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1.
Int J Mol Sci ; 21(23)2020 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-33266352

RESUMEN

Nuclear factor-κB (NF-κB) is an important transcription factor involved in various biological functions, including tumorigenesis. Hence, NF-κB has attracted attention as a target factor for cancer treatment, leading to the development of several inhibitors. However, existing NF-κB inhibitors do not discriminate between its subunits, namely, RelA, RelB, cRel, p50, and p52. Conventional methods used to evaluate interactions between transcription factors and DNA, such as electrophoretic mobility shift assay and luciferase assays, are unsuitable for high-throughput screening (HTS) and cannot distinguish NF-κB subunits. We developed a HTS method named DNA strand exchange fluorescence resonance energy transfer (DSE-FRET). This assay is suitable for HTS and can discriminate a NF-κB subunit. Using DSE-FRET, we searched for RelA-specific inhibitors and verified RelA inhibition for 32,955 compounds. The compound A55 (2-(3-carbamoyl-6-hydroxy-4-methyl-2-oxopyridin-1(2H)-yl) acetic acid) selectively inhibited RelA-DNA binding. We propose that A55 is a seed compound for RelA-specific inhibition and could be used in clinical applications.

2.
Molecules ; 25(11)2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32492961

RESUMEN

Drug resistance is a major problem for breast cancer patients. Docetaxel is an anti-mitotic agent that serves as first line of treatment in metastatic breast cancer, however it is susceptible to cellular drug resistance. Drug-resistant cells are able to spread during treatment, leading to treatment failure and eventually metastasis, which remains the main cause for cancer-associated death. In previous studies, we used single-cell technologies and identified a set of genes that exhibit increased expression in drug-resistant cells, and they are mainly regulated by Lef1. Furthermore, upregulating Lef1 in parental cells caused them to become drug resistant. Therefore, we hypothesized that inhibiting Lef1 could resensitize cells to docetaxel. Here, we confirmed that Lef1 inhibition, especially on treatment with the small molecule quercetin, decreased the expression of Lef1 and resensitized cells to docetaxel. Our results demonstrate that Lef1 inhibition also downregulated ABCG2, Vim, and Cav1 expression and equally decreased Smad-dependent TGF-ß signaling pathway activation. Likewise, these two molecules worked in a synergetic manner, greatly reducing the viability of drug-resistant cells. Prior studies in phase I clinical trials have already shown that quercetin can be safely administered to patients. Therefore, the use of quercetin as an adjuvant treatment in addition to docetaxel for the treatment of breast cancer may be a promising therapeutic approach.

3.
Mol Cancer Res ; 18(9): 1271-1277, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32513897

RESUMEN

The mechanism of cancer induction involves an aberrant expression of oncogenes whose functions can be controlled by RNAi with miRNA. Even foreign bacterial RNA may interfere with the expression of oncogenes. Here we show that bacterial plasmid mucAB and its Escherichia coli genomic homolog umuDC, carrying homologies that match the mouse anti-miR-145, sequestered the miR-145 function in mouse BALB 3T3 cells in a tetracycline (Tet)-inducible manner, activated oncogene Nedd9 and its downstream Aurkb, and further enhanced microcolony formation and cellular transformation as well as the short fragments of the bacterial gene containing the anti-miR-145 sequence. Furthermore, mucAB transgenic mice showed a 1.7-fold elevated tumor incidence compared with wild-type mice after treatments with 3-methylcolanthrene. However, the mutation frequency in intestinal stem cells of the mucAB transgenic mice was unchanged after treatment with X-rays or ethyl-nitrosourea, indicating that the target of mucAB/umuDC is the promotion stage in carcinogenesis. IMPLICATIONS: Foreign bacterial genes can exert oncogenic activity via RNAi, if endogenously expressed. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/9/1271/F1.large.jpg.

4.
Cancer Sci ; 111(5): 1856-1861, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32249523

RESUMEN

The telomere G-tail (G-tail) plays an essential role in maintaining chromosome stability. In this study, we assessed the leukocyte G-tail length of breast cancer (BC) patients and cancer-free individuals and evaluated the association between the G-tail length and the presence of BC. A significant shortening of the median G-tail length was observed in BC patients compared with cancer-free individuals and was found in the early phase of BC. Our study indicated that the leukocyte G-tail length might be a potential biomarker for BC detection.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Leucocitos/ultraestructura , Telómero/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/sangre , Neoplasias de la Mama/ultraestructura , Detección Precoz del Cáncer , Femenino , Humanos , Persona de Mediana Edad , Acortamiento del Telómero
5.
Cancers (Basel) ; 12(4)2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32244823

RESUMEN

Cisplatin (cis-diamminedichloroplatinum II [CDDP] ) is a well-known chemotherapeutic drug that has been used for the treatment of various types of human cancers, including head and neck cancer. Cisplatin exerts anticancer effects by causing DNA damage, replication defects, transcriptional inhibition, cell cycle arrest, and the induction of apoptosis. However, drug resistance is one of the most serious problems with cancer chemotherapy, and it causes expected therapeutic effects to not always be achieved. Here, we analyzed global microRNA (miRNA) expression in CD44 standard form (CD44s)-expressing SAS cells, and we identified miR-629-3p as being responsible for acquiring anticancer drug resistance in head and neck cancer. The introduction of miR-629-3p expression inhibited apoptotic cell death under cisplatin treatment conditions, and it promoted cell migration. Among the computationally predicted target genes of miR-629-3p, we found that a number of gene expressions were suppressed by the transfection with miR-629-3p. Using a xenografting model, we showed that miR-629-3p conferred cisplatin resistance to SAS cells. Clinically, increased miR-629-3p expression tended to be associated with decreased survival in head and neck cancer patients. In conclusion, our data suggest that the increased expression of miR-629-3p provides a mechanism of cisplatin resistance in head and neck cancer and may serve as a therapeutic target to reverse chemotherapy resistance.

6.
Cancer Sci ; 111(6): 2104-2115, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32215990

RESUMEN

Emerging evidence indicates that small RNAs, including microRNAs (miRNAs) and their isoforms (isomiRs), and transfer RNA fragments (tRFs), are differently expressed in breast cancer (BC) and can be detected in blood circulation. Circulating small RNAs and small RNAs in extracellular vesicles (EVs) have emerged as ideal markers in small RNA-based applications for cancer detection. In this study, we first undertook small RNA sequencing to assess the expression of circulating small RNAs in the serum of BC patients and cancer-free individuals (controls). Expression of 3 small RNAs, namely isomiR of miR-21-5p (3' addition C), miR-23a-3p and tRF-Lys (TTT), was significantly higher in BC samples and was validated by small RNA sequencing in an independent cohort. Our constructed model using 3 small RNAs showed high diagnostic accuracy with an area under the receiver operating characteristic curve of 0.92 and discriminated early-stage BCs at stage 0 from control. To test the possibility that these small RNAs are released from cancer cells, we next examined EVs from the serum of BC patients and controls. Two of the 3 candidate small RNAs were identified, and shown to be abundant in EVs of BC patients. Interestingly, these 2 small RNAs are also more abundantly detected in culture media of breast cancer cell lines (MCF-7 and MDA-MB-231). The same tendency in selective elevation seen in total serum, serum EV, and EV derived from cell culture media could indicate the efficiency of this model using total serum of patients. These findings indicate that small RNAs serve as significant biomarkers for BC detection.


Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias de la Mama/diagnóstico , MicroARN Circulante/sangre , Vesículas Extracelulares , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Neoplasias de la Mama/sangre , Femenino , Humanos , Persona de Mediana Edad , Sensibilidad y Especificidad
7.
Cancer Sci ; 111(4): 1058-1064, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32073717

RESUMEN

Dysregulation or mutation of DNA binding proteins such as transcription factors (TFs) is associated with the onset and progression of various types of disease, including cancer. Alteration of TF activity occurs in numerous cancer tissues due to gene amplification, deletion, and point mutations, and epigenetic modification. Although cancer-associated TFs are promising targets for cancer therapy, development of drugs targeting these TFs has historically been difficult due to the lack of high-throughput screening methods. Recent advances in technology for identification and selective inhibition of DNA binding proteins enable cancer researchers to develop novel therapeutics targeting cancer-associated TFs. In the present review, we summarize known cancer-associated TFs according to cancer type and introduce recently developed high-throughput approaches to identify selective inhibitors of cancer-associated TFs.


Asunto(s)
Proteínas de Unión al ADN/genética , Terapia Molecular Dirigida , Neoplasias/genética , Factores de Transcripción/genética , Sitios de Unión/genética , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/uso terapéutico , Epigénesis Genética/genética , Humanos , Neoplasias/terapia , Unión Proteica/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/uso terapéutico
8.
J Child Neurol ; 35(3): 208-214, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31709864

RESUMEN

OBJECTIVE: The present study aimed to determine whether granzymes are implicated in the pathogenesis of infection-associated acute encephalopathy (AE). METHODS: We investigated granzyme and cytokine levels in the cerebrospinal fluid of patients with acute encephalopathy or complex febrile seizures (cFS). A total of 24 acute encephalopathy patients and 22 complex febrile seizures patients were included in the present study. Levels of granzymes A and B were measured using enzyme-linked immunosorbent assay, and levels of tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ), interleukin 1ß (IL-1ß), IL-1 receptor antagonist (IL-1RA), IL-4, IL-6, IL-8, and IL-10 were assessed using the Bio-Plex suspension array system. RESULTS: Cerebrospinal fluid levels of granzyme A were significantly higher, and those of TNF-α and IL-1RA were significantly lower in the AE group than in the cFS group; however, no significant differences in the levels of granzyme B, IFN-γ, IL-1ß, IL-4, IL-6, IL-8, and IL-10 were observed between the 2 groups. In addition, no significant differences in granzyme A, granzyme B, or cytokine levels were observed between acute encephalopathy patients with and those without neurologic sequelae. CONCLUSIONS: Our findings indicate the involvement of granzyme A in the pathogenesis of acute encephalopathy.

9.
J Clin Med ; 8(11)2019 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-31766189

RESUMEN

Many types of cells secrete DNA, RNA, and proteins through microvesicles, such as exosomes and apoptotic bodies, for the purpose of extracellular communication [...].

10.
Cancer Res ; 79(17): 4412-4425, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31289135

RESUMEN

Drug resistance is a major obstacle in the treatment of breast cancer. Surviving cells lead to tumor recurrence and metastasis, which remains the main cause of cancer-related mortality. Breast cancer is also highly heterogeneous, which hinders the identification of individual cells with the capacity to survive anticancer treatment. To address this, we performed extensive single-cell gene-expression profiling of the luminal-type breast cancer cell line MCF7 and its derivatives, including docetaxel-resistant cells. Upregulation of epithelial-to-mesenchymal transition and stemness-related genes and downregulation of cell-cycle-related genes, which were mainly regulated by LEF1, were observed in the drug-resistant cells. Interestingly, a small number of cells in the parental population exhibited a gene-expression profile similar to that of the drug-resistant cells, indicating that the untreated parental cells already contained a rare subpopulation of stem-like cells with an inherent predisposition toward docetaxel resistance. Our data suggest that during chemotherapy, this population may be positively selected, leading to treatment failure. SIGNIFICANCE: This study highlights the role of breast cancer intratumor heterogeneity in drug resistance at a single-cell level.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos/genética , Factor de Unión 1 al Potenciador Linfoide/genética , Análisis de la Célula Individual/métodos , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Caveolina 1/genética , Caveolina 2/genética , Línea Celular Tumoral , Docetaxel/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , MicroARNs/genética , Células Madre Neoplásicas/patología , Vimentina/genética , Vía de Señalización Wnt/genética
11.
Oncogene ; 38(28): 5566-5579, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31147602

RESUMEN

Cancer-associated fibroblasts (CAFs), one of the major components of a tumour microenvironment, comprise heterogeneous populations involved in tumour progression. However, it remains obscure how CAF heterogeneity is governed by cancer cells. Here, we show that cancer extracellular vesicles (EVs) induce a series of chemokines in activated fibroblasts and contribute to the formation of the heterogeneity. In a xenograft model of diffuse-type gastric cancer, we showed two distinct fibroblast subpopulations with alpha-smooth muscle actin (α-SMA) expression or chemokine expression. MicroRNAs (miRNAs) profiling of the EVs and the transfection experiment suggested that several miRNAs played a role in the induction of chemokines such as CXCL1 and CXCL8 in fibroblasts, but not for the myofibroblastic differentiation. Clinically, aberrant activation of CXCL1 and CXCL8 in CAFs correlated with poorer survival in gastric cancer patients. Thus, this link between chemokine expression in CAFs and tumour progression may provide novel targets for anticancer therapy.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Quimiocina CXCL1/biosíntesis , Vesículas Extracelulares/metabolismo , Interleucina-8/biosíntesis , Neoplasias Gástricas/patología , Células del Estroma/patología , Actinas/metabolismo , Animales , Línea Celular Tumoral , Xenoinjertos , Humanos , Ratones , Neoplasias Gástricas/metabolismo , Microambiente Tumoral
12.
Cancer Sci ; 110(4): 1140-1147, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30729639

RESUMEN

Over the past few decades, siRNA and miRNA have attracted a great deal of attention from researchers and clinicians. These molecules have been extensively studied from the standpoint of developing biopharmaceuticals against various diseases, including heart disease, diabetes and cancers. siRNA suppresses only a single target, whereas each miRNA regulates the expression of multiple target genes. More importantly, because miRNA are also secreted from cancer cells, and their aberrant expression is associated with tumor development and progression, they represent not only therapeutic targets but also promising biomarkers for diagnosis and prognosis. Therefore, miRNA may be more effective tools against cancers, in which multiple signal pathways are dysregulated. In this review, we summarize recent progress in the development of miRNA therapeutics for the treatment of cancer patients, and describe delivery systems for oligonucleotide therapeutics.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias/genética , Neoplasias/terapia , Interferencia de ARN , Tratamiento con ARN de Interferencia , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Técnicas de Transferencia de Gen , Humanos , Metástasis de la Neoplasia , Neoplasias/metabolismo , Neoplasias/patología , ARN Mensajero/genética
13.
Gan To Kagaku Ryoho ; 45(6): 899-905, 2018 Jun.
Artículo en Japonés | MEDLINE | ID: mdl-30026410

RESUMEN

MicroRNAs(miRNAs)are small non-coding RNAs that function in diverse biological processes and are approximately 20-22 nucleotide RNAs that regulate the expression of target genes, mainly at the post-transcriptional level. A number of studies report that miRNAs are involved in homeostatic maintenance such as cell cycle regulation, cell division and apoptosis, and that aberrant expression of miRNAs is often detected in various types of diseases, including cancer. In cancer biology, miRNAs play functional roles in tumor seeding, drug sensitivity, and metastasis. MiRNAs are also secreted through the small vesicles called exosomes, which are endosome-derived vesicles from various cell types including immune and tumor cells. In addition to cellular miRNAs, secreted miRNAs also play important roles in cancer development and metastasis. Therefore, secreted miRNAs in body fluids have been investigated as a promising biomarkers and therapeutic targets for the treatment of cancer patients. In this review, we introduce the current knowledge of miRNA functions in cancer development and discuss the clinical applications of se-miRNAs, eg, as diagnostic markers and therapeutic targets.


Asunto(s)
Biomarcadores de Tumor/genética , Líquidos Corporales , Detección Precoz del Cáncer/métodos , MicroARNs/análisis , Neoplasias/diagnóstico , Neoplasias/genética , Líquidos Corporales/química , Exosomas , Humanos , MicroARNs/genética , Neoplasias/tratamiento farmacológico
14.
Oncotarget ; 9(11): 10029-10041, 2018 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-29515788

RESUMEN

A number of studies report that epithelial to mesenchymal transition (EMT) supports the generation and maintenance of cancer stem cells (CSCs), which show tumor seeding ability and drug resistance; however, the molecular mechanisms underlying induction of EMT-associated tumor malignancy remain unclear. The present study reports that oral cancer cells switch from expressing the CD44 variant form (CD44v) to expressing the standard form (CD44s) during acquisition of cisplatin-resistance, which resulted in EMT induction. CD44s induced an EMT phenotype in cisplatin resistant cells by up-regulating ZEB1, a transcriptional repressor of E-cadherin. More importantly, CD44s up-regulated ZEB1 by suppressing microRNA-200c, which is a non-coding RNA that directly represses the ZEB1 gene. These results demonstrate the importance of the association between platinum resistance and CD44s during EMT induction in oral cancer cells.

15.
Int J Mol Sci ; 18(12)2017 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-29194401

RESUMEN

Drug resistance represents one of the greatest challenges in cancer treatment. Cancer stem cells (CSCs), a subset of cells within the tumor with the potential for self-renewal, differentiation and tumorigenicity, are thought to be the major cause of cancer therapy failure due to their considerable chemo- and radioresistance, resulting in tumor recurrence and eventually metastasis. CSCs are situated in a specialized microenvironment termed the niche, mainly composed of fibroblasts and endothelial, mesenchymal and immune cells, which also play pivotal roles in drug resistance. These neighboring cells promote the molecular signaling pathways required for CSC maintenance and survival and also trigger endogenous drug resistance in CSCs. In addition, tumor niche components such as the extracellular matrix also physically shelter CSCs from therapeutic agents. Interestingly, CSCs contribute directly to the niche in a bilateral feedback loop manner. Here, we review the recent advances in the study of CSCs, the niche and especially their collective contribution to resistance, since increasingly studies suggest that this interaction should be considered as a target for therapeutic strategies.


Asunto(s)
Resistencia a Antineoplásicos , Matriz Extracelular/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/patología , Diferenciación Celular , Transición Epitelial-Mesenquimal , Retroalimentación Fisiológica , Redes Reguladoras de Genes , Humanos , Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Microambiente Tumoral
16.
PLoS One ; 12(11): e0187638, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29141042

RESUMEN

Since breast cancers in young women are generally aggressive, young patients tend to be intensively treated with anti-cancer drugs. To optimize the strategy for treatment, particularly in young women, prognostic biomarkers are urgently required. The objective of this study was to identify a tissue microRNA (miRNA) signature that predicts prognosis in young breast cancer patients. Total RNA from 45 breast cancer patients aged <35 years was extracted from formalin-fixed paraffin-embedded (FFPE) tissues and analyzed using miRNA microarrays. Patients were categorized into two groups according to recurrence status within the 5 year period after surgery: recurrence (n = 11) and non-recurrent (n = 34). Histological parameters of hormone receptors and Ki-67 were statistically compared between the two groups. Differentially expressed miRNAs were identified, and their associations with overall survival (OS) were evaluated by log-rank test. The median observation period was 5.8 years for the recurrent group, and 9.1 years for the non-recurrent group. Nine miRNAs were significantly differentially expressed between the recurrent and non-recurrent groups. Receiver Operating Characteristic curve analysis was performed to evaluate the prediction accuracy of the identified miRNAs, and the resultant area under the curve was >0.7. Five of the miRNAs were validated by qRT-PCR, and the expression levels of three of those five (miR-183-5p, miR-194-5p, and miR-1285-5p), both alone and in combination, were associated with OS. In conclusion, we identified three candidate miRNAs that could be used separately or in combination as prognostic biomarkers in young breast cancer patients. This miRNA signature may enable selection of better treatment choices for young women with this disease.


Asunto(s)
Neoplasias de la Mama/patología , MicroARNs/genética , Adulto , Neoplasias de la Mama/genética , Femenino , Humanos , Pronóstico
17.
Clin Chem Lab Med ; 55(5): 648-656, 2017 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-28231055

RESUMEN

microRNAs (miRNAs) constitute a large family of small, approximately 20-22 nucleotide non-coding RNAs that regulate the expression of target genes, mainly at the post-transcriptional level. Multiple studies report that miRNAs are involved in homeostatic maintenance and that aberrant expression of miRNAs is often observed in various types of diseases, including cancer. In cancer biology, miRNAs exert functional roles in tumor initiation, drug resistance, and metastasis. miRNAs are also secreted through small vesicles called exosomes, which are endosome-derived vesicles derived from various cell types including immune and tumor cells. In addition to cellular miRNAs (ce-miRNAs), secreted miRNAs (se-miRNAs) play important roles in cancer development and metastasis. Therefore, se-miRNAs in body fluids have been investigated as a promising biomarkers and therapeutic targets for cancer treatment. In this review, we summarize the current knowledge of miRNA functions in cancer development and discuss the potential clinical applications of se-miRNAs, e.g. as diagnostic markers and therapeutic targets.


Asunto(s)
Exosomas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/genética , Neoplasias/patología , Exosomas/genética , Humanos , MicroARNs/biosíntesis , Neoplasias/diagnóstico , Neoplasias/terapia
18.
Cell Stem Cell ; 20(1): 41-55, 2017 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-27840021

RESUMEN

A challenge for advancing approaches to liver regeneration is loss of functional differentiation capacity when hepatocyte progenitors are maintained in culture. Recent lineage-tracing studies have shown that mature hepatocytes (MHs) convert to an immature state during chronic liver injury, and we investigated whether this conversion could be recapitulated in vitro and whether such converted cells could represent a source of expandable hepatocytes. We report that a cocktail of small molecules, Y-27632, A-83-01, and CHIR99021, can convert rat and mouse MHs in vitro into proliferative bipotent cells, which we term chemically induced liver progenitors (CLiPs). CLiPs can differentiate into both MHs and biliary epithelial cells that can form functional ductal structures. CLiPs in long-term culture did not lose their proliferative capacity or their hepatic differentiation ability, and rat CLiPs were shown to extensively repopulate chronically injured liver tissue. Thus, our study advances the goals of liver regenerative medicine.


Asunto(s)
Linaje de la Célula , Hepatocitos/citología , Regeneración , Células Madre/citología , Amidas/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Reprogramación Celular/efectos de los fármacos , Quimera/metabolismo , Diploidia , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hígado/efectos de los fármacos , Hígado/lesiones , Hígado/patología , Regeneración Hepática/efectos de los fármacos , Ratones , Pirazoles/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Ratas , Regeneración/efectos de los fármacos , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/farmacología , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Tiosemicarbazonas/farmacología , Factores de Tiempo
19.
Cancer Res ; 76(1): 150-60, 2016 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-26669863

RESUMEN

The establishment of cancer stem-like cell (CSC) culture systems may be instrumental in devising strategies to fight refractory cancers. Inhibition of the Rho kinase ROCK has been shown to favorably affect CSC spheroid cultures. In this study, we show how ROCK inhibition in human serous ovarian cancer (SOC) cells can help establish a CSC system, which illuminates cancer pathophysiology and its treatment in this setting. In the presence of a ROCK kinase inhibitor, spheroid cultures of SOC cells expressed characteristic CSC markers including ALDH1A1, CD133, and SOX2, along with differentiation and tumorigenic capabilities in mouse xenograft models of human SOC. High expression levels of ALDH, but not CD133, correlated with spheroid formation CSC marker expression and tumor forming capability. In clinical specimens of SOC, high levels of ALDH1A1 correlated with advanced stage and poor prognosis. Pharmacologic or genetic blockade of ALDH blocked cell proliferation and reduced expression of SOX2, the genetic ablation of which abolished spheroid formation, whereas SOX2 overexpression inhibited ALDH1A1 expression and blocked spheroid proliferation. Taken together, our findings illustrated a new method to culture human ovarian CSC, and they defined a reciprocal regulatory relationship between ALDH1A1 and SOX2, which impacts ovarian CSC proliferation and malignant progression.


Asunto(s)
Neoplasias Glandulares y Epiteliales/patología , Células Madre Neoplásicas/patología , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Proliferación Celular/fisiología , Femenino , Humanos , Inmunohistoquímica , Neoplasias Glandulares y Epiteliales/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/metabolismo
20.
PLoS One ; 10(6): e0130808, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26110809

RESUMEN

Diffuse-type solid tumors are often composed of a high proportion of rarely proliferating (i.e., dormant) cancer cells, strongly indicating the involvement of cancer stem cells (CSCs) Although diffuse-type gastric cancer (GC) patients have a poor prognosis due to high-frequent development of peritoneal dissemination (PD), it is limited knowledge that the PD-associated CSCs and efficacy of CSC-targeting therapy in diffuse-type GC. In this study, we established highly metastatic GC cell lines by in vivo selection designed for the enrichment of PD-associated GC cells. By microarray analysis, we found C-X-C chemokine receptor type 4 (CXCR4) can be a novel marker for highly metastatic CSCs, since CXCR4-positive cells can grow anchorage-independently, initiate tumors in mice, be resistant to cytotoxic drug, and produce differentiated daughter cells. In clinical samples, these CXCR4-positive cells were found from not only late metastasis stage (accumulated ascites) but also earlier stage (peritoneal washings). Moreover, treatment with transforming growth factor-ß enhanced the anti-cancer effect of docetaxel via induction of cell differentiation/asymmetric cell division of the CXCR4-positive gastric CSCs even in a dormant state. Therefore, differentiation inducers hold promise for obtaining the maximum therapeutic outcome from currently available anti-cancer drugs through re-cycling of CSCs.


Asunto(s)
Células Madre Neoplásicas/metabolismo , Receptores CXCR4/metabolismo , Neoplasias Gástricas/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Docetaxel , Humanos , Ratones , Células Madre Neoplásicas/patología , Neoplasias Gástricas/patología , Taxoides/farmacología , Factor de Crecimiento Transformador beta/farmacología
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