Krysan Kostyantyn, Kusko Rebecca, Grogan Tristan, O'Hearn James, Reckamp Karen L, Walser Tonya C, Garon Edward B, Lenburg Marc E, Sharma Sherven, Spira Avrum E, Elashoff David, Dubinett Steven M
Authors' Affiliations: Departments of Medicine, 2Pathology and Laboratory Medicine, 3Molecular and Medical Pharmacology, 4Anesthesiology, and 5Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles; 6UCLA Jonsson Comprehensive Cancer Center; 7West Los Angeles VA Healthcare System, Los Angeles; 8City of Hope Comprehensive Cancer Center, Duarte, California; and 9Boston University, Boston, Massachusetts.
Mol Cancer Res. 2014 May;12(5):765-74. doi: 10.1158/1541-7786.MCR-13-0377. Epub 2014 Jan 27.
Aberrant expression of microRNAs (miRNA) with oncogenic capacities (oncomiRs) has been described for several different malignancies. The first identified oncomiR, miR-17-92, is frequently overexpressed in a variety of cancers and its targets include the tumor suppressor PTEN. The transcription factor c-Myc (MYC) plays a central role in proliferative control and is rapidly upregulated upon mitogenic stimulation. Expression of c-Myc is frequently deregulated in tumors, facilitating proliferation and inhibiting terminal differentiation. The c-Myc-regulated network comprises a large number of transcripts, including those encoding miRNAs. Here, prostaglandin E2 (PGE2) exposure rapidly upregulates the expression of the MYC gene followed by the elevation of miR-17-92 levels, which in turn suppresses PTEN expression, thus enhancing apoptosis resistance in non-small cell lung cancer (NSCLC) cells. Knockdown of MYC expression or the miR-17-92 cluster effectively reverses this outcome. Similarly, miR-17-92 levels are significantly elevated in NSCLC cells ectopically expressing COX-2. Importantly, circulating miR-17-92 was elevated in the blood of patients with lung cancer as compared with subjects at risk for developing lung cancer. Furthermore, in patients treated with celecoxib, miR-17-92 levels were significantly reduced. These data demonstrate that PGE2, abundantly produced by NSCLC and inflammatory cells in the tumor microenvironment, is able to stimulate cell proliferation and promote resistance to pharmacologically induced apoptosis in a c-Myc and miR-17-92-dependent manner.
This study describes a novel mechanism, involving c-Myc and miR-17-92, which integrates cell proliferation and apoptosis resistance.
具有致癌能力的微小RNA（miRNA，即癌基因miR）在几种不同的恶性肿瘤中均有异常表达。首个被鉴定出的癌基因miR-17-92在多种癌症中经常过度表达，其靶标包括肿瘤抑制因子PTEN。转录因子c-Myc（MYC）在增殖控制中起核心作用，在有丝分裂原刺激后会迅速上调。c-Myc在肿瘤中的表达经常失调，促进增殖并抑制终末分化。c-Myc调控的网络包含大量转录本，包括那些编码miRNA的转录本。在此，前列腺素E2（PGE2）暴露会迅速上调MYC基因的表达，随后miR-17-92水平升高，这反过来又抑制PTEN的表达，从而增强非小细胞肺癌（NSCLC）细胞的抗凋亡能力。敲低MYC表达或miR-17-92簇可有效逆转这一结果。同样，在异位表达COX-2的NSCLC细胞中，miR-17-92水平显著升高。重要的是，与有患肺癌风险的受试者相比，肺癌患者血液中的循环miR-17-92升高。此外，在接受塞来昔布治疗的患者中，miR-17-92水平显著降低。这些数据表明，NSCLC和肿瘤微环境中的炎症细胞大量产生的PGE2能够以c-Myc和miR-17-92依赖的方式刺激细胞增殖并促进对药物诱导凋亡的抗性。
本研究描述了一种涉及c-Myc和miR-17-92的新机制，该机制整合了细胞增殖和抗凋亡能力。
