Wang Li, Li Jing, Zhao Hongying, Hu Jing, Ping Yanyan, Li Feng, Lan Yujia, Xu Chaohan, Xiao Yun, Li Xia
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Department of Ultrasonic medicine, The 1st Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150040, China.
Mol Biosyst. 2016 Mar;12(3):711-20. doi: 10.1039/c5mb00700c.
Crosstalk among abnormal pathways widely occurs in human cancer and generally leads to insensitivity to cancer treatment. How long non-coding RNAs (lncRNAs) participate in the regulation of an abnormal pathway crosstalk in human cancer is largely unknown. Here, we proposed a strategy that integrates mRNA and lncRNA expression profiles for systematic identification of lncRNA-mediated crosstalk among risk pathways in different breast cancer subtypes. We identified 12 to 44 crosstalking pathway pairs mediated by 28 to 49 lncRNAs in four breast cancer subtypes. An LncRNA-mediated crosstalking pathway network in each breast cancer subtype was then constructed. We observed a number of breast cancer subtype-specific crosstalks of risk pathways. These subtype-specific lncRNA-mediated pathway crosstalks largely determined subtype-selective functions. Notably, we observed that lncRNAs mediated the crosstalk of pathways by cooperating with known important protein-coding genes, which play core roles in the deterioration of breast cancer. And we also identified key lncRNAs contributing to the crosstalk network in each subtype. As an example, the low expression of LIFR-AS1 was associated with poor survival in LumB subtype, and its cooperated genes IL1R and TGFBR located at the most upstream of the MAPK signaling pathway shared a common cascade path (p38 MAPKs-MEF2C) that can result in proliferation, differentiation and apoptosis. In summary, we offer an effective way to characterize complex crosstalks mediated by lncRNAs in breast cancer subtypes, which can be applied to other diseases and provide useful information for understanding the pathogenesis of human cancer.
异常通路之间的串扰在人类癌症中广泛存在，通常会导致对癌症治疗不敏感。长链非编码RNA（lncRNA）如何参与人类癌症中异常通路串扰的调控，目前很大程度上尚不清楚。在此，我们提出了一种整合mRNA和lncRNA表达谱的策略，用于系统鉴定不同乳腺癌亚型风险通路之间lncRNA介导的串扰。我们在四种乳腺癌亚型中鉴定出由28至49个lncRNA介导的12至44对串扰通路对。然后构建了每种乳腺癌亚型中的lncRNA介导的串扰通路网络。我们观察到许多乳腺癌亚型特异性的风险通路串扰。这些亚型特异性的lncRNA介导的通路串扰在很大程度上决定了亚型选择性功能。值得注意的是，我们观察到lncRNA通过与已知的重要蛋白质编码基因合作来介导通路串扰，这些基因在乳腺癌恶化中起核心作用。并且我们还鉴定出了在每个亚型中对串扰网络有贡献的关键lncRNA。例如，LIFR-AS1的低表达与LumB亚型的不良生存相关，其合作基因IL1R和TGFBR位于MAPK信号通路的最上游，共享一条可导致增殖、分化和凋亡的共同级联路径（p38 MAPKs-MEF2C）。总之，我们提供了一种有效的方法来表征乳腺癌亚型中lncRNA介导的复杂串扰，该方法可应用于其他疾病，并为理解人类癌症的发病机制提供有用信息。
