Increased IKKα expression in the basal layer of the epidermis of transgenic mice enhances the malignant potential of skin tumors.

Josefa P Alameda,Rodolfo Moreno-Maldonado,Manuel Navarro,Angustias Page,M Llanos Casanova,Ana Bravo,Ángel Ramírez,José L Jorcano,M Jesús Fernández-Aceñero

doi:10.1371/journal.pone.0021984

Abstract

Non-melanoma skin cancer is the most frequent type of cancer in humans. In this study we demonstrate that elevated IKKα expression in murine epidermis increases the malignancy potential of skin tumors. We describe the generation of transgenic mice overexpressing IKKα in the basal, proliferative layer of the epidermis and in the outer root sheath of hair follicles. The epidermis of K5-IKKα transgenic animals shows several alterations such as hyperproliferation, mislocalized expression of integrin-α6 and downregulation of the tumor suppressor maspin. Treatment of the back skin of mice with the mitogenic agent 12-O-tetradecanoylphorbol-13-acetate causes in transgenic mice the appearance of different preneoplastic changes such as epidermal atypia with loss of cell polarity and altered epidermal tissue architecture, while in wild type littermates this treatment only leads to the development of benign epidermal hyperplasia. Moreover, in skin carcinogenesis assays, transgenic mice carrying active Ha-ras (K5-IKKα-Tg.AC mice) develop invasive tumors, instead of the benign papillomas arising in wild type-Tg-AC mice also bearing an active Ha-ras. Therefore we provide evidence for a tumor promoter role of IKKα in skin cancer, similarly to what occurs in other neoplasias, including hepatocarcinomas and breast, prostate and colorectal cancer. The altered expression of cyclin D1, maspin and integrin-α6 in skin of transgenic mice provides, at least in part, the molecular bases for the increased malignant potential found in the K5-IKKα skin tumors.

Highlights

Keratinocytes of the basal layer of the epidermis are mitotic, providing new cells to replace those that are shed
We have found that the overexpression of IKKa in the epidermis of keratin 5 (K5)-IKKa mice causes several molecular alterations, such as increased cyclin D1 expression, delocalized suprabasal integrin-a6 expression and downregulation of the tumor suppressor maspin
These proteins are important for cancer development and progression, suggesting that the skin of these Tg mice could develop more aggressive lesions when subjected to skin injuries than wild type (WT) skin

Summary

Introduction

Keratinocytes of the basal layer of the epidermis are mitotic, providing new cells to replace those that are shed. Reintroduction of IKKa or a kinase-inactive mutant IKKa induces terminal differentiation of keratinocyte and represses hyperproliferation [9,10]. This demonstrates that IKKa is necessary for epidermal differentiation independently of its kinase activity [9]. We have described that IKKa increases the differentiation of human keratinocytes by a mechanism dependent on E-cadherin [5]. Other adhesion molecules such as claudin-23, occludin and desmoglein 3 have been found to be regulated by IKKa and to play a role in epidermal terminal differentiation and skin barrier function [11]

Methods

Results

Conclusion