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Role of Sox4 transcription factor in human cutaneous melanoma

University of British Columbia

Cutanous melanoma is an aggressive malignancy with very few effective treatment strategies in the early stages and virtually no successful cure in the late stages. So far many aspects of biology of melanoma, especially mechanisms responsible for its metastasis have remained undiscovered. The SRY-related HMG box4 (Sox4) protein is aberrantly expressed in several types of tumors. In this study we investigated the role of Sox4 in human cutaneous melanoma. We hypothesized that expression of this protein is changed during melanoma progression with functional consequences on progression of melanoma. We revealed that Sox4 expression is reduced in metastatic melanomas and this loss of expression correlates with poorer patients survival. We found that Sox4 expression is required for suppression of melanoma cell migration and invasion. We determined that Sox4 uses at least two distinct pathways to suppresses melanoma cell migration and invasion. First, through binding to the regulatory regions and inhibiting the transcription of NF-κB p50. Secondly, it also regulates the miRNA biogenesis pathway at least partially through upregulation of the pre-miRNA processor, Dicer. Moreover, we showed that expression of Sox4 inversely correlates with that of NF-κB p50 in melanoma biopsies but positively correlates with Dicer expression which further supports our in vitro observations. We also revealed that expression of Dicer, similar to its upstream regulator Sox4, decreases in metastatic melanoma and this reduced expression inversely correlates with patient survival. In addition to Dicer, we also found that expression of the pre-miRNA processing enzyme Drosha is reduced in early stages of melanomagenesis. Dicer and Drosha demonstrate different expression patterns which imply differential regulatory mechanisms. Nevertheless, samples that lost expression of both Dicer and Drosha represented worse survival outcome in contrast to those with positive expression of both markers. Finally, we revealed that the subcellular localization of Dicer and Drosha may be deregulated in melanocytic lesions and possibly has relevance to the biology of melanoma. The data presented in this thesis elucidated a hitherto unknown mechanism responsible for suppression of metastasis which is malfunctioned in melanoma. A better understanding of this pathway may help toward treatment or prevention of metastatic melanoma.

Text

2013-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44026

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/