Melanoma Genetics and Therapeutic Approaches in the 21st Century: Moving from the Benchside to the Bedside

Hocker, Thomas L.; Singh, Meena

doi:10.1038/jid.2008.226

Cited by 169 publications

(197 citation statements)

References 183 publications

(255 reference statements)

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“…Although many therapeutic regimens for metastatic melanoma have been tested, very few achieve response rates 425%. 26 Given the rising incidence of melanoma and the paucity of effective treatments, there is much hope for targeted therapies and promising agents, including those that act on apoptosisregulating molecules. 11,27 Herein, we showed a novel role for FKBP51 as a marker of melanocyte malignancy and involvement in the protection of melanoma against Rx-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

et al. 2009

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FK506-binding protein 51 (FKBP51) is an immunophilin with isomerase activity, which performs important biological functions in the cell. It has recently been involved in the apoptosis resistance of malignant melanoma. The aim of this study was to investigate the possible role of FKBP51 in the control of response to ionizing radiation (Rx) in malignant melanoma. FKBP51-silenced cells showed reduced clonogenic potential after irradiation compared with non-silenced cells. After Rx, we observed apoptosis in FKBP51-silenced cells and autophagy in non-silenced cells. The FKBP51-controlled radioresistance mechanism involves NF-jB. FKBP51 was required for the activation of Rx-induced NF-jB, which in turn inhibited apoptosis by stimulating X-linked inhibitor of apoptosis protein and promoting authophagy-mediated Bax degradation. Using a tumor-xenograft mouse model, the in vivo pretreatment of tumors with FKBP51-siRNA provoked massive apoptosis after irradiation. Immunohistochemical analysis of 10 normal skin samples and 80 malignant cutaneous melanomas showed that FKBP51 is a marker of melanocyte malignancy, correlating with vertical growth phase and lesion thickness. Finally, we provide evidence that FKBP51 targeting radiosensitizes cancer stem/initiating cells. In conclusion, our study identifies a possible molecular target for radiosensitizing therapeutic strategies against malignant melanoma.

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Section: Discussionmentioning

confidence: 99%

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

et al. 2009

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“…1 Melanoma presents challenges to pathologists and clinicians, such as the reliable diagnosis of early/developing lesions and effective treatment of metastatic disease, respectively. 2,3 A more complete understanding of the molecular changes accompanying melanoma tumorigenesis and progression promises to identify novel diagnostic and therapeutic targets for melanoma.…”

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confidence: 99%

Expression of the embryonic morphogen Nodal in cutaneous melanocytic lesions

Harms

Pouryazdanparast

et al. 2010

Modern Pathology

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Nodal, a potent embryonic morphogen in the transforming growth factor-b family, is a proposed key regulator of melanoma tumorigenicity. However, there has been no systematic study of Nodal expression in melanocytic lesions. We investigated Nodal expression by immunohistochemistry in 269 melanocytic lesions, including compound nevi, dysplastic nevi, congenital nevi, Spitz nevi, melanoma in situ, malignant melanoma including the variant desmoplastic melanoma, and metastatic melanoma. We found that the Nodal expression was significantly increased in malignant lesions (including melanoma in situ, malignant melanoma, and metastatic melanoma) compared with compound nevi, Spitz nevi, and dysplastic nevi. Surprisingly, congenital nevi expressed a level of Nodal comparable with malignant lesions, whereas desmoplastic melanoma showed lower expression than nondesmoplastic malignant melanoma (Po0.05). Deep melanoma (Breslow depth 41 mm) displayed a higher percentage of Nodal-positive tumor cells than did superficial melanoma (Breslow depth r1 mm), although there was no statistical difference in the overall staining intensity (P ¼ 0.18). Melanomas in situ showed a lower level of Nodal expression than did deep melanomas and metastatic melanomas (Po0.05). The low expression of Nodal in normal and dysplastic nevi, and its increasing expression with the progression of malignant lesions, are suggestive of a role for Nodal in melanoma progression.

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“…Although found predominantly in the skin, primary melanomas are also known to occur in the bowel and eye (18). Malignant melanoma is notoriously one of the most difficult cancers to treat (19). Therefore, identifying and understanding molecules that regulate the aggressive melanoma phenotype is essential for predicting the likelihood of metastasis.…”

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confidence: 99%

Syndecan-2 Regulates the Migratory Potential of Melanoma Cells

Lee

Park

Chung

et al. 2009

Journal of Biological Chemistry

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Syndecan-2, a transmembrane heparan sulfate proteoglycan, is a critical mediator in the tumorigenesis of colon carcinoma cells. We explored the function of syndecan-2 in melanoma, one of the most invasive types of cancers, and found that the expression of this protein was elevated in tissue samples from both nevus and malignant human melanomas but not in melanocytes of the normal human skin tissues. Similarly, elevated syndecan-2 expression was observed in various melanoma cell lines. Overexpression of syndecan-2 enhanced migration and invasion of melanoma cells, whereas the opposite was observed when syndecan-2 levels were knocked down using small inhibitory RNAs. Syndecan-2 expression was enhanced by fibroblast growth factor-2, which is known to stimulate melanoma cell migration; however, ␣-melanocyte-stimulating hormone decreased syndecan-2 expression and melanoma cell migration and invasion in a melanin synthesis-independent manner. Furthermore, syndecan-2 overexpression rescued the migration defects induced by ␣-melanocyte-stimulating hormone treatment. Together, these data strongly suggest that syndecan-2 plays a crucial role in the migratory potential of melanoma cells.

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Melanoma Genetics and Therapeutic Approaches in the 21st Century: Moving from the Benchside to the Bedside

Cited by 169 publications

References 183 publications

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

Expression of the embryonic morphogen Nodal in cutaneous melanocytic lesions

Syndecan-2 Regulates the Migratory Potential of Melanoma Cells

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