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1.
Biochem Biophys Res Commun ; 526(1): 267-272, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32209261

RESUMO

Charcoal-stripped fetal bovine serum (CS-FBS) is frequently used in studies on hormone-responsive cancers to provide hormone-free cell culture conditions. CS-FBS may influence the growth of cancer cells; however, the underlying mechanisms remain unclear. In this study, we aimed to clarify the effects of CS-FBS on distinct subtypes of breast cancer cells. We found that the crucial oncoprotein c-Myc was significantly inhibited in estrogen receptor alpha (ER-α)-positive breast cancer cells when cultured in CS-FBS-supplemented medium, but it was not suppressed in ER-α-negative cells. The addition of 17ß-estradiol (E2) to CS-FBS-supplemented medium rescued the CS-FBS-induced inhibition of c-Myc, while treatment with 5α-dihydrotestosterone (DHT) suppressed c-Myc expression. Our data demonstrated that CS-FBS may impede the growth of ER-α-positive breast cancer cells via c-Myc inhibition, and this was possibly due to the removal of estrogen. These results highlighted that the core drivers of c-Myc expression were subtype-specific depending on the distinct cell context and special caution should be exercised when using CS-FBS in studies of hormone-responsive cancer cells.


Assuntos
Neoplasias da Mama/patologia , Carvão Vegetal/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Soro/química , Animais , Neoplasias da Mama/genética , Bovinos , Linhagem Celular Tumoral , Di-Hidrotestosterona/farmacologia , Células Epiteliais/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores Androgênicos/metabolismo , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
2.
Mol Oncol ; 12(11): 1949-1964, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30171794

RESUMO

miR-372/373, a cluster of stem cell-specific microRNAs transactivated by the Wnt pathway, has been reported to be dysregulated in various cancers, particularly colorectal cancer (CRC); however, the unique role of these microRNAs in cancer remains to be discovered. In the present study, we characterized the upregulation in expression of miR-372/373 in CRC tissues from The Cancer Genome Atlas data, and then showed that overexpression of miR-372/373 enhanced the stemness of CRC cells by enriching the CD26/CD24-positive cell population and promoting self-renewal, chemotherapy resistance and the invasive potential of CRC cells. To clarify the mechanism underlying microRNA-induced stemness, we profiled 45 cell signaling pathways in CRC cells overexpressing miR-372/373 and found that stemness-related pathways, such as Nanog and Hedgehog, were upregulated. Instead, differentiation-related pathways, such as NFκB, MAPK/Erk and VDR, were markedly repressed by miR-372/373. Numerous new targets of miR-372/373 were identified, including SPOP, VDR and SETD7, all of which are factors important for cell differentiation. Furthermore, in contrast to the increase in miR-372/373 expression in CRC tissues, the expression levels of SPOP and VDR mRNA were significantly downregulated in these tissues, indicative of the poor differentiation status of CRC. Taken together, our findings suggest that miR-372/373 enhance CRC cell stemness by repressing the expression of differentiation genes. These results provide new insights for understanding the function and mechanisms of stem cell-specific microRNAs in the development of metastasis and drug resistance in CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Neoplásico/metabolismo , Animais , Células CACO-2 , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/patologia , RNA Neoplásico/genética
3.
Biochem Biophys Res Commun ; 480(3): 328-333, 2016 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-27751849

RESUMO

27-hydroxycholesterol (27-HC), the most abundant metabolite of cholesterol, is a risk factor for breast cancer. It can increase the proliferation of breast cancer cells and promote the metastasis of breast tumours in mouse models. Myc is a critical oncoprotein overexpressed in breast cancer. However, whether 27-HC affects Myc expression has not been reported. In the current study, we aimed to investigate the effects of 27-HC on Myc and the underlying mechanisms in MCF-7 breast cancer cells. Our data demonstrated that 27-HC activated Myc via increasing its protein stability. Three key negative modulators of Myc protein stability, PP2A, SCP1 and FBW7, were suppressed by 27-HC at the transcriptional level. We performed a data-mining analysis of the chromatin immunoprecipitation with next-generation DNA sequencing (ChIP-Seq) data in the ChIPBase, and discovered that a number of putative transcription factors (TFs), including Myc itself, were involved in the transcriptional regulation of PP2A, SCP1 and FBW7. Our results provide a novel mechanistic insight into the activation of Myc by 27-HC via transcriptional repression of PP2A, SCP1 and FBW7 to increase Myc protein stability in breast cancer cells.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Hidroxicolesteróis/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína 7 com Repetições F-Box-WD , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Ativação Transcricional
4.
Oncotarget ; 7(27): 42513-42526, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27285761

RESUMO

A hallmark of aberrant activation of the Wnt/ß-catenin signaling pathway has been observed in most colorectal cancers (CRC), but little is known about the role of non-coding RNAs regulated by this pathway. Here, we found that miR-150 was the most significantly upregulated microRNA responsive to elevated of Wnt/ß-catenin signaling activity in both HCT116 and HEK293T cells. Mechanistically, the ß-catenin/LEF1 complex binds to the conserved TCF/LEF1-binding element in the miR-150 promoter and thereby transactivates its expression. Enforced expression of miR-150 in HCT116 cell line transformed cells into a spindle shape with higher migration and invasion activity. miR-150 markedly suppressed the CREB signaling pathway by targeting its core transcription factors CREB1 and EP300. Knockdown of CREB1 or EP300 and knockout of CREB1 by CRISPR/Cas9 phenocopied the epithelial-mesenchymal transition (EMT) observed in HCT116 cells in response to miR-150 overexpression. In summary, our data indicate that miR-150 is a novel Wnt effector that may significantly enhance EMT of CRC cells by targeting the CREB signaling pathway.


Assuntos
Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Movimento Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Progressão da Doença , Proteína p300 Associada a E1A/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ativação Transcricional , Transfecção
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