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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.

Project description:Acute renal injury (AKI) causes a long-term risk for progressing into chronic kidney disease (CKD) and interstitial fibrosis. Yes-associated protein (YAP), a key transcriptional cofactor in Hippo signaling pathway, shuttles between the cytoplasm and nucleus, which is required for the renal tubular epithelial cells repair in the acute phase of AKI. In this study we investigated the role of YAP during ischemia-reperfusion (IR)-induced AKI to CKD. Mice were subjected to left kidney IR followed by removal of the right kidney on the day before tissue harvests. Mouse shRNA expression adenovirus (Ad-shYAP or Ad-shKLF4) and mouse KLF4 expression adenovirus (Ad-KLF4) were delivered to mice by intrarenal injection on D7 after IR. We showed that the expression and nucleus distribution of YAP were persistently increased until the end of experiment (D21 after IR). The sustained activation of YAP in post-acute phase of AKI was accompanied by renal dysfunction and interstitial fibrosis. Knockdown of YAP significantly attenuated IR-induced renal dysfunction and decreased the expression of fibrogenic factors TGF-β and CTGF in the kidney. We showed that the expression of the transcription factor KLF4, lined on the upstream of YAP, was also persistently increased. Knockdown on KLF4 attenuated YAP increase and nuclear translocation as well as renal functional deterioration and interstitial fibrosis in IR mice, whereas KLF4 overexpression caused opposite effects. KLF4 increased the expression of ITCH, and ITCH facilitated YAP nuclear translocation via degrading LATS1. Furthermore, we demonstrated in primary cultured renal tubular cells that KLF4 bound to the promoter region of YAP and positively regulates YAP expression. In biopsy sample from CKD patients, we also observed increased expression and nuclear distribution of YAP. In conclusion, the activation of YAP in the post-acute phase of AKI is implicated in renal functional deterioration and fibrosis although it exhibits beneficial effect in acute phase. Reprogramming factor KLF4 is responsible for the persistent activation of YAP. Blocking the activation of KLF4-YAP pathway might be a way to prevent the transition of AKI into CKD.

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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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