UBC Theses and Dissertations
The role of the membrane scaffolding protein KAI1 in human cutaneous melanoma Tang, Yun
Cutaneous melanoma remains to be not only one of the most deadly among all skin cancers, but it’s one of the most deadly of all cancers in general. It is crucial to have an early detection of the disease despite lacking any effective treating options while therapeutic strategies of later stages of melanoma have yet to be discovered. Meanwhile, the mechanism modulating the progression of melanoma is still not well understood. In this study, we investigated KAI1’s role during metastasis regulation in human melanoma. We proposed the tumor suppressor function of KAI1 was directly correlated with KAI1 expression and showed the loss of KAI1 expression in melanoma patient samples significantly correlated with poorer patient survival. Furthermore, forced KAI1 expression was shown to suppress melanoma cell migration and invasion primarily through its regulation of another tumor suppressor gene: inhibitor of growth 4 (ING4). Moreover, KAI1 expression significantly suppressed melanoma angiogenesis by reducing HUVEC cell growth and tubular structure formation. In fact, KAI1’s regulation on angiogenesis was associated with the modulation of IL-6 and VEGF expression. Additionally, we investigated the mechanistic pathway between KAI1 and ING4 and found that KAI1 suppressed Akt phosphorylation through the regulation of EGFR and VEGFR phosphorylation. Meanwhile, the semaphorin 3C (SEMA3C) protein had been identified as an oncogene that induced cancer cell migration and invasion. In this study, we found that SEMA3C was also able to induce melanoma angiogenesis observed in the elevated HUVEC growth and tube formation. Furthermore, we showed that KAI1 expression suppressed SEMA3C-induced melanoma angiogenesis whereas KAI1 knockdown rescued the SEAM3C-suppressed melanoma angiogenesis. According to our study, we have illustrated a regulatory pathway of KAI1 on the regulation of melanoma metastasis which involves the regulation of the PI3K/Akt pathway and the tumor suppressor gene ING4. Also, the restoration of KAI1 expression was shown to significantly suppress melanoma cancer cell migration, invasion and angiogenesis. Taken together, KAI1 was a potential diagnostic marker for advanced melanoma and the restoration of KAI1 expression might shed light on new therapeutic approaches for treating cutaneous human melanoma.
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