dysregulation of the mir-34a-sirt1 axis inhibits breast cancer stemness gary xiao, ph.d. professor...
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Dysregulation of the miR-34a-SIRT1 axis inhibits breast
cancer stemness
Gary Xiao, Ph.D.Professor and Director
School of Pharmaceutical Science & TechnologyDalian University of Technology
Dalian, China2015. 3.16.
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Each day: 1,500 people in the U.S. will die of cancer Each year: 1,220,100 people in the U.S. will be diagnosed with cancer Ultimately: One in four people in the U.S. will die of cancer
Cancer Statistics
Leading Cancer Types:
Breast: 16.3% of all cancer cases with a 40% increase since 1973 7.8% of all cancer deaths
Lung: 13.2% of all cancer cases with a 1.6 percent per year decline from 1992 to 1998 29% of all cancer deaths
Prostate: 14.8% of all cancer cases with an average 5.7 % per year decline from 1992 to 1998 5.9% of all cancer deaths
Colorectal: 11.6% of all cancer cases with sharply different rates among racial and ethnic groups 10.5% of all cancer deaths
www.seer.cancer.gov www.cdc.gov/cancer/ www.naaccr.org/
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Leading New Cancer Cases and Deaths – 2013 Estimates
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Challenge for administration of Breast Cancer
Challenge in the treatment of breast cancer: Recurrence and relapse, which was initiated and maintained by remaining cancer stem cells (CSCs) from either residual tumors or those with intrinsic resistance to adjuvant therapy.
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Breast Cancer Stem Cells (BCSCs)
• The breast CD44+ cells are basal-like, similar to normal breast stem cells; CD24+ cells express markers of luminal differentiation.
• CD44+/CD24- breast cancer cells preferentially survive treatment compared to the more differentiated cancer cells.
Thus, being used as therapeutic target cells.
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Biogenesis of microRNAs
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Benign DCIS IDC
*
Regulatory Role of microRNAs in Tumoregensis ?
Zhao et al., 2011 Breast Cancer Res Trt
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CSC Specific therapy
Tumor regression
Convensional cancer therapy
Tumor relapse
miR-34a: CSC specific therapy?
miR-34a: CSC self-renewal apoptosis?X
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Reciprocal endogenous expression of miR-34a and SIRT1 in CD44+/CD24− BCSCs
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Down-regulation of SIRT1 and over-expression of miR-34a inhibit cell growth and colony formation abilities
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Endogenous expression of SIRT1 in CD44+/CD24− BCSCs
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Inhibitory effect of miR-34a-SIRT1 axis on cellproliferative potential in MCF-7 cells
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Inhibitory effect of miR-34a-SIRT1 axis on cellproliferative potential in MCF-7 cells
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Repression of miR-34a-SIRT1 axis on the proportion of CD44+/CD24- BCSCs
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Repression of miR-34a-SIRT1 axis mammosphere formation capacity
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miR-34a suppressed expression of stem cell markers
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Alteration of miR-34a-SIRT1 axis supressed Nanog
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Modulation of miR-34a- SIRT1 axis enhanced MCF-7 cell apoptosis
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MiR-34a over-expression or silenced SIRT1 inhibited tumor growth in vivo.
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Subcutaneous tumor regeneration from MCF-7 cells infected with lentivirus-miR-34a(miR-34a) or shRNA-SIRT1(shRNA-SIRT1)
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Subcutaneous tumor regeneration from MCF-7 cells infected with lentivirus-miR-34a(miR-34a) or shRNA-SIRT1(shRNA-SIRT1)
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qRT-PCR analyses of miR-34a expression in each group of xenograft tissues
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Protein levels of SIRT1, and ALDH1 in each group of mice tumors
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miR-34a caused breast cancer stem cell apoptosis through its target genes
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AcknowledgementsThis research is supported by
Chinese NSFC (8120734)DLUT seed grant (1003852014)
School of Pharmaceutical Science & TechnologyDalian University of TechnologyDalian, China