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Estrogen receptor b...
Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205-PROX1 mechanism
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Nguyen-Vu, Trang (author)
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Wang, Jun (author)
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Mesmar, Fahmi (author)
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Mukhopadhyay, Srijita (author)
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Saxena, Ashish (author)
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- McCollum, Catherine W. (author)
- Karolinska Institutet
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- Gustafsson, Jan-Ake (author)
- Karolinska Institutet
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Bondesson, Maria (author)
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- Williams, Cecilia (author)
- KTH,Proteomik och nanobioteknologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2016-06-07
- 2016
- English.
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In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 7:27, s. 42159-42171
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https://urn.kb.se/re...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- colorectal cancer
- PROX1
- estrogen receptor
- microRNA
- metastasis
Publication and Content Type
- ref (subject category)
- art (subject category)
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