Molecular classification of cancers has been significantly improved patient outcomes through the implementation of treatment protocols tailored to the abnormalities present in each patient's cancer cells. Breast cancer represents the poster child with marked improvements in outcome occurring due to the implementation of targeted therapies for estrogen receptor or human epidermal growth factor receptor-2 positive breast cancers. Important subtypes with characteristic molecular features as potential therapeutic targets are likely to exist for all tumor lineages including hepatocellular carcinoma (HCC) but have yet to be discovered and validated as targets. Because each tumor accumulates hundreds or thousands of genomic and epigenetic alterations of critical genes, it is challenging to identify and validate candidate tumor aberrations as therapeutic targets or biomarkers that predict prognosis or response to therapy. Therefore, there is an urgent need to devise new experimental and analytical strategies to overcome this problem. Systems biology approaches integrating multiple data sets and technologies analyzing patient tissues holds great promise for the identification of novel therapeutic targets and linked predictive biomarkers allowing implementation of personalized medicine for HCC patients.
Biomarkers ; Breast ; Breast Neoplasms ; Carcinoma, Hepatocellular ; Child ; Clinical Protocols ; Epidermal Growth Factor ; Epigenomics ; Estrogens ; Gene Expression Profiling ; Genome ; Genomics ; Humans ; Precision Medicine ; Liver ; Liver Neoplasms ; Oligonucleotide Array Sequence Analysis ; Prognosis ; Proteomics ; Systems Biology

The small GTP-binding protein Rab25 is associated with tumor formation and progression. However, recent studies have shown discordant effects of Rab25 on cancer cell progression depending on cell lineage. In the present study, we elucidate the underlying mechanisms by which Rab25 induces cellular invasion. We demonstrate that Rab25 increases β1 integrin levels and subsequent activation of EGFR and upregulation of VEGF-A expression, leading to increased Snail expression, epithelial-to-mesenchymal transition and cancer cell invasiveness. Strikingly, we identify that Snail mediates Rab25-induced cancer cell invasiveness through fascin expression and that ectopic expression of Rab25 aggravates metastasis of ovarian cancer cells to the lung. We thus demonstrate a novel role of a β1 integrin/EGFR/VEGF-A/Snail signaling cascade in Rab25-induced cancer cell aggressiveness through induction of fascin expression, thus providing novel biomarkers and potential therapeutic targets for Rab25-expressing cancer cells.
Biomarkers ; Cell Lineage ; Ectopic Gene Expression ; GTP-Binding Proteins ; Lung ; Neoplasm Metastasis ; Ovarian Neoplasms ; Snails ; Up-Regulation ; Vascular Endothelial Growth Factor A