Periodontitis induced alterations of gut microbial metabolite promotes liver cancer through senescence

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18963
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: Hiroshima University
• Principal Investigator: NGUYEN THAO 広島大学, 病院(医), 研究員 (40733837)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: Liver / metabolism / bile acids / Senescence / Invasion / cancer

Outline of Final Research Achievements

This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells. LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors. DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle and the induction of senescence-associated secretory phenotype (SASP) factors. HCC cells were treated with DCA treated LX2-conditioned media, that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFb. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC.

Free Research Field

Oncology

Academic Significance and Societal Importance of the Research Achievements

Our study provided the new insights into the molecular genetics of liver cancer under effects of Deoxycholic acid. In addition, we proposed a novel therapeutic strategy against HCC development, including interventions targeting senescent HSCs and SASP factors, particularly IL8 and TGFβ.