Christopher Hill Thesis Defense

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MicroRNAs (miRNAs) are often dysregulated in ovarian cancer. These short
non-coding RNA sequences regulate gene expression by repressing specific,
targeted mRNAs. We investigated the effects of miRNAs, found to be
upregulated in ovarian cancer, on thousands of genes, and found that certain
miRNAs appeared to be critical to the transformation of ovarian epithelial
cells from normal to cancer. In addition, we found evidence that the
deactivation of powerful transcriptional repressors often results in the
unexpected upregulation of predicted miRNA targets.

We also demonstrated, computationally and empirically, that even a single
nucleotide mutation in the miRNA “seed region” (that portion of a miRNA
that specifies which mRNAs will be targeted) can result in the complete
disablement of that miRNA’s repressive ability against its putative targets.
We built a phenomenological network model by comparing changes in
expression between millions of pairs of genes in normal and cancerous
ovarian epithelial cells. We found that the number of highly correlated gene
pairs decreased dramatically between normal and cancer tissues. This
suggests either a loss of control in cancer, the existence of sub-populations
within the tumors, or the existence of multiple tumor subtypes. We noticed
that most pairs of genes which were highly correlated in normal tissue
remained correlated in cancer. Gene pairs which did not maintain their
correlation in cancer, we termed inconsistent. Inconsistent gene pairs shared
some important characteristics: 1) one of the genes was generally
upregulated; 2) both genes often were enriched for the cell cycle and/or
apoptotic processes; and 3) at least one member of the gene pair had been
previously implicated in ovarian and/or other cancers.

The complexity of these highly interconnected network modules suggests
that there are no master regulators of cancer. Rather, it implies that there
exists an orchestra of dysregulated genes which interact in small ensembles,
disrupting critical biological processes, motivating proliferation and