Differential expression of cell survival and cell cycle regulatory proteins in cutaneous squamoproliferative lesions

• Published in: Journal of dermatological science 1999, Vol.19 (1), p.53-67
• Main Authors: Wrone-Smith, Tamara, Bergstrom, Jane, Quevedo, Maria Eugenia, Reddy, Vijaya, Gutierrez-Steil, Christina, Nickoloff, Brian J
• Format: Article
• Language: English
• Subjects: Apoptosis; bcl-2-Associated X Protein; Bcl-x; bcl-X Protein; Cell Cycle Proteins - biosynthesis; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cell Survival - physiology; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - analysis; Differentiation; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Keratinocyte; Ki-67 Antigen - analysis; Proliferation; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins c-bcl-2 - analysis; Skin - metabolism; Skin - pathology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Squamous cell carcinoma; Tumor Suppressor Protein p53 - analysis
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/S0923-1811(98)00052-8

Previous models of cutaneous carcinogenesis have primarily focused on the regulation of keratinocyte (KC) proliferation and differentiation. However, it has become clear in many neoplastic systems that altered rates of cell death and/or inabilty to undergo growth arrest can also contribute to the development of cancer. Apoptosis-regulatory proteins include those that block apoptosis such as Bcl-2 and Bcl-x, whilst a related protein Bax promotes apoptosis. Cell cycle regulatory proteins include those associated with growth arrest, i.e. p21 waf1, p53, and those associated with proliferation, i.e. Ki-67. Paraffin embedded samples from ten different lesions of squamous cell carcinoma (SCC), Bowen’s disease (BD), keratoacanthomas (KA), and nine normal adult skin samples were stained by immunohistochemistry to detect expression of Bcl-2, Bcl-x, Bax, Ki-67, p21 waf1, p53 and apoptosis (TUNEL assay). Compared to low levels of Bcl-x and Bcl-2 immunostaining in normal skin, all the squamoproliferative lesions had strong and diffuse KC expression of Bcl-x (>80%) but minimal to absent KC Bcl-2 expression (70%). These immunostaining profiles reveal that squamoproliferative lesions, including invasive transformed KCs, preferentially express Bcl-x over Bcl-2, in addition to upregulating their Bax levels. Even though there were numerous TUNEL positive cells in these squamoproliferative lesions, no other evidence of apoptosis was seen reinforcing the necessity to use caution when relying on TUNEL staining for identification of programmed cell death in skin biopsies. Normal sun-exposed skin had low but detectable p53 and rare p21 waf1 KC expression. Significantly higher numbers of p21 waf1 and p53 immunopositive KCs were noted throughout the lesions in BD and SCC in contrast to KA where p53 and rare p21 waf1 immunopositive KCs were primarily limited to the periphery of the tumor cell islands. In general, p53 KC expression was higher in all squamoproliferative lesions and sun-exposed normal skin compared to p21 waf1 expression. Summary of the expression of cell cycle regulatory proteins for both p21 waf1 and p53 KC expression was: SCC>BD>KA, in marked contrast to Ki-67 KC expression which was: BD>KA>SCC. The relatively few malignant cells in SCC that were acti