Intermediate filament proteins make up the largest family of cytoskeletal proteins, and mutation or altered expression of intermediate filament proteins cause or significantly correlate with more than 80 human diseases. One key feature of the intermediate filament-associated diseases is altered expression profiles of genes that directly contribute to disease progression. One such disease type is epithelial cancers, where keratin intermediate filament proteins are widely used as diagnostic and prognostic markers for human patients, and select keratins promote tumor progression in animal models. In breast cancer, Keratin 19 (K19) is one of the most reliable and extensively studied diagnostic markers, and its higher expression correlates with worse patient prognosis. However, the specific impact of this biomarker in the tumor development remains unknown. Based on our preliminary data in human breast cancer cells and previous work on a related keratin in skin cancer cells, we propose that K19 regulates the expression of metastasis-related genes and promote metastatic cell behaviors through a direct interaction with hnRNP K. hnRNP K is a RNA-binding protein that regulates the expression of a host of pro-tumorigenic genes and promotes metastasis when accumulated in the cytoplasm. We hypothesize that K19 filaments function as cytoplasmic scaffolds for hnRNP K to post- transcriptionally regulate genes that promote invasive cell behaviors that lead to tumor metastasis. This proposal is aimed at uncovering the mechanistic details of how K19 and hnRNP K interact (Aim 1), and identifying the impact of K19-hnRNP K cooperation at the molecular and cellular levels, as well as the in vivo significance of their expression in tumor metastasis (Aim 2). Meeting the above aims will identify the contribution of a tumor marker towards metastasis, determine the regulatory mechanism governing expression of metastasis-associated genes, and reveal how the cytoplasmic accumulation of hnRNP K promotes metastasis. This proposal also has the potential to identify a novel regulator of intermediate filament organization. Ultimately, the knowledge gained can help develop novel therapeutic strategies to combat cancer and serve as a blueprint to better understand a myriad of diseases where intermediate filament genes are mutated or show altered expression.
(Relevance to Public Health) High expressions of select keratins in tumors significantly correlate with poor patient prognoses. The proposed research examines a novel interaction of a keratin protein and a regulator of gene expression and its impact on promoting breast cancer metastasis. Our proposal has the potential to elucidate a key pathway in tumor metastasis and provide an underlying mechanism to design and develop more effective therapeutic strategies.
