Loss of Krüppel-like factor-10 facilitates the development of chemical-induced liver cancer in mice.

Abstract

BACKGROUND:

Krüppel-like factor 10 (KLF10) is involved in a positive feedback loop that regulates transforming growth factor β (TGFβ) signaling, and TGFβ plays an important role in the pathogenesis of liver disease. Here, we investigated whether KLF10 deletion affects the development of liver fibrosis and hepatocellular carcinoma (HCC).

METHODS:

We induced KLF10 deletion in C57BL/6 mice. Liver fibrosis was induced by feeding a diet high in fat and sucrose (high-fat diet [HFD]), whereas HCC was produced by intraperitoneal administration of N-diethylnitrosamine (DEN). An in vitro experiment was performed to evaluate the role of KLF10 in the cancer microenvironment using Hep3B and LX2 cells. An immunohistochemical study of KLF10 expression was performed using human HCC samples from 60 patients who had undergone liver resection.

RESULTS:

KLF10 deletion resulted in an increased DEN-induced HCC burden with significant upregulation of SMAD2, although loss of KLF10 did not alter HFD-induced liver fibrosis. DEN-treated mice with KLF10 deletion exhibited increased levels of mesenchymal markers (N-cadherin and SNAI2) and tumor metastasis markers (matrix metalloproteinases 2 and 9). KLF10 depletion in Hep3B and LX2 cells using siRNA was associated with increased invasiveness. Compared with co-culture of KLF10-preserved Hep3B cells and KLF10-intact LX2 cells, co-culture of KLF10-preserved Hep3B cells and KLF10-depleted LX2 cells resulted in significantly enhanced invasion. Low KLF10 expression in resected human HCC specimens was associated with poor survival.

CONCLUSION:

The results of this study suggest that loss of KLF10 facilitates liver cancer development with alteration in TGFβ signaling.

• Authors: Sung Hwan Yoo, Ji Hae Nahm, Woon Kyu Lee, Hyun Woong Lee, Hye Young Chang, Jung Il Lee
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 29 Issue 1 Pg. 156 (Nov 09 2023) ISSN: 1528-3658 [Electronic] England
• PMID: 37946098 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• Kruppel-Like Transcription Factors
• Transforming Growth Factor beta
• KLF10 protein, mouse

Topics

• Animals
• Humans
• Mice
• Carcinoma, Hepatocellular (chemically induced, genetics, pathology)
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Liver Cirrhosis (chemically induced, genetics)
• Liver Neoplasms (chemically induced, genetics)
• Mice, Inbred C57BL
• Transforming Growth Factor beta (metabolism)
• Tumor Microenvironment