title: Long-term use of indomethacin leads to poor prognoses through promoting the expression of PD-1 and PD-L2 via TRIF/NF-κB pathway and JAK/STAT3 pathway to inhibit TNF-α and IFN-γ in hepatocellular carcinoma.
abstract: HCC still has a poor prognosis in clinical due to high recurrence and metastasis rates worldwide nowadays. Indomethacin pretreatment is used as a potential chemopreventive agent in cancers for it could assist in anti-tumor functions of other agents and exert anti-tumor effect. Our study aims to discuss the effects and mechanisms of long-term use of indomethacin in HCC. The HepA mouse models were used to observe tumor recurrence, intrahepatic metastasis and remote metastasis. NK cell, αβ T cell and γδ T cell were used to explore the underlying mechanisms for anti-tumor effect of indomethacin. The results showed that long-term use of indomethacin facilitated intrahepatic recurrence, intrahepatic dissemination and lung metastasis, and indomethacin inhibits TNF-α and IFN-γ in vivo and in vitro in a dose-dependent manner. Furthermore, long-term use of indomethacin increased the expression of PD-1 and PD-L2 in programmed death-1 pathway. Blockade of PD-1 and PD-L2 reversed the reduced production of TNF-α and IFN-γ induced by indomethacin in γδ T cells. In addition, long-term use of indomethacin activates TRIF/NF-κB and JAK/STAT3 pathways, and indomethacin promotes the expression of PD-1 and PD-L2 via TRIF/NF-κB pathway and JAK/STAT3 pathway respectively in γδ T cells. Given these findings, we drew a conclusion that long-term use of indomethacin leads to poor prognoses through promoting the expression of PD-1 and PD-L2 via TRIF/NF-κB pathway and JAK/STAT3 pathway to inhibit TNF-α and IFN-γ in HCC.
authors.affiliation: Department of Anesthesiology, Fudan University Shanghai Cancer Center, No. 270, Dong an Road, Shanghai 200032, China.
authors.forename: Pingbo
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Fudan University Shanghai Cancer Center, No. 270, Dong an Road, Shanghai 200032, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Fudan University Shanghai Cancer Center, No. 270, Dong an Road, Shanghai 200032, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Fudan University Shanghai Cancer Center, No. 270, Dong an Road, Shanghai 200032, China. Electronic address: changhongmiaosh@163.com.
authors.forename: Changhong
authors.initials: C
authors.lastname: Miao
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects*; D007371:Interferon-gamma / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011379:Prognosis; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin; D007371:Interferon-gamma; D053612:Janus Kinases; D016328:NF-kappa B; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; C494086:STAT3 protein, human; C476286:Ticam1 protein, mouse
keywords: Hepatocellular carcinoma; IFN-γ; Indomethacin; PD-1/PD-L2 pathway; TNF-α; TRIF/NF-κB