Abstract A18: Assessing microRNA regulatory networks for biomarker discovery in cancer
Authors: Andre Fujita, Carme Camps, Jiannis Ragoussis, Gencapo Head, Neck Brazilian Genome, Satoru Miyano, Patricia Severino
Journal: Clinical Cancer Research (2010)

Abstract MicroRNAs are small noncoding RNA sequences that take part in essential regulatory networks through targeting of mRNAs. Compelling evidence show that alterations in microRNAs expression are involved in the initiation and progression of human cancers. Squamous cell carcinoma of the head and neck is among the leading cancers in the world, whereas a suitable marker for screening or tailored therapy is currently unavailable. MicroRNAs could be used, in the future, to improve outcomes of this disease. In this work we performed global microRNA expression profiling of 15 tumor samples and 15 matched tumor-free surgical margins by means of DNA microarray. Maximum entropy linear discriminant analysis (MLDA) was applied in order to verify whether microRNA expression levels might be useful to discriminate between tumor/tumor-free samples. An accuracy of ~93% (28 of 30) were obtained by leave-one-out cross validation. The microRNAs most likely to discriminate between tumor and tumor-free tissue selected by means of MLDA were miR-375, miR-196a, miR-1, miR-203, and miR-133a. Partial Spearman correlation was used in order to identify regulatory networks among these five genes. Significant functional connectivity changes were observed between tumor/tumor-free tissues indicating that not only the difference in expression is important, but also the difference in connectivity. While these microRNAs were interconnected in tumorfree tissue, the only functional connectivity kept in tumor samples was between miR-133a and miR-1. Their correlation is acknowledged in normal tissues, while their role in cancer is poorly understood. Using TargetScan, we searched for common predicted targets for both microRNAs; when performing functional enrichment analysis 66% of their common targets were phosphoproteins (p-value &amp;lt;0.05 after Bonferroni correction). Deregulation of phosphoprotein expression can ultimately lead to abnormal activation of signaling pathways, a common feature that accompanies tumor initiation and progression. In this context, both miR-133a and miR-1 target a PIK3 gene, and the epidermal growth factor receptor (EGFR), presently exploited for efficient management of head and neck cancer, is a predicted target for miR-133a. Although anti-EGFR therapies are active in some patients, eventually disease will become refractory to therapy. Mechanisms that mediate resistance to anti-EGFR therapies include misregulation and the activation of downstream mediators, both of which could be associated with microRNA regulation, as demonstrated here. At this time there are strong indications that microRNAs may represent viable targets for anticancer therapies, but understanding their global impact in regulation is needed before researchers can select or avoid pathways for treatment purposes. Here we show that microRNAs could interfere in anti-EGFR response in head and neck squamous cell carcinoma patients by directly targeting EGFR, or could be themselves used as drug targets, but their broad range of action in the cellular system should be carefully accessed. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A18.