HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

Abstract

The HOX homeodomain proteins are fundamental regulators of organ and tissue development, where they are thought to function as transcription factors, and HOX gene expression has been associated with numerous types of cancers. Previous studies have demonstrated that enforced expression of the HOXB4 protein transforms cultured fibroblasts and leads to a selective expansion of the hematopoietic stem cell pool, suggesting that this protein might play a role in cellular proliferation. In support of this concept, we now show that enforced expression of HOXB4 in human neonatal keratinocytes results in increased cellular proliferation and colony formation as well as decreased expression of the alpha-2-integrin and CD44 cell surface adhesion molecules. We previously have reported HOXB4 gene expression in the basal and suprabasal layers of developing human skin and now show extensive HOXB4 mRNA in psoriatic skin and basal cell carcinoma. In fetal human skin HOXB4 protein expression was both nuclear and cytoplasmic within epidermal basal cells and in hair follicle inner and outer root sheath cells, whereas strong nuclear signals were observed in the bulge region. In adult skin, HOXB4 protein expression was both nuclear and cytoplasmic, but was predominantly localized to the intermediate and differentiated cell layers. In contrast to the striking gradient patterns of HOX gene and protein expression previously described in developing spinal cord and limb, HOXB4 protein was uniformly detected in all regions of the fetal and adult skin. Although little HOXB4 signal localized to proliferative cell layers, as marked by proliferating cell nuclear antigen (PCNA) staining, in normal adult epidermis, nuclear HOXB4 protein expression substantially overlapped with PCNA-positive cell in a series of samples of hyperproliferative skin. Taken together, these data suggest that nuclear HOXB4 protein may play a role in the regulation of cellular proliferation/adhesion in developing fetal human epidermis and in hyperproliferation conditions, including cancers, in adult epidermis.Published 2002 Wiley-Liss, Inc. †

Cell Motility and Spreading Are Suppressed by HOXA4 in Ovarian Cancer Cells: Possible Involvement of β1 Integrin

“…Moreover, it is still uncertain whether the changes in β1 integrin are responsible for, or the product of, the phenotypic changes observed. Interestingly, enforced expression of HOXB4 (a paralog of HOXA4) in human neonatal keratinocytes decreased adhesion to plastic and was associated with reductions in the surface expression of CD44 and α2 integrin (34). CD44 also participates, in concert with β1 integrins, in the adhesion of ovarian cancer cells to peritoneal mesothelial cells (19,20).…”

Cellular and molecular insights into Hox protein action

“…By contrast, TGM1 is activated by HOXA7 in carcinoma. This context specificity and versatility in Hoxcontrolled cellular functions is further exemplified by HOXB4, which is expressed in the basal cell layer of the developing skin and in supra-basal cell layers in adult skin (Komuves et al, 2002). Whereas the basal cells of the developing skin are proliferating and exhibit strong HOXB4 expression, the supra-basal cell layers of the adult skin are PCNA negative and show low or no proliferation.…”

Hoxb13 Up-regulates Transglutaminase Activity and Drives Terminal Differentiation in an Epidermal Organotypic Model

“…During embryogenesis, Hox proteins function as important regulators in differentiation and cell fate determination, and they are critical for axial patterning. Because of their distinct spatio-temporal expression patterns in developing and adult skin, Hox genes have been implicated in the patterning and regenerative processes of skin and hair, as well as in certain skin pathologies including cancer (13)(14)(15)(16)(17). Interestingly, once the roles of certain Hox genes in axial patterning are complete, these genes may be utilized in a spatially ubiquitous way throughout tissues that are not segmentally restricted, such as the skin.…”