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

2020 Fiscal Year Annual Research Report

• Project/Area Number: 19K18963
• 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 cancer / Metabolism / Bile acids / Cancer / Senescence / invasion

Outline of Annual Research Achievements

Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. 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 arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with 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. Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFb.

Research Products

• [Journal Article] Periostin antisense oligonucleotide prevents hepatic steatosis and fibrosis in a mouse model (2020)
  • Author(s): Tomoki Kobayashi, Keishi Kanno, Phuong Thao Nguyen, Akihito Kawahara, Yuichiro Otani, Nobusuke Kishikawa, Masanori Ito, Susumu Tazuma
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 35 Pages: 2140-2150
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma (2020)
  • Author(s): Phuong Thao Nguyen, Keishi Kanno, Quoc Thang Pham, Yuka Kikuchi, Masaki Kakimoto, Tomoki Kobayashi, Yuichiro Otani, Nobusuke Kishikawa, Mutsumi Miyauchi, Koji Arihiro, Masanori Ito, Susumu Tazuma
  • Journal Title: Journal of Cancer Research and Clinical Oncology volume Volume: 146 Pages: 3255-3268
  • DOI: 10.1007/s00432-020-03374-9
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Contributions of hepatic stellate cells into hepatocellular carcinoma (2020)
  • Author(s): Nguyen PT, Tazuma S, Otani Y, Ito M.
  • Organizer: The 79th annual meeting of Japanese Cancer Association
  • Int'l Joint Research
• [Presentation] Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma. (2020)
  • Author(s): Nguyen PT, Kanno K, Pham QT, Kobayashi T, Miyauchi M, Arihiro K, Tazuma S, Ito M.
  • Organizer: The 43rd annual meeting of The molecular Biology Society
  • Int'l Joint Research