The family of tripartite-motif (TRIM) proteins is involved in diverse cellular processes, ranging from innate immunity, oncoprotein, and tumor suppressor roles. TRIM16 overexpression confers retinoid sensitivity in retinoid-resistant cancer cells. Previously, we found a strong correlation between loss of TRIM16 expression and disease progression in two human cancers: neuroblastoma and squamous cell carcinoma of skin. Moreover, TRIM16 acted as a tumor suppressor in both cancers through effects on cell cycle and migration. Here we examined the potential role of TRIM16 as a tumor suppressor in melanoma1&2.
We found that the endogenous TRIM16 expression level in seven melanoma cell lines was significantly lower than in normal human melanocytes. Overexpression of TRIM16 reduced cell viability and proliferation in multiple melanoma tumor cell lines, compared to empty vector controls (P < 0.01). Immunohistochemical analysis demonstrated that TRIM16 expression is decreased in human metastatic melanoma tissue samples (Stage 3 and 4) compared to dysplastic compound nevi and primary melanomas (n=91). Most importantly, we have demonstrated that high TRIM16 expression is a favourable prognostic marker of survival (P=0.025) in a cohort of 170 melanoma patients with lymph node metastases. Median survival was 59 months in the high TRIM16 expression group (n=64), compared to 16 months in the low TRIM16 expression group (n=106). We also show overexpression of TRIM16 in melanoma cells lines induced interferon-beta 1 (IFNB1) mRNA expression, and IFNB1 expression is required for inhibition of cell proliferation by TRIM16. IFNB1 expression was also reduced in human metastatic melanoma tissue samples (n=91), and positively correlated with TRIM16 expression in patient samples. Our in vitro and in vivo data suggest that TRIM16 acts as a tumor suppressor in melanoma cells via the IFNB1 signaling pathway, and may play an important role in melanoma tumor progression and metastasis.