Klf4 Overexpression Activates Epithelial Cytokines and Inflammation-Mediated Esophageal Squamous Cell Cancer in Mice

Abstract

BACKGROUND & AIMS Esophageal squamous cell cancer accounts for more than 90% of cases of esophageal cancers. Its pathogenesis involves chronic epithelial irritation, although the factors involved in the inflammatory process and the mechanisms of carcinogenesis are unknown. We sought to develop a mouse model of this cancer. METHODS We used the ED-L2 promoter of Epstein-Barr virus to overexpress the transcriptional regulator Krüppel-like factor 4 (Klf4) in esophageal epithelia of mice; we used mouse primary esophageal keratinocytes to examine the mechanisms by which KLF4 induces cytokine production. RESULTS KLF4 was an epithelial-specific mediator of inflammation; we developed a new mouse model of esophageal squamous dysplasia and inflammation-mediated squamous cell cancer. KLF4 activated a number of proinflammatory cytokines, including TNF-α, CXCL5, G-CSF and IL-1α, within keratinocytes in an NF-κB– dependent manner. KLF4 was not detected in proliferating or cancer cells, indicating a non-cell autonomous effect of KLF4 on proliferation and carcinogenesis. CONCLUSIONS KLF4 has distinct functions in carcinogenesis; upregulation of Klf4 specifically in esophageal epithelial cells induces inflammation. This mouse model might be used to determine the molecular mechanisms of esophageal squamous cell cancer and inflammation-mediated carcinogenesis.

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

“…Since inflammation and innate immunity against bacteria are hallmarks of sepsis [41,42], enhancing the latter while mitigating the former is a worthwhile therapeutic strategy [43]. One possibility is to exploit Klf4, a zinc-finger transcription factor that was shown to either promote [44,45] or inhibit inflammatory signaling [33,46]. In light of these contradictory results, we now present strong evidence that Klf4 overexpression, at least under our experimental conditions, significantly suppresses the inflammatory response of macrophages to lipopolysaccharide, markedly decreasing the release of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and MCP-1.…”

KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions

“…In addition, tumor-promoting inflammation is an emerging hallmark of cancer, 38 and Klf4 overexpression in murine esophageal epithelia in vivo promotes inflammation and causes inflammation-mediated ESCC. 16 As such, it will be important to assess the consequences of KLF4 on cancer stem cells and other hallmarks of cancer during ESCC progression.…”

“…[10][11][12] In mice, Klf4 loss leads to the development of esophageal squamous cell dysplasia, and KLF4 is downregulated in human ESCC suggesting that KLF4 has tumor suppressive functions in ESCC. [13][14][15] Moreover, while Klf4 overexpression in murine esophagus leads to the development of inflammation-mediated ESCC, KLF4 is absent from these tumors, 16 suggesting that Klf4 silencing may be required for tumor formation. As such, KLF4 appears to be important for the development of ESCC, although the precise functions of KLF4 during ESCC development and progression and the mechanisms of KLF4 downregulation in ESCC are not well understood.…”

The potential of CXCL5 as a target for liver cancer – what do we know so far?

“…Kruppel-like factor 4 regulates genes involved in cell-cycle progression and epithelial differentiation and can activate CXCL5 during the development of cancer in an NF-kB-dependent manner [16]. The up-regulation of the proto-oncogene Ron, a human receptor for the macrophage-stimulating protein, was associated with CXCL5-induced angiogenesis, since Ron-negative cancer cells had low capacities of producing CXCL5 and generating angiogenesis, which could be prevented by exogenous Ron [17].…”