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- Nguyen-Vu, Trang, et al.
(författare)
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Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205-PROX1 mechanism
- 2016
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 7:27, s. 42159-42171
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Tidskriftsartikel (refereegranskat)abstract
- Colon cancer is a common cause of cancer death in the Western world. Accumulating evidence supports a protective role of estrogen via estrogen receptor beta (ER beta) but the mechanism of action is not known. Here, we elucidate a molecular mechanism whereby ER beta represses the oncogenic prospero homebox 1 (PROX1) through the upregulation of miR-205. We show that PROX1 is a potential target of miR-205 and that in clinical specimens from The Cancer Genome Atlas data, ER beta and miR-205 are decreased in colorectal cancer tissue compared to non-tumorous colon, while PROX1 levels are increased. Through mechanistic studies in multiple colorectal cancer cell lines, we show that ER beta upregulates miR-205, and that miR-205 targets and represses PROX1 through direct interaction with its 3' UTR. Through the generation of intestine-specific ER beta knockout mice, we establish that this pathway is correspondingly regulated in normal intestinal epithelial cells in vivo. Functionally, we demonstrate that miR-205 decreases cell proliferation and decreases migratory and invasive potential of colon cancer cells, leading to a reduction of micrometastasis in vivo. In conclusion, ER beta in both normal and cancerous colon epithelial cells upregulates miRNA-205, which subsequently reduces PROX1 through direct interaction with its 3' UTR. This results in reduced proliferative and metastatic potential of the cells. Our study proposes a novel pathway that may be exploited using ER beta-selective agonists and/or miR-205-replacement therapy in order to improve preventive and therapeutic approaches against colon cancer.
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| 3. |
- Reins, Rose Y., et al.
(författare)
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Vitamin D Induces Global Gene Transcription in Human Corneal Epithelial Cells : Implications for Corneal Inflammation
- 2016
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 57:6, s. 2689-2698
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Our previous studies show that human corneal epithelial cells (HCEC) have a functional vitamin D receptor (VDR) and respond to vitamin D by dampening TLR-induced inflammation. Here, we further examined the timing of the cytokine response to combined vitamin D-TLR treatment and used genome-wide microarray analysis to examine the effect of vitamin D on corneal gene expression. METHODS. Telomerase-immortalized HCEC (hTCEpi) were stimulated with polyinosinicpolycytidylic acid (poly[I: C]) and 1,25-dihydroxyvitamin D-3 (1,25D(3)) for 2 to 24 hours and interleukin (IL)-8 expression was examined by quantitative (q) PCR and ELISA. Telomeraseimmortalized HCEC and SV40-HCEC were treated with 1,25D(3) and used in genome-wide microarray analysis. Expression of target genes was validated using qPCR in both cell lines and primary HCEC. For confirmation of IjBa protein, hTCEpi were treated with 1,25D(3) for 24 hours and cell lysates used in an ELISA. RESULTS. Treatment with 1,25D(3) increased poly(I: C)-induced IL-8 mRNA and protein expression after 2 to 6 hours. However, when cells were pretreated with 1,25D(3) for 24 hours, 1,25D(3) decreased cytokine expression. For microarray analysis, 308 genes were differentially expressed by 1,25D(3) treatment in hTCEpi, and 69 genes in SV40s. Quantitative (q) PCR confirmed the vitamin D-mediated upregulation of target genes, including nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (I kappa B alpha). In addition to increased transcript levels, I kappa B alpha protein was increased by 28% following 24 hours of vitamin D treatment. CONCLUSIONS. Microarray analysis demonstrates that vitamin D regulates numerous genes in HCEC and influences TLR signaling through upregulation of I kappa B alpha. These findings are important in dissecting the role of vitamin D at the ocular surface and highlight the need for further research into the functions of vitamin D and its influence on corneal gene expression.
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