Reduced Organic Anion Transporter Expression Is a Risk Factor for Hepatocellular Carcinoma in Chronic Hepatitis C Patients: A Propensity Score Matching Study

Yasui, Yutaka; Kudo, Atsushi; Kurosaki, Masayuki; Matsuda, Shuya; Muraoka, Masaru; Tamaki, Nobuharu; Suzuki, Shinichi; Hosokawa, Takanori; Ueda, Ken; Matsunaga, Kotaro; Nakanishi, Hiroyuki; Tsuchiya, Kaoru; Itakura, Jun; Takahashi, Yuka; Tanaka, Shinji; Asahina, Yasuhiro; Enomoto, Nobuyuki; Arii, Shigeki; Izumi, Namiki

doi:10.1159/000356643

Cited by 20 publications

(16 citation statements)

References 57 publications

(28 reference statements)

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“…In contrast, some other genes were shown to be down-regulated in HCC or have anti-tumor effects during HCC development. Several solute carrier family 22 members including SLC22A1, SLC22A3, and SLC22A7 were shown to be under-expressed in HCC and their down-regulation was associated with the poor prognosis of HCC patients (Heise et al, 2012; Schaeffeler et al, 2011; Yasui et al, 2014). CD5 molecule-like (CD5L), also named inhibitor of microphage (AIM), was reported to have potent preventive effect on HCC (Maehara et al, 2014; Ozawa et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Identification of special key genes for alcohol-related hepatocellular carcinoma through bioinformatic analysis

Zhang¹,

Kang²,

Li³

et al. 2019

PeerJ

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BackgroundAlcohol-related hepatocellular carcinoma (HCC) was reported to be diagnosed at a later stage, but the mechanism was unknown. This study aimed to identify special key genes (SKGs) during alcohol-related HCC development and progression.MethodsThe mRNA data of 369 HCC patients and the clinical information were downloaded from the Cancer Genome Atlas project (TCGA). The 310 patients with certain HCC-related risk factors were included for analysis and divided into seven groups according to the risk factors. Survival analyses were applied for the HCC patients of different groups. The patients with hepatitis B virus or hepatitis C virus infection only were combined into the HCC-V group for further analysis. The differentially expressed genes (DEGs) between the HCCs with alcohol consumption only (HCC-A) and HCC-V tumors were identified through limma package in R with cutoff criteria│log2 fold change (logFC)|>1.0 and p < 0.05. The DEGs between eight alcohol-related HCCs and their paired normal livers of from the Gene Expression Omnibus (GEO) were identified through GEO2R (a built-in tool in GEO database) with cutoff criteria |logFC|> 2.0 and adj.p < 0.05. The intersection of the two sets of DEGs was considered SKGs which were then investigated for their specificity through comparisons between HCC-A and other four HCC groups. The SKGs were analyzed for their correlations with HCC-A stage and grade and their prognostic power for HCC-A patients. The expressional differences of the SKGs in the HCCs in whole were also investigated through Gene Expression Profiling Interactive Analysis (GEPIA). The SKGs in HCC were validated through Oncomine database analysis.ResultsPathological stage is an independent prognostic factor for HCC patients. HCC-A patients were diagnosed later than HCC patients with other risk factors. Ten SKGs were identified and nine of them were confirmed for their differences in paired samples of HCC-A patients. Three (SLC22A10, CD5L, and UROC1) and four (SLC22A10, UROC1, CSAG3, and CSMD1) confirmed genes were correlated with HCC-A stage and grade, respectively. SPP2 had a lower trend in HCC-A tumors and was negatively correlated with HCC-A stage and grade. The SKGs each was differentially expressed between HCC-A and at least one of other HCC groups. CD5L was identified to be favorable prognostic factor for overall survival while CSMD1 unfavorable prognostic factor for disease-free survival for HCC-A patients and HCC patients in whole. Through Oncomine database, the dysregulations of the SKGs in HCC and their clinical significance were confirmed.ConclusionThe poor prognosis of HCC-A patients might be due to their later diagnosis. The SKGs, especially the four stage-correlated genes (CD5L, SLC22A10, UROC1, and SPP2) might play important roles in HCC development, especially alcohol-related HCC development and progression. CD5L might be useful for overall survival and CSMD1 for disease-free survival predication in HCC, especially alcohol-related HCC.

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Section: Introductionmentioning

confidence: 99%

Identification of special key genes for alcohol-related hepatocellular carcinoma through bioinformatic analysis

Zhang¹,

Kang²,

Li³

et al. 2019

PeerJ

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“…Our results showed that ALF did not alter urinary excretion of AZT or its metabolite, GAZT, thus suggesting that the functions of OAT1 and OAT3 in renal proximal tubule cells may not be changed by ALF. Decreased hepatic OAT2 activity and expression may also contribute to the higher oral exposure of AZT in ALF rats observed in this study, as evidenced by the decrease in liver OAT2 expression found in chronic hepatitis C patients [65] .…”

Section: Discussionmentioning

confidence: 55%

Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp

et al. 2017

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HIV infection is often associated with liver failure, which alters the pharmacokinetics of many drugs. In this study we investigated whether acute liver failure (ALF) altered the pharmacokinetics of the first-line anti-HIV agent zidovudine (AZT), a P-gp/BCRP substrate, in rats. ALF was induced in rats by injecting thioacetamide (TAA, 300 mg·kg·d, ip) for 2 days. On the second day after the last injection of TAA, the pharmacokinetics of AZT was investigated following both oral (20 mg/kg) and intravenous (10 mg/kg) administration. ALF significantly increased the plasma concentrations of AZT after both oral and intravenous doses of AZT, but without affecting the urinary excretion of AZT. AZT metabolism was studied in rat hepatic microsomes in vitro, which revealed that hepatic UGT2B7 was the main enzyme responsible for the formation of AZT O-glucuronide (GAZT); ALF markedly impaired AZT metabolism in hepatic microsomes, which was associated with the significantly decreased hepatic UGT2B7 expression. Intestinal absorption of AZT was further studied in rats via in situ single-pass intestinal perfusion. Intestinal P-gp function and intestinal integrity were assessed with rhodamine 123 and FD-70, respectively. We found that ALF significantly downregulated intestinal P-gp expression, and had a smaller effect on intestinal BCRP. Further studies showed that ALF significantly increased the intestinal absorption of both rhodamine 123 and AZT without altering intestinal integrity, thus confirming an impairment of intestinal P-gp function. In conclusion, ALF significantly increases the oral plasma exposure of AZT in rats, a result partly attributed to the impaired function and expression of hepatic UGT2B7 and intestinal P-gp.

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“… 6–9 In humans, hepatitis is related to viral infection, leading to a chronic lesion and later fibrosis. 9 As hepatic fibrosis progresses, hepatocytes with reduced function or dysfunction display impaired Gd-EOB-DTPA uptake mediated via OATP. 24 Therefore, liver enhancement in the hepatocyte phase is reduced.…”

Section: Discussionmentioning

confidence: 99%

Assessment of hepatitis and fibrosis using Gd‐EOB‐DTPA MRI in dogs

Tanaka

Nishida

Mie

et al. 2020

Veterinary Record Open

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BackgroundGadoxetate sodium (Gd-EOB-DTPA) is taken into hepatocytes and excreted into the bile. Hepatocytes with reduced function or dysfunction due to hepatocellular carcinoma (HCC), hepatitis or hepatic fibrosis show impaired Gd-EOB-DTPA uptake. The purpose of the present retrospective case series was to assess the relationship between liver function and contrast enhancement using Gd-EOB-DTPA MRI.MethodsSixteen dogs with a histopathological diagnosis of liver disease, including six with HCC, three with nodular hyperplasia, two with hepatocellular adenoma, two with liver fibrosis and three with hepatitis were included in the study along with three dogs with suspected liver disease but no histopathological diagnosis of liver disease. Relative signal intensities (RSI) of the common bile duct and gall bladder were calculated, and their relationship with the following serum biochemical parameters was assessed: total bilirubin, alanine transaminase, alkaline phosphatase and albumin (Alb). To assess anatomical liver function, relative contrast enhancement indices (RCEI) of the liver were calculated, and differences were assessed between normal and diseased liver.ResultsRSI showed no significant differences between dogs without and with a histopathological diagnosis of liver disease (P=0.88) although they were significantly correlated with Alb (ρ=0.57, P=0.02) in dogs with a histopathological diagnosis of liver disease. RCEI was significantly higher in normal liver tissue than that in livers with hepatitis/fibrosis (P=0.048) and HCC (P=0.03) but not nodular hyperplasia/hepatocellular adenoma (P=0.51).ConclusionsGd-EOB-DTPA MRI may be potentially useful in the assessment of anatomical liver function in dogs with liver disease.

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Reduced Organic Anion Transporter Expression Is a Risk Factor for Hepatocellular Carcinoma in Chronic Hepatitis C Patients: A Propensity Score Matching Study

Cited by 20 publications

References 57 publications

Identification of special key genes for alcohol-related hepatocellular carcinoma through bioinformatic analysis

Identification of special key genes for alcohol-related hepatocellular carcinoma through bioinformatic analysis

Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp

Assessment of hepatitis and fibrosis using Gd‐EOB‐DTPA MRI in dogs

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