Background: Cutaneous malignant melanoma is one of the most aggressive forms of skin cancer with an extremely poor prognosis for the patients diagnosed with metastatic disease. Ulceration has been correlated with an increased risk of death within a given thickness range, however, the biologic basis for the development of ulceration is poorly understood. Livin, an inhibitor of apoptosis protein (IAP), is overexpressed in various cancers and possesses both the ability to protect from cell death and to promote it once it is cleaved. It is unknown whether there is a differential cellular expression of livin in ulcerated versus non-ulcerated melanomas. Methods: To explore the role of livin in relation to ulceration, other clinicopathological factors and survival of melanoma patients, we have performed semiquantitative immunohistochemical analysis of livin expression as measured by percentage and intensity (levels) of cells immunoreactive for livin in tumor specimens having both ulcerated and non-ulcerated areas from 50 melanoma lesions. Results: Superficial as well as deep melanoma cells located in non-ulcerated areas of tumor had higher percentage of cytoplasmic immunopositivity for livin when compared with melanocytes in the ulcerated areas of the melanoma (p<0.0001). We also observed nuclear expression of livin protein in this subset of melanoma patients. Compared to the ulcerated areas, the superficially located melanoma cells from the non-ulcerated areas showed significantly higher intensity of livin immunoreactivity in their nuclei (p = 0.048) but not those from the deep non-ulcerated areas (p = 0.32). Ulcerated melanomas with low tumor stage (I/II) had higher percentage of tumor cells with nuclear livin expression than those from higher tumor stage (III/IV) (p = 0.002). Interestingly, we observed that patients with higher intensity of cytosolic expression of livin protein in the ulcerated area of tumor were more likely to have a brisk tumor-infiltrating lymphocytes (TILs) response (p = 0.001). Patients with higher intensity of cytoplasmic livin protein of tumor cells in ulcerated areas had higher risk of death compared to those with lower levels (p = 0.005). On the other hand, patients with higher intensity of cytoplasmic expression of livin in melanoma cells located superficially in the non-ulcerated areas of tumor had better prognosis (p = 0.045). Conclusion: Our data indicate that there is a decrease of nuclear as well as cytoplasmic expression of livin protein in melanoma cells from ulcerated when compared to non-ulcerated areas. Also, cytoplasmic livin expression is an indicator of poor prognosis, but apparently only in patients with ulcerated lesions. Although IAPs regulate caspases, they also regulate signaling pathways that activate NF-κB modulating immunity. The prominent TILs response in livin-positive tumors suggests a possible involvement in tumor immunity in melanoma.
Citation Format: Nitin Chakravarti, Dawen Sui, Denái R. Milton, Wen-Jen Hwu, Elizabeth A. Grimm, Victor G. Prieto. Differential expression of the melanoma inhibitor of apoptosis protein (ML-IAP)/Livin in patients with ulcerated and non-ulcerated melanomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3570.