Investigation of the Role of P47 in Stress Granule and Oral Cancer Metastasis with Proteome-Wide Analysis

Oral cancer is the fifth leading cause of cancer-related mortality and leads to approximately 3000 deaths each year in Taiwan. Despite advances in oral cancer treatment, more than 50% of patients die within 5 years after initial diagnosis, mostly ascribed to lymphatic metastasis of cancer cells. Five-year survival rate of oral cancer patients with lymphatic metastasis is less than 40% compared with 90% of patients without metastasis, suggesting that it is needed to identify biomarkers and therapeutic targets for diagnosis and treatment of oral cancer metastasis. We consider that NSFL1 cofactor p47 (p47) is a potential therapeutic target or biomarker of oral cancer metastasis, based on our proteomics analyses that the p47 level in oral cancer tissues is higher than that in adjacent non-cancerous oral tissues, and noteworthily, p47 level in the oral cancer tissues with lymphatic metastasis is significantly elevated compared to that without lymphatic metastasis. In addition, the p47 level in the oral cancer tissues is also found to be correlated with expression of protein components in stress granules. p47 is involved in the reassembly of Golgi stacks at the end of mitosis via the interaction with valosin-containing protein (VCP/p97), a cytosolic ATPase associated with various cellular activities. However, its expressional profiles and functions in cancers remain limited to date. Our preliminary data have revealed that p47 is over-expressed in oral cancer tissues compared to adjacent non-cancerous counterparts, and plays a promoting role in oral cancer cell migration and invasion. Given that oral cancer is a highly metastatic head and neck cancer, deciphering the mechanism underlying the p47-mediated metastasis will accelerate the understanding of oral cancer progression. In the present proposal, we attempt to (1) identify proteins dysregulated in p47-knockdown oral cancer cells, especially the protein components in stress granules, and (2) characterize the role of p47 in stress granule formation to understand whether stress granule is involved in p47-mediated promotion of cell migration and cancer metastasis. Finally, (3) the therapeutic potential of p47 and/or stress granule will be further evaluated in cell and mouse xenograft models. This study will not only provide the novel insights of p47 in cancer formation and progression, but also lead to therapeutic targets to limit the spreading of oral cancer.

Project ID:PC10901-1926
External Project ID:MOST108-2320-B182-030-MY3