Sun Michael, Estrov Zeev, Ji Yuan, Coombes Kevin R, Harris David H, Kurzrock Razelle
Department of Investigational Cancer Therapeutics (Phase I Program), University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mol Cancer Ther. 2008 Mar;7(3):464-73. doi: 10.1158/1535-7163.MCT-07-2272.
A major challenge in cancer chemotherapy has been developing safe and clinically efficacious chemotherapeutic agents. With its low toxicity profile, curcumin (diferuloylmethane), a naturally occurring flavinoid derived from the rhizome of Curcuma longa, has great promise. In vitro and in vivo preclinical studies have shown its inhibitory anticancer, antioxidant, anti-inflammatory, antiproliferative, and proapoptotic activities. The multiple mechanisms of the antitumor effect of curcumin putatively include down-regulating the expression of gene products such as nuclear factor-kappaB, growth suppression, inducing apoptosis, and modulating various signal transduction pathways and the expression of many oncogenes. The mechanisms underlying the antitumor activity of curcumin have not, however, been completely delineated.
An oligonucleotide microarray chip was developed and used to profile microRNA (miRNA) expressions in pancreatic cells treated with curcumin. Transcripts with regulated expression patterns on the arrays were validated by real-time PCRs. Additionally, potential mRNA targets were analyzed bioinformatically and confirmed with flow cytometry experiments.
Curcumin alters miRNA expression in human pancreatic cells, up-regulating miRNA-22 and down-regulating miRNA-199a*, as confirmed by TaqMan real-time PCR. Upregulation of miRNA-22 expression by curcumin or by transfection with miRNA-22 mimetics in the PxBC-3 pancreatic cancer cell line suppressed expression of its target genes SP1 transcription factor (SP1) and estrogen receptor 1 (ESR1), while inhibiting miRNA-22 with antisense enhanced SP1 and ESR1 expression.
These observations suggest that modulation of miRNA expression may be an important mechanism underlying the biological effects of curcumin.
癌症化疗中的一个主要挑战是开发安全且临床有效的化疗药物。姜黄素（二阿魏酰甲烷）是一种从姜黄根茎中提取的天然类黄酮，具有低毒性，极具应用前景。临床前的体外和体内研究已显示其具有抑制抗癌、抗氧化、抗炎、抗增殖和促凋亡活性。姜黄素抗肿瘤作用的多种机制可能包括下调核因子-κB等基因产物的表达、抑制生长、诱导凋亡以及调节各种信号转导通路和许多癌基因的表达。然而，姜黄素抗肿瘤活性的潜在机制尚未完全阐明。
开发了一种寡核苷酸微阵列芯片，并用于分析用姜黄素处理的胰腺细胞中的微小RNA（miRNA）表达。通过实时聚合酶链反应（PCR）验证阵列上具有调控表达模式的转录本。此外，通过生物信息学分析潜在的信使核糖核酸（mRNA）靶点，并用流式细胞术实验进行确认。
通过TaqMan实时PCR证实，姜黄素可改变人胰腺细胞中的miRNA表达，上调miRNA-22并下调miRNA-199a*。在PxBC-3胰腺癌细胞系中，姜黄素或转染miRNA-22模拟物上调miRNA-22表达，可抑制其靶基因SP1转录因子（SP1）和雌激素受体1（ESR1）的表达，而用反义核酸抑制miRNA-22则增强SP1和ESR1的表达。
这些观察结果表明，miRNA表达的调节可能是姜黄素生物学效应的重要潜在机制。
