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  • 1
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    Abstract LB-171: Repression of miR-125b-1 by epigenetic mechanisms in breast cancer cell lines
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-171-LB-171
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-171-LB-171
    Abstract: miR-125b-1 downregulates targets as ERBB2, BAK1 and ETS1. These targets are involved in cell proliferation, apoptosis and cell migration, respectively. Previous studies on tumor cells reveal that downregulation of miR-125b-1 is associated with poor prognosis in breast cancer patients. DNA methylation of the miR-125b-1 promoter can repress its expression, in addition, this promoter is embedded in an intermediate CpG island thus, DNA methylation and histone modifications could also affect its transcription. Repression by DNA methylation has been well characterized, but there is no information about the role of histone modifications in the regulation of miR-125b-1 promoter. We evaluated the enrichment of two histone modifications involved in gene repression, H3K9me3 and H3K27me3, on the miR-125b-1 promoter of two breast cancer cell lines, a luminal A, MCF 7, and a triple negative, MDA-MB-231, compared with a non-transformed breast cell line, MCF 10A. We found that breast cancer cell lines are enriched with H3K27me3 and H3K9me3 in MCF 7 and MDA-MB-231, respectively. Then, we focused on reactivating miR-125b-1 in MCF 7 using an EZH2 inhibitor. After the treatment with the EZH2 inhibitor, we evaluated the transcriptional levels of the pri-miR-125b-1 and the mature miR-125b by qRT-PCR. Our results suggest that transcripts, pri-miRNA and mature miRNA, increase their expression levels after the treatment in the MCF7 cell line, but not in the MDA-MB-231 and MCF 10A cell lines. Subsequently, we evaluated the BAK1 expression and protein levels to investigate whether the miR-125b-1 reactivation could affect some targets. We observed a 60% and 70% decrease in the expression and protein levels of after treatment with the EZH2 inhibitor. To determine if the H3K9me3 is involved on miR-125b-1 silencing in MDA-MB-231, we over-expressed KDM4B/JMJD2B to reactivate this miRNA. Then, we evaluated the transcript. A three-fold increase was observed compared. We conclude that the miR-125b-1 can be repressed by different epigenetic mechanisms depending on the breast cancer subtype; the miR-125b-1 reactivation by removing the repression histone modification marks affect the expression of BAK1, a pro-apoptotic target. Citation Format: Fernanda Cisneros-Soberanis, Marco Alonso Andonegui, Clementina Castro, Luis Alonso Herrera. Repression of miR-125b-1 by epigenetic mechanisms in breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-171.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-LB-171
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
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    Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in patients with non-seminomatous testicular germ cell tumors.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 4555-4555
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 4555-4555
    Abstract: 4555 Background: Cisplatin-based chemotherapy cures over 80% of testicular germ cell tumors (TGCTs); nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. In this work we explored the association between NER-proteins and their polymorphisms (SNPs) with cisplatin-sensitivity (CPS) and overall survival (OS) of patients with advanced non-seminomatous (ns)-TGCTs treated with bleomycin-etoposide-cisplatin (BEP). Methods: ERCC1, XPA-expression and gammaH2AX-presence, were tested in cisplatin-treated cancer cell lines. ERCC1 and XPA-expression were also analyzed in ns-TGCTs by qPCR. Immunohistochemistry was performed to detect ERCC1 protein in ns-TGCTs specimens. The SNPs were genotyped by PCR-RFLPs technique. Results: High basal ERCC1-expression was observed in non-CPS cancer cell lines; ERCC1-expression augmented further, as well as gammaH2AX, after cisplatin-treatment. Basal ERCC1 expression increases in the non-CPS patients in Mexican and Peruvian populations compared to CPS patients (p 〈 0.001; p=0.002). XPAexpression levels weren’t different. These polymorphisms weren’t associated with CPS or OS. ERCC1-positive immunostaining was observed in 30/108 patients (27.8%). From 76 patients that were CPS, 59 (77.6%) were ERCC1-negative, compared with 17 (22.4%) that were ERCC1-positive (p=0.05). 5-year OS probability was smaller for those patients ERCC1-positive and non-CPS (15.38%) than tumor ERCC1-negative and CPS (89.3%) (p 〈 0.001). Using the Cox Model, adjusted on the prognosis groups, the hazard ratio (HR) of death in patients with ERCC1-negative and non-CPS was 〉 14.43 and in patients ERCC1-positive and non-CPS the HR was 〉 11.86 (p 〈 0.001). Conclusions: High-levels of ERCC1-expression and ERCC1-protein are associated with non-CPS, suggesting the use of ERCC1 as a potential indicator of response to cisplatin-based chemotherapy and the prognosis in patients with ns-TGCTs. Moreover, it’s important to identify patients potentially non-CPS in order to diminish the toxicity of cisplatin and improved quality of life avoiding adverse effects due to this agent. Work supported by CONACYT 83959 and PAPIIT IN213311-3.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.4555
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 3
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    Abstract 2728: In silico identification of a MAD2-interacting motif in MAD2 spliced isoforms suggest a functional interaction with the spindle assemble checkpoint in cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2728-2728
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2728-2728
    Abstract: Abnormal chromosome segregation plays a key role in cancer development. MAD2 is a component of the spindle assembly checkpoint (SAC), a cell cycle control mechanism that ensures an accurate segregation of chromosomes during mitosis. Changes in MAD2 expression have been associated with chemo-resistance both to spindle inhibitors and to DNA damaging agents. Also, a previous study has shown that the exogenous expression of MAD2β, a splicing variant of MAD2, was associated with resistance to Adriamycin and Vincristine in gastric cell lines. Additionally, we have previously identified that exogenous overexpression of MAD2γ upon paclitaxel-induced SAC activation in the colorectal cancer cell HCT116, reduces drug-induced mitotic arrest. These findings suggested a possible structural interaction of MAD2 isoforms with SAC components. To determine possible structural interactions between MAD2 isoforms and key SAC components (i.e. MAD1 and CDC20), we performed an in silico analysis of MAD2 isoforms, Interestingly, we found that alternative splicing of MAD2 generates a premature stop codon and a frameshift in exon 4 in MAD2γ and MAD2β. This change generates a new C-terminal region in MAD2γ and MAD2β isoforms that comprise 16 amino acids, which are not present in the major isoform (MAD2α). We aligned this region with the amino acid sequence of CDC20 from various species and identified a MAD2-interacting motif (MIM). This finding suggests that MAD2 isoforms may interact with the active conformation of MAD2 (C-MAD2). Since MAD2 isoforms and CDC20 may compete for the same region in MAD2, we propose a new model whereby MAD2 isoforms inhibits SAC by interfering with C-MAD2/CDC20 formation. This model helps to explain previous results where MAD2 isoforms over expression seem to have an opposite role in SAC signaling. Citation Format: Miguel Ramirez-Otero, Alejandro Lopez-Saavedra, Marco Andonegui, Jose Diaz-Chavez, Luis Alonso Herrera. In silico identification of a MAD2-interacting motif in MAD2 spliced isoforms suggest a functional interaction with the spindle assemble checkpoint in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2728.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-2728
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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