismo , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Imidazoles/farmacología , Tubulina (Proteína)/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Apoptosis/efectos de los fármacos , Células CACO-2 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Daño del ADN/efectos de los fármacos , Doxorrubicina/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HCT116 , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Paclitaxel/farmacología
13.
Gene ; 726: 144132, 2020 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-31669643

RESUMEN

The NF-κB signaling pathway is a key regulator of CRC cell proliferation, apoptosis, angiogenesis, inflammation, metastasis, and drug resistance. Over-activation of the NF-κB pathway is a feature of colorectal cancer (CRC). While new combinatorial treatments have improved overall patient outcome; quality of life, cost of care, and patient survival rate have seen little improvement. Suppression of the NF-κB signaling pathway using biological or specific pharmacological inhibitors is a potential therapeutic approach in the treatment of colon cancer. This review summarizes the regulatory role of NF-κB signaling pathway in the pathogenesis of CRC for a better understanding and hence a better management of the disease.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , FN-kappa B/metabolismo , Transducción de Señal/fisiología , Animales , Apoptosis/fisiología , Proliferación Celular/fisiología , Humanos , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Calidad de Vida , Tasa de Supervivencia
14.
Cancer Sci ; 111(1): 137-147, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31724799

RESUMEN

As a member of the epidermal growth factor receptor (EGFR) family, ERBB3 plays an essential role in development and disease independent of inherently inactive kinase domain. Recently, ERBB3 has been found to bind to ATP and has catalytic activity in vitro. However, the biological function of ERBB3 kinase activity remains elusive in vivo. Here we have identified the physiological function of inactivated ERBB3 kinase activity by creating Erbb3-K740M knockin mice in which ATP cannot bind to ERBB3. Unlike Erbb3 knockout mice, kinase-inactive Erbb3K740M homozygous mice were born in Mendelian ratios and showed normal development. After dextran sulfate sodium-induced colitis, the kinase-inactive Erbb3 mutant mice showed normal recovery. However, the outgrowth of ileal organoids by neuregulin-1 treatment was more attenuated in Erbb3 mutant mice than in WT mice. Moreover, in combination with the ApcMin mouse, the proportion of polyps less than 1 mm in diameter in mutant mice was higher than in control mice and an increase in the number of apoptotic cells was observed in polyps from mutant mice compared with polyps from control mice. Taken together, the ERBB3 kinase activity contributes to the outgrowth of ileal organoids and intestinal tumorigenesis, and the development of ERBB3 kinase inhibitors, including epidermal growth factor receptor family members, can be a potential way to target colorectal cancer.


Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Intestinos/patología , Organoides/metabolismo , Organoides/patología , Receptor ErbB-3/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Carcinogénesis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Intestinos/efectos de los fármacos , Ratones , Ratones Noqueados , Organoides/efectos de los fármacos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Pólipos/tratamiento farmacológico , Pólipos/patología , Inhibidores de Proteínas Quinasas/farmacología
15.
Life Sci ; 241: 117114, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31790687

RESUMEN

AIMS: Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide. Over-expression of tetraspanin 8 (TSPAN8) is related to the development and progression of CRC. Whether TSPAN8 plays a role in the growth of colorectal cancer and its epigenetic mechanisms regulated by Lysine Specific Demethylase 1 (LSD1) are still unknown. MAIN METHODS: In this study, RT-PCR and western blotting were used to analyze the mRNA and protein expression, respectively; cell viability was assayed with MTS analysis; cell migration was measured with Trans-well analysis. KEY FINDINGS: In the present study, the results indicated that the mRNA levels of LSD1 and TSPAN8 in CRC were significantly higher than that in corresponding adjacent non-tumor tissue. Down-regulation of LSD1 or TSPAN8 as well as LSD1 inhibitor Tranylcypromine hemisulfate inhibited the proliferation and migration of CRC cells, while over-expression of LSD1 exhibited opposite effects. LSD1 up-regulated TSPAN8 expression and reduced H3K9me2 occupancy on the TSPAN8 promoter in CRC cells. TSPAN8 promoted epithelial-mesenchymal transition (EMT) in CRC cells in LSD1-dependent manner. SIGNIFICANCE: TSPAN8 may be considered as a promising biomarker for the diagnosis and prognosis in patients with CRC. Furthermore, TSPAN8 could be a novel therapeutic target and potent LSD1 inhibitors could be designed and developed in the treatment of CRC.


Asunto(s)
Neoplasias Colorrectales/patología , Histona Demetilasas/metabolismo , Tetraspaninas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas/genética , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilación , Regiones Promotoras Genéticas , Tetraspaninas/genética
16.
Gene ; 727: 144232, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31715300

RESUMEN

Colorectal cancer (CRC) is a global disease with high incidence and mortality rate. Hsp90 inhibitors induce cell death in various cancers, including CRC. However, the underlying mechanisms need to be clarified further. In this study, Caco-2 cells were treated with 0.25 µM SNX-2112, an Hsp90 inhibitor, for 48 h; subsequently, whole-transcriptome sequencing was performed. At the mRNA level in SNX-2112-treated Caco-2 cells, 1588 genes were upregulated, and 433 genes were downregulated. Six genes were found to be associated with necroptosis and apoptosis, and these 6 upregulated genes were validated by RT-qPCR. Hundred and six miRNAs were upregulated, and 48 miRNAs were downregulated in SNX-2112-treated Caco-2 cells. Eleven downregulated miRNAs were found to interact with the 6 upregulated genes. Moreover, 676 circRNAs were upregulated, and 291 circRNAs were downregulated in SNX-2112-treated Caco-2 cells. Among them, 126 circRNAs were found to be the target of the 11 downregulated miRNAs. The circRNA-miRNA-mRNA regulatory network of Hsp90 inhibitor-induced cell death in colorectal cancer was constructed. This regulatory network extends the underlying mechanism of Hsp90 and improves our understanding of Hsp90 inhibitors as potential targeted therapeutic agents.


Asunto(s)
Neoplasias Colorrectales/genética , Redes Reguladoras de Genes/genética , Células CACO-2 , Neoplasias del Colon/genética , Neoplasias Colorrectales/metabolismo , Regulación hacia Abajo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/genética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/genética , ARN/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia Arriba
17.
Life Sci ; 244: 116936, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31610194

RESUMEN

AIMS: Long non-coding RNAs (lncRNAs) play key roles in regulating multiple cancers. TTN-AS1 was reported to function in several human malignancies. However, the biological function of TTN-AS1 in colorectal cancer (CRC) has not been explored. In this study, we aimed to investigate the role and the underlying mechanisms of TTN-AS1 in CRC progression. MAIN METHODS: RT-qPCR was used to detect the expression levels of TTN-AS1, miR-376a-3p and KLF15 in colorectal cancer tissues and cells. CCK-8, colony formation, flow cytometry and transwell assays were performed to determine the cell proliferation, apoptotic rate and invasion ability. Target genes were predicted using bioinformatics methods. si-RNA and miRNA inhibitor were transfected into CRC cells to explore the underlying mechanisms. Tumor xenografts were created to confirm the function of TTN-AS-1 in vivo. KEY FINDINGS: TTN-AS1 upregulation was observed both in CRC tissues and cell lines. Functional investigation showed that knockdown of TTN-AS1 inhibited CRC cell proliferation and invasion, while enhanced cell apoptosis. Bioinformatics analysis identified miR-376a-3p as a target of TTN-AS1. Transfection of miR-376a-3p inhibitor mitigated the alterations induced by TTN-AS1 knockdown. Moreover, TTN-AS1 positively regulated KLF15 via sponging miR-376a-3p. Additionally, these findings were supported by in vivo experiments. SIGNIFICANCE: In conclusions, TTN-AS1 promoted CRC proliferation and invasion through miR-376a-3p/KLF15 axis. Our findings suggested that TTN-AS1 might be a potential therapeutic target in CRC treatment.


Asunto(s)
Neoplasias Colorrectales/genética , Conectina/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , MicroARNs/genética , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , China , Neoplasias Colorrectales/metabolismo , Conectina/metabolismo , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , ARN sin Sentido/genética , ARN sin Sentido/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Regulación hacia Arriba
18.
Cancer Sci ; 111(2): 477-488, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31840304

RESUMEN

ATP6L, the C subunit of the V-ATPase V0 domain, is involved in regulating the acidic tumor micro-environment and may promote tumor progression. However, the expression and functional role of ATP6L in tumors have not yet been well explored. In this study, we found that ATP6L protein overexpression was related to colorectal cancer histological differentiation (P < 0.001), presence of metastasis (P < 0.001) and recurrence (P = 0.02). ATP6L expression in the liver metastatic foci was higher than in the primary foci (P = 0.04). ATP6L expression was notably concomitant with epithelial-mesenchymal transition (EMT) immunohistochemical features, such as reduced expression of the epithelial marker E-cadherin (P = 0.021) and increased expression of the mesenchymal marker vimentin (P = 0.004). Results of in vitro and in vivo experiments showed that ATP6L expression could alter cell morphology, regulate EMT-associated protein expression, and enhance migration and invasion. The effect of ATP6L on metastasis was further demonstrated in a tail vein injection mice model. In addition, the mouse xenograft model showed that ATP6L-overexpressing HCT116 cells grew into larger tumor masses, showed less necrosis and formed more micro-vessels than the control cells. Taken together, our results suggest that ATP6L promotes metastasis of colorectal cancer by inducing EMT and angiogenesis, and is a potential target for tumor therapy.


Asunto(s)
Neoplasias Colorrectales/patología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , ATPasas de Translocación de Protón Vacuolares/metabolismo , Animales , Antígenos CD/metabolismo , Cadherinas/metabolismo , Movimiento Celular , Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal , Femenino , Células HCT116 , Células HT29 , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Trasplante de Neoplasias , Pronóstico , Vimentina/metabolismo
19.
Int J Cancer ; 146(7): 1780-1790, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31291465

RESUMEN

The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids-microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids-microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Animales , Ácidos y Sales Biliares/metabolismo , Terapia Biológica , Biomarcadores , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Disbiosis , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Mucosa Intestinal/patología , Redes y Vías Metabólicas/efectos de los fármacos , Terapia Molecular Dirigida , Unión Proteica , Receptores Citoplasmáticos y Nucleares/metabolismo
20.
Int J Cancer ; 146(6): 1700-1716, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31381140

RESUMEN

Long noncoding RNAs (lncRNAs) are involved in the pathology of colorectal cancer (CRC). Current efforts to eradicate CRC predominantly focused on targeting the proliferation of rapidly growing cancer epithelial cells. This is largely ineffective with resistance arising in most tumors after exposure to chemotherapy. Despite the long-standing recognition of the crosstalk between carcinoma-associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment, how CAFs may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that lncRNA CCAL (colorectal cancer-associated lncRNA) promotes oxaliplatin (Oxa) resistance of CRC cells. RNA-ISH shows higher CCAL expressed in the tumor stroma compared to cancer nests of CRC tissues. Functional studies reveal that CCAL is transferred from CAFs to the cancer cells via exosomes, where it suppresses CRC cell apoptosis, confers chemoresistance and activates ß-catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase ß-catenin mRNA and protein levels. Our findings indicate that CCAL expressed by CAFs of the colorectal tumor stroma contributes to tumor chemoresistance and CCAL may serve as a potential therapeutic target for Oxa resistance.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos/genética , Exosomas/metabolismo , ARN Largo no Codificante/genética , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Ratones , Interferencia de ARN , ARN Mensajero/genética , Transducción de Señal , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismo
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