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An investigation into the role of C-terminal tensin-like protein (Cten) in melanomagenesis Sjoestroem, Anna Cecilia

Abstract

C-terminal tensin-like protein (Cten) is a focal adhesion protein with no or limited protein expression in normal tissues, which has recently been reported to be overexpressed and act as an oncoprotein in numerous cancers. Since its expression status in human cutaneous melanoma is currently unknown, I used tissue microarrays and immunohistochemical staining to examine the protein expression of Cten throughout melanoma progression. I found that Cten was significantly up-regulated in dysplastic nevi (DN) compared to normal nevi (NN), and in primary melanoma (PM) compared to both DN and NN. Strong Cten staining was associated with a poorer 5- and 10-year overall and disease-specific survival for PM patients, and was an adverse independent prognostic factor for the 5-year survival of the same patients. In vitro studies using two melanoma cell lines supported these findings and indicated that Cten functions as an oncogene in melanoma. Since relatively little is known about how Cten contributes to tumorigenesis, I next investigated the expression profile of the RhoGAP Deleted in Liver Cancer-1 (DLC1), the only protein known to bind to Cten, in melanomas. Both cytoplasmic and nuclear DLC1 were detected, and both were down-regulated in metastatic melanoma (MM) compared to PM and nevi, with nuclear DLC1 expression additionally being reduced in PM compared to nevi. Both cytoplasmic and nuclear DLC1 were associated with the 5-year overall and disease-specific survival of all melanoma and MM patients, and with the disease-specific 10-year survival of all melanoma patients. Combined analysis of cytoplasmic and nuclear DLC1 revealed that for MM patients, concurrent loss of both cytoplasmic and nuclear DLC1 was associated with the worst survival outcome, with loss of either or both forms being a significant adverse independent prognostic factor for the 5-year survival of all melanoma and MM patients. A preliminary investigation into the relationship between Cten and DLC1 indicated that the effects of Cten on patient survival were dependent on the levels of DLC1, as expected. In summary, I here provide an initial characterization of the expression status and role of Cten in melanomagenesis, and speculate that it functions partly via interactions with the tumour suppressor DLC1.

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