Differential Roles of HMGA2 Isoforms in Prostate-Cancer Bone Microenvironmental Interactions

Prostate cancer (PCa) is the second leading cause of cancer related deaths in American men. Compared to Caucasian men, African American males have a higher bone density, as well as mortality rate due to PCa bone metastasis. Recent studies have shown that high mobility group A2 (HMGA2), a non-histone chromatin binding protein, plays a critical role in promoting epithelial-mesenchymal transition (EMT) and metastasis. HMGA2 full-length/wild-type and truncated (lacking the 3’UTR) isoforms are overexpressed in several cancers, however, their distinct roles in metastasis have not been reported. Our laboratory focuses on tumor-microenvironmental interactions, particularly, how PCa cells interact with bone at the metastatic site. We have previously published that PCa cells may degrade hydroxyapatite, the major inorganic component of bone, to release calcium which promotes paracrine cell proliferation and migration, and this signaling increases with increased bone density. We hypothesize that HMGA2 isoforms may play differential roles at the bone metastatic site to increase paracrine cell migration. LNCaP PCa cell line stably overexpressing either wild-type or truncated HMGA2 was co-cultured with low (100 mg) or high (200 mg) hydroxyapatite bone density, for 6 days followed by collection of conditioned media (CM). CM was analyzed for calcium levels, and also added to parental LNCaP cells for various timepoints followed by analysis of paracrine cell migration across collagen-coated boyden chambers, and the effect on various signaling pathways further analyzed using western blot analysis. Truncated HMGA2 co-cultured with hydroxyapatite led to increased paracrine phospho-ERK expression, and higher paracrine cell migration, compared to wild-type HMGA2. Our study shows that HMGA2 isoforms may differentially mediate PCa/hydroxyapatite interactions at the bone metastatic site.