LDOC1 Suppresses Microbe-Induced Production of IL-1β in Human Normal and Cancerous Oral Cells through the PI3K/Akt/GSK-3β Axis
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Cancers - 12(2020), 11 vom: 27. Okt. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lee, Chia-Huei [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 28.11.2020 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3390/cancers12113148 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316895415 |
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| 100 | 1 | |a Lee, Chia-Huei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a LDOC1 Suppresses Microbe-Induced Production of IL-1β in Human Normal and Cancerous Oral Cells through the PI3K/Akt/GSK-3β Axis |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Candida albicans | |
| 650 | 4 | |a Glycogen Synthase Kinase-3 Beta (GSK-3β) | |
| 650 | 4 | |a Phosphoinositide 3-kinase (PI3K) | |
| 650 | 4 | |a Protein Kinase B (PKB Akt) | |
| 650 | 4 | |a interleukin 1beta (IL-1β) | |
| 650 | 4 | |a leucine-zipper downregulated in cancer 1 (LDOC1) | |
| 650 | 4 | |a oral squamous cell carcinoma (OSCC) | |
| 650 | 4 | |a poor oral hygiene (POH) | |
| 700 | 1 | |a Hung, Pin-Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ko-Jiunn |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Hsuan-Lien |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Wen-Chan |e verfasserin |4 aut | |
| 700 | 1 | |a Hsu, Kai-Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Fong, Tsorng-Harn |e verfasserin |4 aut | |
| 700 | 1 | |a Lo, Hsiu-Jung |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ya-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Ji-Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Yen, Ching-Yu |e verfasserin |4 aut | |
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