title: LPS receptor subunits have antagonistic roles in epithelial apoptosis and colonic carcinogenesis.
abstract: Colorectal carcinoma (CRC) is characterized by unlimited proliferation and suppression of apoptosis, selective advantages for tumor survival, and chemoresistance. Lipopolysaccharide (LPS) signaling is involved in both epithelial homeostasis and tumorigenesis, but the relative roles had by LPS receptor subunits CD14 and Toll-like receptor 4 (TLR4) are poorly understood. Our study showed that normal human colonocytes were CD14(+)TLR4(-), whereas cancerous tissues were CD14(+)TLR4(+), by immunofluorescent staining. Using a chemical-induced CRC model, increased epithelial apoptosis and decreased tumor multiplicity and sizes were observed in TLR4-mutant mice compared with wild-type (WT) mice with CD14(+)TLR4(+) colonocytes. WT mice intracolonically administered a TLR4 antagonist displayed tumor reduction associated with enhanced apoptosis in cancerous tissues. Mucosa-associated LPS content was elevated in response to CRC induction. Epithelial apoptosis induced by LPS hypersensitivity in TLR4-mutant mice was prevented by intracolonic administration of neutralizing anti-CD14. Moreover, LPS-induced apoptosis was observed in primary colonic organoid cultures derived from TLR4 mutant but not WT murine crypts. Gene silencing of TLR4 increased cell apoptosis in WT organoids, whereas knockdown of CD14 ablated cell death in TLR4-mutant organoids. In vitro studies showed that LPS challenge caused apoptosis in Caco-2 cells (CD14(+)TLR4(-)) in a CD14-, phosphatidylcholine-specific phospholipase C-, sphingomyelinase-, and protein kinase C-ζ-dependent manner. Conversely, expression of functional but not mutant TLR4 (Asp299Gly, Thr399Ile, and Pro714His) rescued cells from LPS/CD14-induced apoptosis. In summary, CD14-mediated lipid signaling induced epithelial apoptosis, whereas TLR4 antagonistically promoted cell survival and cancer development. Our findings indicate that dysfunction in the CD14/TLR4 antagonism may contribute to normal epithelial transition to carcinogenesis, and provide novel strategies for intervention against colorectal cancer.
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: W-T
authors: WT
authors: Kuo
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: T-C
authors: TC
authors: Lee
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: H-Y
authors: HY
authors: Yang
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: C-Y
authors: CY
authors: Chen
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Y-C
authors: YC
authors: Au
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Y-Z
authors: YZ
authors: Lu
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: L-L
authors: LL
authors: Wu
authors: Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: S-C
authors: SC
authors: Wei
authors: Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Y-H
authors: YH
authors: Ni
authors: Department of Surgery, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.
authors: B-R
authors: BR
authors: Lin
authors: Department of Surgery, Far Eastern Memorial Hospital, New Taipei, Taiwan.|Department of Chemical Engineering and Material Science, Yuan-Ze University, Tao-Yuan, Taiwan.
authors: Y
authors: Y
authors: Chen
authors: Department of Surgery, Far Eastern Memorial Hospital, New Taipei, Taiwan.|Department of Chemical Engineering and Material Science, Yuan-Ze University, Tao-Yuan, Taiwan.
authors: Y-H
authors: YH
authors: Tsai
authors: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors: J T
authors: JT
authors: Kung
authors: Department of Horticulture, National Taiwan University, Taipei, Taiwan.
authors: F
authors: F
authors: Sheu
authors: Department of Pathology, National Taiwan University Hospital, Yunlin Branch, Yunlin, Taiwan.
authors: L-W
authors: LW
authors: Lin
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: L C-H
authors: LC
authors: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis; D018938:Caco-2 Cells; D063646:Carcinogenesis; D003106:Colon / Q000378:metabolism / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D018950:Lipopolysaccharide Receptors; D051197:Toll-Like Receptor 4
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