利用MAPK訊息傳導路徑相關的miRNAs來治療BRAF抑制劑的抗藥性在黑色素瘤細胞中之研究;Study of MAPK signaling pathway-related miRNAs in resistance to BRAF inhibitor in melanoma cells

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Title:	利用MAPK訊息傳導路徑相關的miRNAs來治療BRAF抑制劑的抗藥性在黑色素瘤細胞中之研究;Study of MAPK signaling pathway-related miRNAs in resistance to BRAF inhibitor in melanoma cells
Authors:	蔡仁傑;Tsai, Jen-Chieh
Contributors:	系統生物與生物資訊研究所
Keywords:	MAPK訊息傳導路徑;微型RNA;抗藥性黑色素瘤
Date:	2016-11-04
Issue Date:	2017-01-23 16:35:41 (UTC+8)
Publisher:	國立中央大學
Abstract:	MAPK/ERK訊息傳導路徑的活化在黑色素瘤中扮演了很重要的角色，在之前的研究中大約有50%的黑色素瘤包含BRAF基因突變，其中80%是BRAFV600E的取代突變，這個突變持續性地誘導MAPK/ERK訊息傳導路徑的活化也造成癌症的惡性表現型。標靶藥物PLX4032是一個強效的小分子抑制劑，抑制BRAFV600E突變蛋白質來治療黑色素瘤，在第三期的病人中，經過PLX4032治療後至少有48%的人有效，然而這個治療受限於有些病人在治療七個月後迅速產生抗藥性。我們建立了對PLX4032產生抗藥性的細胞株，我們發現黑色素瘤對PLX4032產生抗藥性是透過過度活化MAPK/ERK跟PI3K/AKT訊息傳導路徑，微型RNA是一個很有潛力的治療藥物，因為它可以一次抑制多個訊息RNA跟抑制多個致癌相關訊息傳導路徑。我們利用先前微陣列晶片實驗的結果和GEO資料庫篩選出與MAPK相關的微型RNA，實驗結果顯示出分別的過度表現4個微型RNA可以有效的抑制細胞增生跟細胞爬行，以上證據說明了微型RNA可能是個很有潛力的治療用來對抗產生PLX4032抗藥性的黑色素瘤。;The activity of mitogen-activated protein kinase (MAPK/ERK) signaling plays an essential role in melanoma. It has been reported that approximately 50% of melanoma harbors activating BRAF mutations (over 80% BRAFV600E). The mutation constitutively induces high activity in MAPK/ERK signaling pathway and causes malignant phenotypes of cancers. PLX4032 is a selective and potent small molecule inhibitor of the V600E mutant form the BRAF protein used in the treatment of melanoma. In a phase III trial in patients, PLX4032 treatment resulted in a 48% response. However, this therapeutic success is limited by the rapid emergence of drug resistance after an average 7 months. We constructed a cell model of resistance to PLX4032 progressed by treatment of BRAFV600E melanoma cells with the BRAF inhibitor PLX4032. We demonstrated that MAPK/ERK and PI3K/AKT signaling pathways activity were reactivate in PLX4032-resistant melanoma cells. miRNA are excellent therapeutic candidates because of their ability to repress several mRNA or multiple oncogenic pathways at once. We screen out MAPK-related candidate miRNAs from the prior microarray results and GEO data analysis. Our data showed that overexpression of four miRNAs individually could decrease cell proliferation, anchorage-independent growth and migration. These results suggest that miRNAs could be a potent therapeutic candidate for counteracting treatment resistance of PLX4032 in melanoma.
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