Guo Haiyang, Zhang Xiyu, Dong Ruifen, Liu Xiaolin, Li Yinuo, Lu Shan, Xu Limei, Wang Yuqiong, Wang Xiyao, Hou Dong, Wei Jian-Jun, Shao Changshun, Liu Zhaojian
Department of Molecular Medicine and Genetics and Ministry of Education Key Laboratory of Experimental Teratology, Shandong University, Jinan, Shandong, China. These authors contributed equally to this work.
Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
Oncotarget. 2014 Sep 30;5(18):8625-36. doi: 10.18632/oncotarget.2349.
Global expression profiling studies showed that miRNAs are aberrantly expressed in uterine leiomyomas (ULMs) and are involved in ULM pathogenesis. Long noncoding RNAs (lncRNAs) are another group of regulatory RNA whose expression and roles in ULMs have not been explored. In this study, we examined the global expressions of lncRNAs and mRNAs in ULMs using microarray and interrogated their interrelationship through co-expression analysis. We found that lncRNAs and mRNAs were dysregulated in ULMs and the degree of dysregulation was positively correlated with tumor size. Further analysis showed that lncRNAs correlate to their cis mRNAs in expression levels depending on genomic locations and orientations. Moreover, we identified several dysregulated pathways that were correlated to dysregulated lncRNAs. We validated several aberrantly expressed lncRNAs in extended samples and confirmed that AK023096 was down-regulated and chromatin-associated RNA (CAR) Intergenic 10 was up-regulated in the majority of leiomyomas. Knockdown of Intergenic 10 inhibited the proliferation of leiomyoma cells in vitro, indicating its functional importance in ULM pathogenesis. The neighboring protein-coding gene ADAM12 was also downregulated in Intergenic 10 knockdown leiomyoma cells. We showed for the first time that lncRNAs were dysregulated in uterine leiomyomas. Aberrantly expressed lncRNAs may contribute to the pathogenesis of uterine leiomyomas.
全球表达谱研究表明，微小RNA（miRNAs）在子宫平滑肌瘤（ULMs）中异常表达，并参与子宫平滑肌瘤的发病机制。长链非编码RNA（lncRNAs）是另一类调控RNA，其在子宫平滑肌瘤中的表达及作用尚未得到探索。在本研究中，我们使用微阵列检测了子宫平滑肌瘤中lncRNAs和mRNAs的整体表达情况，并通过共表达分析探究了它们之间的相互关系。我们发现lncRNAs和mRNAs在子宫平滑肌瘤中表达失调，且失调程度与肿瘤大小呈正相关。进一步分析表明，lncRNAs与其顺式mRNA的表达水平根据基因组位置和方向相关。此外，我们鉴定了几条与失调的lncRNAs相关的失调通路。我们在扩大样本中验证了几种异常表达的lncRNAs，并证实AK023096在大多数平滑肌瘤中表达下调，而染色质相关RNA（CAR）基因间10上调。基因间10的敲低抑制了平滑肌瘤细胞在体外的增殖，表明其在子宫平滑肌瘤发病机制中的功能重要性。在基因间10敲低的平滑肌瘤细胞中，相邻的蛋白质编码基因ADAM12也下调。我们首次表明lncRNAs在子宫平滑肌瘤中表达失调。异常表达的lncRNAs可能有助于子宫平滑肌瘤的发病机制。
