MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms.
MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms.
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DOI：
10.1038/bjc.2015.125
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发表时间：
2015-04-28
影响因子：
8.8
通讯作者：
Smith, G.
中科院分区：
文献类型：
--
作者：
Amankwatia, E. B.;Chakravarty, P.;Carey, F. A.;Weidlich, S.;Steele, R. J. C.;Munro, A. J.;Wolf, C. R.;Smith, G.
结直肠癌起源于良性腺瘤，尽管并非所有腺瘤都进展为癌症，并且疾病进展存在显著的患者间差异。我们先前将KRAS突变与结直肠癌患者的疾病进展和生存率降低相关联。我们使用TaqMan低密度阵列（TLDA）qRT-PCR分析来鉴定在正常结直肠粘膜、腺瘤和癌症以及同基因KRAS WT和突变HCT 116细胞中差异表达的miRNA，并使用各种表型测定来评估miRNA表达对KRAS活性、化疗敏感性、增殖和侵袭的影响。microRNA-224在异型增生性结直肠疾病和同基因KRAS WT和突变型HCT 116细胞中差异表达。在HCT 116 KRAS WT细胞中，Antagomir介导的miR-224沉默表型模拟KRAS突变，增加KRAS活性以及ERK和AKT磷酸化。在miR-224敲减细胞和表达KRAS和BRAF突变蛋白的NIH 3 T3细胞中，5-FU化疗敏感性显著增加。预测的miR-224靶基因的生物信息学分析预测了改变的细胞增殖、侵袭和上皮-间质转化（EMT）表型，这些表型在miR-224敲低细胞中得到实验证实。我们描述了一种新的KRAS调节机制，并强调了结直肠癌特异性miRNA作为疾病进展或临床反应生物标志物的临床实用性。
Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. We used TaqMan low-density array (TLDA) qRT–PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial–mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers.
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DOI：
10.1158/1078-0432.ccr-11-1452
发表时间：
2011-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bartley AN;Yao H;Barkoh BA;Ivan C;Mishra BM;Rashid A;Calin GA;Luthra R;Hamilton SR
通讯作者：
Hamilton SR
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
9
作者：
Kanaan, Ziad;Roberts, Henry;Galandiuk, Susan
通讯作者：
Galandiuk, Susan
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
37.3
作者：
Bandrés E;Cubedo E;Agirre X;Malumbres R;Zárate R;Ramirez N;Abajo A;Navarro A;Moreno I;Monzó M;García-Foncillas J
通讯作者：
García-Foncillas J