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

ABSTRACT: Non-melanoma skin cancer is the most frequent type of cancer in humans. In this study we demonstrate that elevated IKK? expression in murine epidermis increases the malignancy potential of skin tumors. We describe the generation of transgenic mice overexpressing IKK? in the basal, proliferative layer of the epidermis and in the outer root sheath of hair follicles. The epidermis of K5-IKK? transgenic animals shows several alterations such as hyperproliferation, mislocalized expression of integrin-?6 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-IKK?-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 IKK? 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-?6 in skin of transgenic mice provides, at least in part, the molecular bases for the increased malignant potential found in the K5-IKK? skin tumors.

SUBMITTER: Alameda JP

PROVIDER: S-EPMC3130791 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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

Alameda Josefa P JP Moreno-Maldonado Rodolfo R Fernández-Aceñero M Jesús MJ Navarro Manuel M Page Angustias A Jorcano José L JL Bravo Ana A Ramírez Ángel Á Casanova M Llanos ML

PloS one 20110706 7

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 ...[more]

PMID: 21755017

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Project description:The mammalian skin epidermis is a stratified epithelium composed of multiple layers of epithelial cells that exist in appropriate sizes and proportions, and with distinct boundaries separating each other. How the epidermis develops from a single layer of committed precursor cells to form a complex multilayered structure of multiple cell types remains elusive. Here, we construct stochastic, three-dimensional, and multiscale models consisting of a lineage of multiple cell types to study the control of epidermal development. Symmetric and asymmetric cell divisions, stochastic cell fate transitions within the lineage, extracellular morphogens, cell-to-cell adhesion forces, and cell signaling are included in model. A GPU algorithm was developed and implemented to accelerate the simulations. These simulations show that a balance between cell proliferation and differentiation during lineage progression is crucial for the development and maintenance of the epidermal tissue. We also find that selective intercellular adhesion is critical to sharpening the boundary between layers and to the formation of a highly ordered structure. The long-range action of a morphogen provides additional feedback regulations, enhancing the robustness of overall layer formation. Our model is built upon previous experimental findings revealing the role of Ovol transcription factors in regulating epidermal development. Direct comparisons of experimental and simulation perturbations show remarkable consistency. Taken together, our results highlight the major determinants of a well-stratified epidermis: balanced proliferation and differentiation, and a combination of both short- (symmetric/asymmetric division and selective cell adhesion) and long-range (morphogen) regulations. These underlying principles have broad implications for other developmental or regenerative processes leading to the formation of multilayered tissue structures, as well as for pathological processes such as epidermal wound healing.

Dataset Information

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

Publications

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

Similar Datasets

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