Abstract

Malignant melanoma is the most aggressive type of skin cancer, which initiates in the pigment-producing cells called melanocytes. Exposure to ultra violet radiation (UVR) of the sun and family history increases the risk of developing melanoma. Early detection of tumors improves survival. However, for patients with metastatic melanoma, there are few treatment options and a 5-year survival rate of less than 5%. Therefore, it is of importance to identify the molecular mechansims that drive metastasis of melanoma cells. 

High expression of wingless-type MMTV integration site family 5A (WNT5A) has been reported in melanoma and correlates with increased migration and invasion of melanoma cells. In this thesis, we investigate that WNT5A and interleukin-6 (IL-6) form a positive feedback loop, which accelerates the invasive property of melanoma cells. In  addition, we demonstrate that combined targeting of IL-6 signaling and WNT5A expression, using an anti-IL-6 antibody and a WNT5A antagonist peptide (Box5), respectively, more effectively reduces melanoma cell dissemination, as compared to each factor alone. Moreover, we show that the RNA-binding protein human antigen R (HuR) drives melanoma cell motility, and targeting HuR with a specific HuR inhibitor, MS-444, significantly reduces melanoma cell migration. Further analyses revealed that simultaneously targeting HuR, with MS-444, and WNT5A signaling, with Box5, reduces melanoma cell migration and invasion via two different and partially overlapping signaling pathways, which are PKC and PI3K-AKT. Our results also show that acquired BRAF-inhibitor (BRAFi) resistance leads to increased expression of HuR and WNT5A in malignant melanoma cells, and simultaneous therapeutic inhibition of HuR function and WNT5A signaling could be an efficient treatment strategy to impair the invasive migration of BRAFi-resistant melanomas.

Taken together, our results extend our knowledge about WNT5A regulation in melanoma and highlight the importance of HuR and WNT5A in melanoma cell migration and invasion.