上海 2012年8月10日 訊 /生物谷BIOON/ --最近,，研究人員發(fā)現(xiàn)通過抑制一個關(guān)鍵的microRNA抑制乳腺癌細(xì)胞獲得干細(xì)胞樣特性的能力,，在他們還沒有分化前，而一旦分化獲得干細(xì)胞樣特性時會更耐化療,，患者預(yù)后也較差,。相關(guān)研究論文發(fā)表在Oncogene雜志上。
論文的第一作者Diana Cittelly博士表示：我們將尋找microRNAs在乳腺癌細(xì)胞分化成具有侵略性,、耐化療特性的癌細(xì)胞表型中的作用,，化療耐藥表型的乳腺癌細(xì)胞分化的microRNA。因為一個microRNA可以調(diào)節(jié)許多基因參與癌癥信號途徑,，我們希望找到一個能產(chǎn)生很多后續(xù)效應(yīng)的靶基因。
具體來說,，該項研究表明孕激素能調(diào)節(jié)miRNA-29,，miRNA-29是一個能決定細(xì)胞基因能否翻譯表達(dá)成蛋白的分子。孕激素對miRNA-29的這種調(diào)節(jié)導(dǎo)致了一個級聯(lián)反應(yīng)刺激乳腺癌細(xì)胞獲到干細(xì)胞樣特性,。在動物模型中,，這些干細(xì)胞樣細(xì)胞幫助乳腺癌細(xì)胞抵抗目前的治療手段。
Cittelly說我們可以操縱這個細(xì)胞系的miRNA-29,，我們希望技術(shù)不是太遠(yuǎn),，這將使我們能夠在未來遞送miRNA-29進(jìn)入人乳腺癌細(xì)胞中去。抑制miRNA-29的作用，乳腺癌細(xì)胞將無法獲得干細(xì)胞樣特性,，失去他們的激素依賴特性,。（生物谷：Bioon.com）
編譯自：The Making and Unmaking of Stem-Like, Aggressive Breast Cancer Cells
doi:10.1038/onc.2012.275
PMC:
PMID:
Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4
D M Cittelly, J Finlay-Schultz, E N Howe, N S Spoelstra, S D Axlund, P Hendricks, B M Jacobsen, C A Sartorius and J K Richer
The female hormone progesterone (P4) promotes the expansion of stem-like cancer cells in estrogen receptor (ER)- and progesterone receptor (PR)-positive breast tumors. The expanded tumor cells lose expression of ER and PR, express the tumor-initiating marker CD44, the progenitor marker cytokeratin 5 (CK5) and are more resistant to standard endocrine and chemotherapies. The mechanisms underlying this hormone-stimulated reprogramming have remained largely unknown. In the present study, we investigated the role of microRNAs in progestin-mediated expansion of this dedifferentiated tumor cell population. We demonstrate that P4 rapidly downregulates miR-29 family members, particularly in the CD44+ cell population. Downregulation of miR-29 members potentiates the expansion of CK5+ and CD44+ cells in response to progestins, and results in increased stem-like properties in vitro and in vivo. We demonstrate that miR-29 directly targets Krüppel-like factor 4 (KLF4), a transcription factor required for the reprogramming of differentiated cells to pluripotent stem cells, and for the maintenance of breast cancer stem cells. These results reveal a novel mechanism, whereby progestins increase the stem cell-like population in hormone-responsive breast cancers, by decreasing miR-29 to augment PR-mediated upregulation of KLF4. Elucidating the mechanisms whereby hormones mediate the expansion of stem-like cells furthers our understanding of the progression of hormone-responsive breast cancers.
