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Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia.

ABSTRACT: KLF4/GKLF normally functions in differentiating epithelial cells, but also acts as a transforming oncogene in vitro. To examine the role of this zinc finger protein in skin, we expressed the wild-type human allele from inducible and constitutive promoters. When induced in basal keratinocytes, KLF4 rapidly abolished the distinctive properties of basal and parabasal epithelial cells. KLF4 caused a transitory apoptotic response and the skin progressed through phases of hyperplasia and dysplasia. By 6 weeks, lesions exhibited nuclear KLF4 and other morphologic and molecular similarities to squamous cell carcinoma in situ. p53 determined the patch size sufficient to establish lesions, as induction in a mosaic pattern produced skin lesions only when p53 was deficient. Compared with p53 wild-type animals, p53 hemizygous animals had early onset of lesions and a pronounced fibrovascular response that included outgrowth of subcutaneous sarcoma. A KLF4-estrogen receptor fusion protein showed tamoxifen-dependent nuclear localization and conditional transformation in vitro. The results suggest that KLF4 can function in the nucleus to induce squamous epithelial dysplasia, and indicate roles for p53 and epithelial-mesenchymal signaling in these early neoplastic lesions.

SUBMITTER: Foster KW

PROVIDER: S-EPMC1361530 | biostudies-literature | 2005 Feb

REPOSITORIES: biostudies-literature

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Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia.

Foster K Wade KW Liu Zhaoli Z Nail Clinton D CD Li Xingnan X Fitzgerald Thomas J TJ Bailey Sarah K SK Frost Andra R AR Louro Iuri D ID Townes Tim M TM Paterson Andrew J AJ Kudlow Jeffrey E JE Lobo-Ruppert Susan M SM Ruppert J Michael JM

Oncogene 20050201 9

KLF4/GKLF normally functions in differentiating epithelial cells, but also acts as a transforming oncogene in vitro. To examine the role of this zinc finger protein in skin, we expressed the wild-type human allele from inducible and constitutive promoters. When induced in basal keratinocytes, KLF4 rapidly abolished the distinctive properties of basal and parabasal epithelial cells. KLF4 caused a transitory apoptotic response and the skin progressed through phases of hyperplasia and dysplasia. By ...[more]

PMID: 15674344

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Project description:PurposePersistent infection with high-risk human papillomavirus (HR-HPV) is thought to play a prominent role in the initiation and progression of almost all cases of cervical cancer. Previously, we and others found that microRNA 34a (miR-34a) may be regulated by HR-HPV E6 to contribute to the development of cervical cancer. Here, we aimed to identify the oncogenic potential and clinical significance of a known miR-34a target, WNT1, in cervical squamous cell carcinoma (SCC) development and to investigate the associated mechanisms underlying cervical SCC cell proliferation and invasion.MethodsWNT1 and miR-34a expression levels were assessed in primary cervical lesions using immunohistochemistry and qRT-PCR, respectively. The cellular effects and the expression of its associated genes were examined in cervical SCC-derived Siha and Caski cells after siRNA-WNT1 (downregulation) or miR-34a mimic (upregulation) treatment. A cervical SCC xenograft mouse model was used to investigate the in vivo effects of miR-34a overexpression. HPV-16 E6/E7 expression was inhibited by gene promoter siRNA targeting, after which the levels of miR-34a and WNT1 were examined.ResultsWNT1 protein upregulation was found to be associated with a poor prognosis in cervical SCC patients. In vitro assays in Siha and Caski cells revealed that WNT1 downregulation decreased cell proliferation and invasion, inhibited WNT/β-catenin activation and affected the expression of E-cadherin and P-cadherin. MiR-34a upregulation resulted in decreased WNT1 expression. An inverse correlation between miR-34a and WNT1 expression was also observed in primary cervical SCC tissues. In addition, we found that MiR-34a could regulate an E-cadherin to P-cadherin switch (E-P cadherin switch) to inhibit cell proliferation and tumorigenesis in vitro and in vivo via inactivation of the WNT1/β-catenin pathway. Finally, we found that decreased HPV-16 E6/E7 expression resulted in miR-34a upregulation and WNT1 downregulation in Siha and Caski cells.ConclusionsFrom our results we conclude that WNT1, as a target of miR-34a, can promote cervical SCC cell proliferation and invasion by induction of an E-P cadherin switch via the WNT1/β-catenin pathway. Our results may provide new options for the treatment of patients with cervical SCC.

Dataset Information

Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia.

Publications

Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia.

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