Nuclear Krüppel-like factor 4 expression is associated with human skin squamous cell carcinoma progression and metastasis

Abstract

Krüppel-like factor 4 (KLF4) is a transcription factor regulating cell growth and differentiation. It has been postulated as a tumor suppressor gene in several tumors including colon cancer and prostate cancer; whereas, it is activated in other tumors such as breast cancer and oropharyngeal carcinomas. To understand the significance KLF4 on clinicopathologic implications in human squamous cell carcinoma skin (SCC) progression, thirty six formalin-fixed paraffin-embedded samples of cutaneous SCC and 28 samples of Bowen's disease were stained with anti-KLF4 antibodies. A semiquantitative evaluation of the degree of staining intensity and localization of expression were analyzed and correlated with histological and clinical features. Nuclear KLF4 staining was seen in differentiated epithelium including suprabasal keratinocyte of non-lesional skin. Strong nuclear KLF4 staining was observed in tumor parts of both SCC and Bowen's disease, when compared with their non-tumor parts (p = 0.001). Increased expression of KLF4 protein and mRNA were found in squamous cell carcinoma cell line studies and fresh skin tissue respectively, using western blotting and semi-quantitative real time polymerase chain reaction (PCR). SCC with moderately and poorly differentiated tumors tend to have maturation independent (MI) staining pattern (p = 0.0004), compared to maturation dependent (MD) staining in well-differentiated tumors. Finally, constitutive nuclear KLF4 staining pattern was significantly associated with moderately and poorly differentiated tumors (p = 0.0006), and tumor metastasis (p = 0.024). We propose that KLF4 expression is associated with human skin SCC progression and metastases.