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Loss of SNAIL regulated miR-128-2 on chromosome 3p22.3 targets multiple stem cell factors to promote transformation of mammary epithelial cells
- Source :
- Cancer research. 72(22)
- Publication Year :
- 2012
-
Abstract
- A discontinuous pattern of LOH at chromosome 3p has been reported in 87% of primary breast cancers. Despite the identification of several tumor suppressor genes in this region, there has yet to be a detailed analysis of noncoding RNAs including miRNAs in this region. In this study, we identified 16 aberrant miRNAs in this region and determined several that are frequently lost or amplified in breast cancer. miR-128-2 was the most commonly deleted miRNA. Embedded in the intron of the ARPP21 gene at chromosome 3p22.3, miR-128-2 was frequently downregulated along with ARPP21 in breast cancer, where it was negatively associated with clinicopathologic characteristics and survival outcome. Forced expression of miR-128 impeded several oncogenic traits of mammary carcinoma cells, whereas depleting miR-128-2 expression was sufficient for oncogenic transformation and stem cell-like behaviors in immortalized nontumorigenic mammary epithelial cells, both in vitro and in vivo. miR-128-2 silencing enabled transforming capacity partly by derepressing a cohort of direct targets (BMI1, CSF1, KLF4, LIN28A, NANOG, and SNAIL), which together acted to stimulate the PI3K/AKT and STAT3 signaling pathways. We also found that miR-128-2 was directly downregulated by SNAIL and repressed by TGF-β signaling, adding 2 additional negative feedback loops to this network. In summary, we have identified a novel TGF-β/SNAIL/miR-128 axis that provides a new avenue to understand the basis for oncogenic transformation of mammary epithelial cells. Cancer Res; 72(22); 6036–50. ©2012 AACR.
- Subjects :
- Homeobox protein NANOG
STAT3 Transcription Factor
Cancer Research
Transplantation, Heterologous
Down-Regulation
Loss of Heterozygosity
Mice, Nude
Breast Neoplasms
Biology
Kruppel-Like Factor 4
Mice
Cell Movement
Transforming Growth Factor beta
Cell Line, Tumor
microRNA
medicine
Gene silencing
Animals
Humans
Neoplasm Invasiveness
PI3K/AKT/mTOR pathway
Chromosome Aberrations
Stem Cell Factor
Cancer
medicine.disease
Cell biology
Oncogene Protein v-akt
MicroRNAs
Cell Transformation, Neoplastic
Oncology
KLF4
BMI1
Neoplastic Stem Cells
Female
Chromosomes, Human, Pair 3
Snail Family Transcription Factors
Stem cell
Transcription Factors
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 72
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....fcf44fb6eec0ac279a65455bc9253e78