@article{TEXTUAL,
      recid = {10221},
      author = {Lee, Younghee and Yang, Xinan and Huang, Yong and Fan,  Hanli and Zhang, Qingbei and Wu, Youngfei and Li, Jianrong  and Hasina, Rifat and Cheng, Chao and Lingen, Mark W. and  Gerstein, Mark B. and Weichselbaum, Ralph R. and Xing, H.  Rosie and Lussier, Yves A.},
      title = {Network Modeling Identifies Molecular Functions Targeted  by miR-204 to Suppress Head and Neck Tumor Metastasis},
      journal = {PLOS Computational Biology},
      address = {2010-04-01},
      number = {TEXTUAL},
      abstract = {<p>Due to the large number of putative microRNA gene  targets predicted by sequence-alignment databases and the  relative low accuracy of such predictions which are  conducted independently of biological context by design,  systematic experimental identification and validation of  every functional microRNA target is currently challenging.  Consequently, biological studies have yet to identify, on a  genome scale, key regulatory networks perturbed by altered  microRNA functions in the context of cancer. In this  report, we demonstrate for the first time how phenotypic  knowledge of inheritable cancer traits and of risk factor  loci can be utilized jointly with gene expression analysis  to efficiently prioritize deregulated microRNAs for  biological characterization. Using this approach we  characterize miR-204 as a tumor suppressor microRNA and  uncover previously unknown connections between microRNA  regulation, network topology, and expression dynamics.  Specifically, we validate 18 gene targets of miR-204 that  show elevated mRNA expression and are enriched in  biological processes associated with tumor progression in  squamous cell carcinoma of the head and neck (HNSCC). We  further demonstrate the enrichment of bottleneckness, a key  molecular network topology, among miR-204 gene targets.  Restoration of miR-204 function in HNSCC cell lines  inhibits the expression of its functionally related gene  targets, leads to the reduced adhesion, migration and  invasion in vitro and attenuates experimental lung  metastasis in vivo. As importantly, our investigation also  provides experimental evidence linking the function of  microRNAs that are located in the cancer-associated genomic  regions (CAGRs) to the observed predisposition to human  cancers. Specifically, we show miR-204 may serve as a tumor  suppressor gene at the 9q21.1–22.3 CAGR locus, a well  established risk factor locus in head and neck cancers for  which tumor suppressor genes have not been identified. This  new strategy that integrates expression profiling, genetics  and novel computational biology approaches provides for  improved efficiency in characterization and modeling of  microRNA functions in cancer as compared to the state of  art and is applicable to the investigation of microRNA  functions in other biological processes and diseases.</p>},
      url = {http://knowledge.uchicago.edu/record/10221},
}