Samantarrai Devyani, Sahu Mousumi, Roy Jyoti, Mohanty Bedanta Ballav, Singh Garima, Bhushan Chandra, Mallick Bibekanand
RNAi and Functional Genomics Laboratory, Department of Life Science, National Institute of Technology, Rourkela, India.
Sci Rep. 2015 May 18;5:9742. doi: 10.1038/srep09742.
Cancer metastasis is a disease of extreme clinical relevance, as it is responsible for more than 90% of cancer-associated mortality. The molecular mechanism and critical regulators involved in this complex multi-stage process of metastasis is poorly deciphered in soft tissue sarcomas (STS), a heterogeneous group of rare tumors with high metastatic potential. Therefore, we aimed at identifying miRNA and transcription factor (TF) regulatory networks and paths in STS metastasis. We integrated mRNA and miRNA expression profiles with curated regulations (TF→gene, TF→miRNA, miRNA→gene) from different databases and constructed a potentially active regulatory sub-network in STS metastasis. From functional and topological analysis, we found nine novel regulators of Notch signaling sub-network which are conjectured to play critical role in metastasis of STS. This illustrated that the sub-network is promising for identification of critical regulators. Further analysis deploying our developed tool 'RiNAcyc' and computing coverage ratio of known STS associated genes and miRNAs identified a 15 node active path. This potential path highlights the crucial role of BMP2, hsa-miR-24, AP2 and MYC as the up-stream regulators of the path and hsa-miR-215 and TYMS as potential indicator of chemotherapeutic benefit in STS metastasis.
癌症转移是一种具有极高临床相关性的疾病，因为它导致了超过90%的癌症相关死亡。软组织肉瘤（STS）是一类具有高转移潜能的罕见异质性肿瘤，在这种复杂的多阶段转移过程中涉及的分子机制和关键调节因子尚未得到充分解析。因此，我们旨在识别STS转移中的miRNA和转录因子（TF）调控网络及路径。我们将mRNA和miRNA表达谱与来自不同数据库的 curated 调控（TF→基因、TF→miRNA、miRNA→基因）整合在一起，并构建了一个在STS转移中可能活跃的调控子网。通过功能和拓扑分析，我们发现了Notch信号子网的九个新型调节因子，推测它们在STS转移中起关键作用。这表明该子网在识别关键调节因子方面具有前景。进一步使用我们开发的工具“RiNAcyc”进行分析，并计算已知的STS相关基因和miRNA的覆盖率，确定了一条由15个节点组成的活跃路径。这条潜在路径突出了BMP2、hsa-miR-24、AP2和MYC作为该路径上游调节因子的关键作用，以及hsa-miR-215和TYMS作为STS转移中化疗获益潜在指标的作用。
