Cholangiocyte senescence caused by lysophosphatidylcholine as a potential implication in carcinogenesis

Shimizu, Rina; Kanno, Keishi; Sugiyama, Akiko; Ohata, Hiroki; Araki, Anna; Kishikawa, Nobusuke; Kimura, Yasuhiro; Yamamoto, H; Kodama, Mitsuo; Kihira, Kenji; Tazuma, Susumu

doi:10.1002/jhbp.256

Cited by 28 publications

(29 citation statements)

References 31 publications

(44 reference statements)

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“…Therefore, LPC may be a novel biomarker allowing early detection of biliary tract cancer [ 30 ]. Recent studies have shown that LPC may trigger cholangiocyte senescence, thereby potentially contributing to the pathogenic development of biliary tract cancer [ 42 ]. LPC also inhibited cholangiocyte apoptosis by inducing COX-2 expression via a Raf-1-dependent mechanism [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced levels of N’-methyl-2-pyridone-5-carboxamide and lysophosphatidylcholine 16:0 in the serum of patients with intrahepatic cholangiocarcinoma, and the correlation with recurrence-free survival

et al. 2017

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We searched for metabolic biomarkers that may predict the prognosis of patients with intrahepatic cholangiocarcinoma (IHCC). To this end, a total of 237 serum samples were obtained from IHCC patients (n = 87) and healthy controls (n = 150), and serum metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two stratified algorithms were used to select the metabolites, the levels of which predicted the prognosis of IHCC patients. We performed MS/MS and multiple-reaction-monitoring MS analyses to identify and quantify the selected metabolites. Continuous biomarker levels were dichotomized based on cutoffs that maximized between-group differences in recurrence-free survival (RFS) in terms of the log-rank test statistic. These RFS differences were analyzed using the log-rank test, and survival curves were drawn with the aid of the Kaplan–Meier method. Six metabolites (l-glutamine, lysophosphatidylcholine [LPC] 16:0, LPC 18:0, N’-methyl-2-pyridone-5-carboxamide [2PY], fibrinopeptide A [FPA] and uric acid) were identified as candidate metabolic biomarkers for predicting the prognosis of IHCC patients. Of these metabolites, levels of l-glutamine, uric acid, LPC 16:0, and LPC 18:0 were significantly lower in the serum from IHCC patients, whereas levels of 2PY and FPA were significantly higher (p < 0.01). 2PY and LPC 16:0 showed significantly better RFS at low level than high level (2PY, median RFS: 15.16 months vs. 5.90 months, p = 0.037; LPC 16:0, median RFS: 15.62 months vs. 9.83 months, p = 0.035). The findings of this study suggest that 2PY and LPC 16:0 identified by metabolome-based approaches may be useful biomarkers for IHCC patients.

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Section: Discussionmentioning

confidence: 99%

Reduced levels of N’-methyl-2-pyridone-5-carboxamide and lysophosphatidylcholine 16:0 in the serum of patients with intrahepatic cholangiocarcinoma, and the correlation with recurrence-free survival

et al. 2017

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“…The sources of ROS in endothelial cells are derived mainly from NADPH oxidase, xanthine oxidase, arachidonic acid (AA) metabolism or mitochondrial electron transfer. LPC has been shown to be the ROS inducer in endothelial cells [ 12 – 15 ] and may induce oxidative DNA damage and gene hypomethylation in cholangiocytes [ 16 ]. ROS and DNA damage may stimulate ataxia-telangiectasia mutated (ATM)/checkpoint kinase-1 (Chk2) and ATM and RAD3-related (ATR)/Chk1 to regulate cell cycle progression and induce apoptosis [ 17 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidylcholine induces cytotoxicity/apoptosis and IL-8 production of human endothelial cells: Related mechanisms

et al. 2017

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Increased levels of oxidized low-density lipoprotein oxLDL) are shown to elevate the risk of cardiovascular diseases such as atherosclerosis, thrombosis, stroke, and myocardial infarction. This is possibly due to the toxic effects of oxLDLs on vascular cells. Various oxLDLs including lysophosphatidylcholine (LPC) and 7-ketocholesterol injure vascular endothelial cells and stimulate inflammatory reaction. However the toxicity of LPC on endothelial cells is not clear. In this study, human endothelial cells were exposed to LPC. Cytotoxicity was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Propidium iodide (PI) staining or PI/Annexin V dual staining flow cytometry were used to determine cell cycle progression and apoptosis. Reactive oxygen species (ROS) level was analyzed by DCFH-DA labeling flow cytometry. RNA and protein expression of endothelial cells was studied by reverse transcriptase-polymerase chain reaction and western blotting. IL-8 secretion was measured by enzyme-linked immunosorbant assay. LPC showed cytotoxicity to endothelial cells (>50 µg/ml). LPC induced cell cycle arrest and apoptosis with concomitant inhibition of cdc2 and cyclin B1 expression. LPC stimulated intracellular ROS production and ATM/Chk2, ATR/Chk1 and Akt activation. IL-8 expression and secretion in endothelial cells were induced by LPC. LPC-induced apoptosis, and IL-8 expression/secretion was attenuated by LY294002, a PI3K/Akt inhibitor. These results reveal that LPC is involved in the pathogenesis of atherosclerosis and vascular diseases by stimulation of inflammation and injury to endothelial cells. These events are related to ROS, ATM/Chk2, ATR/Chk2 and PI3K/Akt signaling. Understanding the toxic mechanisms of LPC is useful for future prevention and treatment atherosclerosis.

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“…In addition to our previous finding that PC inhibits cholangiocyte damage in response to LPC, accumulating reports have revealed the biological properties of PC, including its anti-inflammatory and anti-oxidant activities [9,23]. Indeed, PC plays a rate-limiting role in the activation of numerous membrane-located enzymes, including superoxide dismutase and glutathione, important antioxidants that protect cellular membranes from ROS damage [24].…”

Section: Discussionmentioning

confidence: 99%

“…Lysophosphatidylcholine is produced from phosphatidylcholine (PC) through the hydrolysis of phospholipase A2 (PLA2), which is caused by the entry of pancreatic juice into the bile duct or by biliary infections . We have previously reported that LPC causes cytotoxicity through the induction of apoptosis and induces oxidative DNA damage by reactive oxygen species (ROS) in cholangiocytes. Furthermore, LPC causes cellular senescence with the induction of senescence‐associated secretory phenotype (SASP) .…”

Section: Introductionmentioning

confidence: 99%

Protective effect of phosphatidylcholine on lysophosphatidylcholine‐induced cellular senescence in cholangiocyte

Ohigashi

Kanno

Sugiyama

et al. 2019

J Hepato Biliary Pancreat

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Background Pancreaticobiliary maljunction and intrahepatic gallstones are at a high risk for biliary malignancy. Lysophosphatidylcholine (LPC) is increased in the bile of these patients, and we have previously reported that LPC‐induced cytotoxicity causes senescence‐associated secretory phenotype (SASP) in cholangiocytes. We aimed to determine the protective effect of phosphatidylcholine (PC) on LPC‐induced cholangiocyte cytotoxicity. Methods MMNK‐1, a human immortalized cholangiocyte cell line was treated with LPC with or without PC. To assess the biological effects of SASP components on cholangiocarcinoma, HuH28 and HuCCT1 (human cholangiocarcinoma cell lines) were cultured in the conditioned media where MMNK‐1 cells treated with LPC. Results The presence of PC reduced reactive oxygen species generation and oxidative DNA damage in MMNK‐1 treated with LPC. Moreover, SA‐β‐gal activity was markedly downregulated by PC. The secretion of SASP components, including interleukin (IL)‐8, IL‐6, and C‐C motif chemokine ligand 2 was also substantially reduced in the presence of PC. Cellular proliferation and migration were enhanced in HuCCT1 and HuH28 cells when cultured in the conditioned media, and these observations were suppressed by simultaneous addition of PC. Conclusion PC protects cholangiocytes against LPC‐induced cytotoxicity and cellular senescence, suggesting its potential as a target for inhibiting LPC‐related carcinogenesis and its promotion.

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Cholangiocyte senescence caused by lysophosphatidylcholine as a potential implication in carcinogenesis

Abstract: Based on these data, cholangiocyte senescence and SASP caused by LPC are potential pathogenic mechanisms in the development of biliary tract cancer.

Cited by 28 publications

References 31 publications

Reduced levels of N’-methyl-2-pyridone-5-carboxamide and lysophosphatidylcholine 16:0 in the serum of patients with intrahepatic cholangiocarcinoma, and the correlation with recurrence-free survival

Reduced levels of N’-methyl-2-pyridone-5-carboxamide and lysophosphatidylcholine 16:0 in the serum of patients with intrahepatic cholangiocarcinoma, and the correlation with recurrence-free survival

Lysophosphatidylcholine induces cytotoxicity/apoptosis and IL-8 production of human endothelial cells: Related mechanisms

Protective effect of phosphatidylcholine on lysophosphatidylcholine‐induced cellular senescence in cholangiocyte

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