Begum Shahnaz, Hayashi Masamichi, Ogawa Takenori, Jabboure Fayez J, Brait Mariana, Izumchenko Evgeny, Tabak Sarit, Ahrendt Steven A, Westra William H, Koch Wayne, Sidransky David, Hoque Mohammad O
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231 USA.
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland, 21231 USA.
Sci Rep. 2015 Aug 28;5:13236. doi: 10.1038/srep13236.
In spite of significant technical advances, genesis and progression of non-small cell lung cancer (NSCLC) remain poorly understood. We undertook an integrated genetic approach to discover novel microRNAs that were deregulated in NSCLCs. A total 119 primary NSCLCs with matched normal were analyzed for genome-wide copy number changes. We also tested a subset of matched samples by microRNA expression array, and integrated them to identify microRNAs positioned in allelic imbalance area. Our findings support that most of the identified deregulated microRNAs (miR-21, miR-23b, miR-31, miR-126, miR-150, and miR-205) were positioned in allelic imbalance areas. Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32-4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30-4.19) in multivariable analysis. In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time. In summary, integration of genomic analysis and microRNA expression profiling could identify novel cancer-related microRNAs, and miR-23b could be a potential prognostic marker for early stage NSCLCs. Further biological studies of miR-23b are warranted for the potential development of targeted therapy.
尽管技术取得了重大进展，但非小细胞肺癌（NSCLC）的发生和进展仍知之甚少。我们采用综合遗传学方法来发现NSCLC中失调的新型微小RNA。对总共119例配对正常的原发性NSCLC进行全基因组拷贝数变化分析。我们还通过微小RNA表达阵列检测了一部分配对样本，并将它们整合起来以鉴定位于等位基因不平衡区域的微小RNA。我们的研究结果支持，大多数鉴定出的失调微小RNA（miR-21、miR-23b、miR-31、miR-126、miR-150和miR-205）位于等位基因不平衡区域。在独立检测的114例NSCLC中，多变量分析显示miR-23b过表达是无复发生存（HR = 2.40，P = 0.005，95%CI：1.32 - 4.29）和总生存（HR = 2.35，P = 0.005，95%CI：1.30 - 4.19）的显著不良预后因素。此外，H1838细胞系中miR-23b过表达显著增加细胞增殖，而H1437和H1944细胞系中miR-23b抑制显著缩短细胞倍增时间。总之，基因组分析和微小RNA表达谱的整合可以鉴定新型癌症相关微小RNA，miR-23b可能是早期NSCLC的潜在预后标志物。有必要对miR-23b进行进一步的生物学研究以开发靶向治疗。
