Oncotarget Co-activation of Sonic Hedgehog and epidermal growth factor

Oncotarget Volume 11 Issue 15 reported that The Research Team re-analyzed publicly available data to study how SHH and EGF cooperate to affect the dynamic activity of the gene population.

They also identified cross-talk genes that exhibited expression profiles dissimilar to that seen under SHH or EGF stimulation alone.

These unique cross-talk patterns were validated in a cell culture model.

These cross-talk genes identified here may serve as valuable markers to study or test for EGF co-stimulatory effects in an SHH+ environment.

Dr. Michihisa Umetani from The Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA and The HEALTH Research Institute, University of Houston, Houston, TX, USA as well as Hulin Wu from The Department of Biostatistics and Data Science, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA said, "It is now well known that, in most cancer patients, there are multiple genetic aberrations and deregulation of multiple signaling pathways that work in a synergistic manner to initiate and promote the tumor."

"It is now well known that, in most cancer patients, there are multiple genetic aberrations and deregulation of multiple signaling pathways that work in a synergistic manner to initiate and promote the tumor"

- Dr. Michihisa Umetani, The Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, The HEALTH Research Institute, University of Houston & Hulin Wu - The Department of Biostatistics and Data Science, School of Public Health, University of Texas Health Science Center at Houston

Studying the cooperation between these oncogenic pathways could help identify genes commonly regulated by oncogenic pathways and, importantly, genes that are synergistically regulated, the latter of which are likely to play important roles in tumor-initiation and cancer growth.

In addition, the upstream activators of the SHH pathway are dependent on EGF- receptor-mediated activation of the RAS/RAF/MEK/ERK pathway, but not of the PI3K/AKT pathway.

They used publicly available gene expression profiling datasets from a human medulloblastoma cell line that possesses a fully inducible endogenous SHH pathway according to gene expression profiling.

Figure 1: Gene response modules under Control and SHH+ conditions. Matching large size GRMs under Control (left column) or SHH+ (right column). The Spearman correlation between the mean curves (red curves) is also reported for each pair.

However, only 12 genes with a documented role either in EGF or SHH pathways were used for further validation, and under co-activation of both pathways, canonical SHH target genes such as GLI1, PTCH, and HHIP were downregulated, while selected EGF target genes such as MMP7, VEGFA, and IL8 were synergistically upregulated.

The authors also looked at the influence of the synergistic co-activation of the EGF and SHH pathways on individual gene levels and the overall effect at the gene network level.

The Umetani/Wu Research Team concluded in their Oncotarget Research Paper, "Our statistical and computational methods have been tested and confirmed via multiple simulation studies. In addition, in this study, we validated our in silico results with cell culture experiments in a biological context. These results indicate that our approach has the power to identify novel therapeutic targets from publicly available datasets in a more credible manner than conventional methods."

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DOI - https://doi.org/10.18632/oncotarget.27547

Full text - https://www.oncotarget.com/article/27547/text/

Correspondence to - Michihisa Umetani - mumetani@uh.edu and Hulin Wu - hulin.wu@uth.tmc.edu

Keywords - pathway cross-talk, gene expression dynamics, gene regulatory network, Sonic Hedgehog, epidermal growth factor

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