KLF4 and PCNA identify stages of tumor initiation in a conditional model of cutaneous squamous epithelial neoplasia

Abstract

Research Paper KLF4 and PCNA Identify Stages of Tumor Initiation in a Conditional Model of Cutaneous Squamous Epithelial Neoplasia ABSTRACTKLF4 is induced upon growth-arrest in vitro and during epithelial maturation in vivo, and is essential for proper cell fate specification of post-mitotic cells. In spite of a normal role in post-mitotic cells, expression is upregulated and constitutive in certain tumor types. KLF4 functions as an oncogene in vitro, and enforced expression in basal cells of mouse skin rapidly induces lesions similar to hyperplasia, dysplasia and squamous cell carcinoma (SCC). Here we used conditional expression to characterize early steps in KLF4-mediated tumor initiation. In contrast to SCC-like lesions that result when using a conditional, keratin 14 promoter-dependent strategy, lower conditional expression achieved using a MMTV promoter induced only epidermal cycling within morphologically normal skin, a process we termed occult cell turnover. Surprisingly, KLF4-induced hyperplastic lesions showed increased transgene-derived mRNA and protein in maturing, PCNA-negative cells, a property of endogenous KLF4. In contrast, hyperplastic lesions induced by GLI1, a control, showed uniform transgene expression. In KLF4-induced dysplasia and SCC the complementarity of KLF4 and PCNA was replaced by concordance of the two proteins. These studies show that KLF4 transcripts are normally suppressed in cycling cells in a promoter-independent fashion, consistent with a post-transcriptional control, and reveal loss of this control in the transition from hyperplasia to dysplasia. Like the mouse tumors, human cutaneous SCCs and adjacent dysplasias frequently showed maturation-independence of KLF4, with co-expression of KLF4 and PCNA. A smaller subset of human SCCs showed complementarity of KLF4 and PCNA, similar to hyperplastic mouse skin. The results identify parallels between a mouse model and human primary tumors, and show that successive increases of KLF4 in the nuclei of basal keratinocytes leads to occult cell turnover followed by hyperplasia, dysplasia, and invasive SCC.

Krüppel-like Factor 4 Promotes Esophageal Squamous Cell Carcinoma Differentiation by Up-regulating Keratin 13 Expression

“…1A and Table 4). KLF4 epithelial cells in transgenic mice manifested an increased expression of KLF4 in maturing PCNA-negative cells (34), which provide additional evidence for the role of KLF4 in squamous cell differentiation. Molecular investigation further supported the morphologic findings as KLF4 regulated the expression level of epithelial differentiation markers such as KRT4 and KRT13 (Fig.…”

Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin

“…This pattern is opposite to the pattern of E-cad in these lesions (Li et al, 2006). As Gli1 is uniformly induced by tet in the epidermis (Huang et al, 2005;Li et al, 2006), the apparent restriction of Gli1 effects to infiltrating cells may reflect post-translational regulation. In contrast, antibody to total b-catenin uniformly stained the tumor cells (not shown).…”

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

“…In the intestine, genetic and expression profiling data indicate that it indeed functions as a tumor suppressor, often inactivated by epigenetic mechanisms in carcinomas (reviewed by Wei et al, 2006). On the other hand, KLF4 has emerged in profiling experiments as a gene overexpressed in breast and skin cancers, and overexpression in immortalized rat kidney cells results in hyperplasia and dysplasia (Foster et al, 1999(Foster et al, , 2000Huang et al, 2005;Chen et al, 2008). Transgenic mice in which KLF4 was expressed in the basal layer of the epidermis showed hyperplasia/dysplasia and, in the context of a p53 hemizygous background, these mice developed subcutaneous sarcomas .…”