Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K- Ras activation in mice

Abstract

Oral squamous cell carcinoma (SCC) is among the most prevalent cancers in the world and is characterized by high morbidity and few therapeutic options. Like most cancers, oral SCC arises from a multistep process involving alterations of genes responsible for balancing proliferation and differentiation. Among these, Krϋppel-like factor 4 (Klf4) suppresses cell proliferation and promotes differentiation and thus helps to maintain epithelial homeostasis. However, the prevailing role of Klf4 in maintenance of normal homeostasis in oral epithelium has not been established in vivo. Here, we used an inducible oral-specific mice model to selectively ablate Klf4 in the oral cavity. We generated K14-CreER(Tam)/Klf4 (f/f) mice that survived to adulthood and did not present overt phenotype. However, histologically these mice showed dysplastic lesions, increased cell proliferation and abnormal differentiation in the tongue 4 months after induction, supporting a homeostatic role of Klf4 in the oral epithelia. Furthermore, by breeding these mutants with a transgenic line expressing at endogenous levels K-ras (G12D), we assessed the role of disrupting differentiation gene programs to the carcinogenesis process. The K14-CreER(TAM)/K-ras (G12D)/Klf4 (-) (/-) mice rapidly develop oral SCC in the tongue. Thus, our findings support the emerging notion that activation of differentiating gene programs may represent a barrier preventing carcinogenesis in epithelial cells harboring oncogenic mutations, and thus that molecules acting upstream and downstream of Klf4 may represent components of a novel tumor-suppressive pathway.

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

“…Our findings are consistent with the previous finding that Klf4 deletion sufficiently initiated carcinoma development upon K-ras activation in mouse tongue. 35 Multiple mechanisms of KLF4 downregulation in lung cancer. KLF4 mutations were identified in fewer than 2% of the total patients (Figure 1a), suggesting that genetic mutation is not the main cause of KLF4 downregulation in lung cancer.…”

KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis

“…These data suggest that KLF4 may maintain a tumor-suppressive function in cells of ductal and islet epithelial lineages, whereas overexpression of KLF4 in acinar cells may result in acinar-to-ductal reprogramming, which potentiates the initiation of PanIN in the presence of mutant KRAS . However, Klf4 deletion was found to synergize with mutant KRas to facilitate carcinoma development in mouse tongue and lung (Abrigo et al, 2014). Of note, we also observed accelerated development of skin neoplastic lesions in PRK mice compared with PR mice, and specific Klf4 gene ablation was detected in the skin tumor tissues derived from PRK mice, which is consistent with previous studies showing that Pdx-1 is expressed in skin epidermal cells (Mazur et al, 2010), and Klf4 deficiency promoted the skin tumorigenesis in a classical DMBA/TPA mouse skin cancer model (Li et al, 2012a).…”

Overexpression of tumor suppressor gene ZNF750 inhibits oral squamous cell carcinoma metastasis

“…Loss of ZNF750 has been reported to result in impaired differentiation and enhanced proliferation of cancer cells (8). ZNF750 interacts with the terminal epidermal differentiation factor KLF4 to induce the expression of differentiation-associated genes (7), and KLF4 deletion is sufficient to impair squamous cell differentiation and initiate tongue carcinoma development (2). In line with these previous reports, the present study revealed that ZNF750 upregulates the differentiation genes LCE3A and SPRR1a, and increases the expression of KLF4, while reducing the expression of MMP28.…”

“…Oral squamous cell carcinoma (OSCC) is associated with a high rate of morbidity and mortality, with few therapeutic options (2). The survival rate for patients with OSCC has not improved in recent decades despite the development of novel therapies (3).…”

“…ZNF750-driven epidermal differentiation occurs partially through the induction of Kruppel-like factor 4 (KLF4), a transcription factor that activates late epidermal differentiation-associated genes and is critical for the epithelial-mesenchymal transition (EMT) (10,11). Deletion of KLF4 has been reported to be sufficient to initiate tongue carcinoma development (2 At present, the biological function of ZNF750 in the pathogenesis of OSCC is unknown. The present study aimed to investigate the effect of overexpressed ZNF750 on cell viability, invasion, migration and expression of EMT-associated genes in OSCC.…”