Meis1 Regulates Epidermal Stem Cells and Is Required for Skin Tumorigenesis

Abstract

Previous studies have shown that Meis1 plays an important role in blood development and vascular homeostasis, and can induce blood cancers, such as leukemia. However, its role in epithelia remains largely unknown. Here, we uncover two roles for Meis1 in the epidermis: as a critical regulator of epidermal homeostasis in normal tissues and as a proto-oncogenic factor in neoplastic tissues. In normal epidermis, we show that Meis1 is predominantly expressed in the bulge region of the hair follicles where multipotent adult stem cells reside, and that the number of these stem cells is reduced when Meis1 is deleted in the epidermal tissue of mice. Mice with epidermal deletion of Meis1 developed significantly fewer DMBA/TPA-induced benign and malignant tumors compared with wild-type mice, suggesting that Meis1 plays a role in both tumor development and malignant progression. This is consistent with the observation that Meis1 expression increases as tumors progress from benign papillomas to malignant carcinomas. Interestingly, we found that Meis1 localization was altered to neoplasia development. Instead of being localized to the stem cell region, Meis1 is localized to more differentiated cells in tumor tissues. These findings suggest that, during the transformation from normal to neoplastic tissues, a functional switch occurs in Meis1.

Meis1 Is Required for c-Met Inhibition to Suppress Cell Proliferation of Skin Squamous Cell Carcinoma Cells

“…This situation is similar to the alterations observed in epidermis, HSCs and cardiomyocytes with a Meis1 deficiency, indicating a role for Meis1 in the promotion of cell quiescence in order to suppress cell cycle entry [16] [18] [21]. As a transcriptional factor or co-regulator, Meis1 may affect the cell cycle machinery by promoting downstream gene expression.…”

“…Our previous study demonstrated Meis1 is required for epidermal tumorigenesis and regulates epidermal stem cells [16]. However, this study shows Meis1 down-regulates the proliferation of B9 and D3 cells.…”

“…As in leukemia, gene expression studies in lung adenocarcinomas [10], neuroblastomas [11]- [13], ovarian carcinomas [14], and nephroblastomas [15] have shown that the expression of Meis1 is up-regulated in tumor tissues, which is suggestive of an oncogenic role. A previous study indicated that Meis1 is required for skin tumorigenesis in a mouse model [16]. However, the mechanisms underlying the functions of Meis1 in skin tumorigenesis remain poorly understood.…”

“…However, the mechanisms underlying the functions of Meis1 in skin tumorigenesis remain poorly understood. On the other hand, several studies have suggested that Meis1 plays a functional role in several tissues, such as hematopoietic stem cells (HSCs) [17], cardiomyocytes [18], lung cancer cell lines [19], thymus [20] and skin [16]. These findings suggest that Meis1 exerts anti-proliferative effects as well as oncogenic activities, and has complex roles in cell proliferation, which may depend on the cellular context.…”

Targets of the StBEL5 Transcription Factor Include the FT Ortholog StSP6A

“…For example, several animal TALE TFs play significant roles in organogenesis and differentiation during embryogenesis (Lukowski et al, 2011;Sonnet et al, 2012) and in enhancing cell proliferation in certain cancer types (Rosales-Aviña et al, 2011;Okumura et al, 2014). All TALE types contain a highly conserved homeodomain composed of three helices with a Pro-Tyr-Pro link between helices 1 and 2.…”