LDOC1 suppresses microbe-induced production of il-1β in human normal and cancerous oral cells through the PI3K/AKT/GSK-3β axis

Chia Huei Lee, Pin Feng Hung, Ko Jiunn Liu, Hsuan Lien Chung, Wen Chan Yang, Kai Cheng Hsu, Tsorng Harn Fong, Hsiu Jung Lo, Ya Ping Chen, Ji Rui Yang, Ching Yu Yen

Research output: Contribution to journalArticlepeer-review

Abstract

Poor oral hygiene (POH) is associated with oral squamous cell carcinoma (OSCC). Oral microbes often proliferate due to POH. Array data show that LDOC1 plays a role in immunity against pathogens. We investigated whether LDOC1 regulates the production of oral microbe-induced IL-1β, an oncogenic proinflammatory cytokine in OSCC. We demonstrated the presence of Candida albicans (CA) in 11.3% of OSCC tissues (n = 80). CA and the oral bacterium Fusobacterium nucleatum stimulate higher levels of IL-1β secretion by LDOC1-deficient OSCC cells than by LDOC1-expressing oral cells. CA SC5314 increased OSCC incidence in 4-NQO (a synthetic tobacco carcinogen) and arecoline-cotreated mice. Loss and gain of LDOC1 function significantly increased and decreased, respectively, CA SC5314-induced IL-1β production in oral and OSCC cell lines. Mechanistic studies showed that LDOC1 deficiency increased active phosphorylated Akt upon CA SC5314 stimulation and subsequent inhibitory phosphorylation of GSK-3βS9 by activated Akt. PI3K and Akt inhibitors and expression of the constitutively active mutant GSK-3βS9A significantly reduced the CA SC5314-stimulated IL-1β production in LDOC1-deficient cells. These results indicate that the PI3K/Akt/pGSK-3β signaling pathway contributes to LDOC1-mediated inhibition of oral microbe-induced IL-1β production, suggesting that LDOC1 may determine the pathogenic role of oral microbes in POH-associated OSCC.

Original languageEnglish
Article number3148
Pages (from-to)1-20
Number of pages20
JournalCancers
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 2020

Keywords

  • Candida albicans
  • Glycogen Synthase Kinase-3 Beta (GSK-3β)
  • Interleukin 1beta (IL-1β)
  • Leucine-zipper downregulated in cancer 1 (LDOC1)
  • Oral squamous cell carcinoma (OSCC)
  • Phosphoinositide 3-kinase (PI3K)
  • Poor oral hygiene (POH)
  • Protein Kinase B (PKB Akt)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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