Enhanced FHL2 and TGF-ß1 Expression Is Associated With Invasive Growth and Poor Survival in Malignant Melanomas.

ABSTRACT

OBJECTIVES: This study examines the expression and the role of four-and-a-half LIM domains protein 2 (FHL2) and transforming growth factor ß1 (TGF-ß1) in human malignant melanoma. It is determined whether both proteins influence melanoma survival time. METHODS: We analyzed the immunohistochemical staining intensities of FHL2 and TGF-ß1 in normal skin and in 50 malignant melanomas with different mutation status (BRAF-V600E, NRAS codon 61 mutation, and wild type). Survival data were available for 45 cases. RESULTS: In melanocytes of nonneoplastic human skin, FHL2 expression was absent. In contrast, 38 (76%) of 50 melanomas showed strong cytoplasmic and partly nuclear FHL2 expression. At the invasion front, cytoplasmic TGF-ß1 staining was observed in 32 (64%) of 50 melanomas, and a correlation of FHL2 and TGF-ß1 staining intensities was detectable. In follow-up analyses, enhanced FHL2 and TGF-ß1 staining intensities in the tumor invasion front were associated with poor survival. CONCLUSIONS: Enhanced FHL2 and TGF-ß1 expression is correlated with poor survival in human malignant melanoma. Protumorigenic effects of autocrine TGF-ß1 secretion might be exerted by induction of FHL2 expression in melanoma cells. Since melanomas treated with targeted therapies often do not show sufficient response rates, inhibition of FHL2 and/or TGF-ß1 might be a promising therapeutic approach.