Suppression of osteopontin inhibits chemically induced hepatic carcinogenesis by induction of apoptosis in mice

Lee, Su-Hyung; Park, Junwon; Woo, Sang-Ho; Go, Du-Min; Kwon, Hyo Jung; Jang, Ja‐June; Kim, Dae-Yong

doi:10.18632/oncotarget.13529

Cited by 19 publications

(21 citation statements)

References 45 publications

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“…However, the role of Opn at early stages of HCC development is still not clear, although it has been proposed to modulate the immunosuppressive activity of myeloid-derived suppressor cells (42). Notably, 2 studies exploring the role of Opn in HCC development using the same model of Opn-deficient mice showed opposite results (43,44). Noncancerous hepatocytes of HCC patients did not express Opn (45).…”

Section: Discussionmentioning

confidence: 99%

Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

et al. 2019

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Chronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin‐1 (Gal1) is involved in the regulation of inflammation, angiogenesis, and tumorigenesis, exhibiting multiple anti‐inflammatory and protumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI‐mediated HCC development, Abcb4 [multidrug‐resistance 2 (Mdr2)]‐knockout (KO) mice, which express high levels of Gal1 in the liver. We generated double‐KO (dKO) Gal1‐KO/Mdr2‐KO mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2‐KO strains. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice of both strains starting from an early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared with control Mdr2‐KO mice. We found that osteopontin, a well‐known modulator of HCC development, and oncogenic proteins Ntrk2 (TrkB) and S100A4 were overexpressed in dKO compared with Mdr2‐KO livers. Our results demonstrate that in Mdr2‐KO mice, a model of CLI‐mediated HCC, Gal1‐mediated protection from hepatitis, liver fibrosis, and HCC initiation dominates over its known procarcinogenic activities at later stages of HCC development. These findings suggest that anti‐Gal1 treatments may not be applicable at all stages of CLI‐mediated HCC.—Potikha, T., Pappo, O., Mizrahi, L., Olam, D., Mailer, S. M., Rabinovich, G. A., Galun, E., Goldenberg, D. S. Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model. FASEB J. 33, 7995–8007 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

et al. 2019

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“…It should be noted that many known industrial chemicals and environmental toxicants, as well as procarcinogens (eg, nitrosamines, benzene, and vinyl chloride) are metabolized by CYP2E1 . Diethylnitrosamine (DEN), known as a level 1 carcinogen, has been found in a variety of products, such as tobacco smoke, salted fish, and food color additives and has been linked to the occurrence of hyperplastic liver nodules and HCC due to CYP2E1‐mediated metabolic activation …”

Section: Introductionmentioning

confidence: 99%

“…21,22 Diethylnitrosamine (DEN), known as a level 1 carcinogen, has been found in a variety of products, such as tobacco smoke, 23 salted fish, 24 and food color additives 25 and has been linked to the occurrence of hyperplastic liver nodules and HCC due to CYP2E1mediated metabolic activation. 22,26,27 For patients with severe hepatofibrosis, CYP2E1-mediated probe (chlorzoxazone) metabolic metabolism in vivo was decreased. 28 In addition, CYP2E1-mediated N,N-dimethylnitrosamine N-demethylase activity in vitro was decreased or unchanged in cholestatic fibrosis and other typical fibroses.…”

Section: Introductionmentioning

confidence: 99%

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

Gao

Wang

et al. 2018

Molecular Carcinogenesis

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Hepatofibrosis is an important susceptibility factor for hepatocarcinogenesis. However, only a handful of cases of hepatofibrosis will develop into hepatocellular carcinoma (HCC). As cytochrome P450 2E1 (CYP2E1) is involved in the metabolism and activation of many known environmental toxicants and procarcinogens, this enzyme may play a role in the development of hepatocarcinogenesis subsequent to hepatofibrosis. Herein, we evaluated whether higher CYP2E1 activity is a risk factor for the development of hepatocarcinogenesis from hepatofibrosis. CYP2E1 activity in fibrotic tissues from 72 HCC patients and in normal liver tissues from 59 control subjects was determined along with the severity of hepatofibrosis in hepatocarcinogenesis patients. Similarly, using a rat diethylnitrosamine-induced hepatocarcinogenesis model, CYP2E1 activity at the hepatofibrosis and hepatocarcinogenesis stages was determined, the correlation between CYP2E1 activity at the hepatofibrosis stage and hepatocarcinogenesis was explored, and the impact of inhibition of CYP2E1 activity on hepatocarcinogenesis was studied. The results showed that while CYP2E1 activity in HCC patients with underlying hepatofibrosis was increased, the severity of hepatofibrosis did not correlate with CYP2E1 activity. In the rat hepatocarcinogenesis model, unexpectedly, CYP2E1 activity was found to decrease from hepatofibrosis to hepatocarcinogenesis. Importantly, however, hepatofibrotic rats with higher CYP2E1 activity developed a more severe form of HCC. Moreover, inhibition of CYP2E1 activity could decrease the occurrence and development of HCC in rats. In conclusion, higher CYP2E1 activity may be a risk factor for hepatocarcinogenesis from hepatofibrosis, which raises the possibility of screening patients with hepatofibrosis for CYP2E1 activity to better estimate their risk for hepatocarcinogenesis.

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“…Nevertheless, in mice models of liver injury induced by diethylnitrosamine or ischemia/reperfusion, OPN exerted a protective effect by ameliorating the production of IL-6 and TNF-α in macrophages and inhibiting inflammation (11,12). Furthermore, OPN may serve a key role in the expansion of hepatic progenitor cells (HPC) and in promoting liver regeneration during liver cancer (13,14) and acute liver failure (15,16).…”

Section: Introductionmentioning

confidence: 99%

Serum osteopontin is a predictor of prognosis for HBV‑associated acute‑on‑chronic liver failure

Liu

et al. 2017

biom rep

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Abstract. Acute-on-chronic liver failure (ACLF) is a syndrome with a high rate of short-term mortality, and clinically it is important to identify patients at high risk of mortality. The present study evaluated the value of osteopontin (OPN) in the prediction of 90-day mortality in patients with ACLF. A total of 54 patients with HBV-associated ACLF were enrolled, and serum OPN levels were determined in a prospective, observational study design. Survival analysis was performed using Kaplan-Meier curves, and multivariate Cox proportional hazards regression was used to analyze independent risk factors of mortality. Serum OPN was significantly higher in HBV-ACLF patients compared with patients with chronic hepatitis B and healthy controls (both P<0.01), and furthermore, was higher in those patients who succumbed to HBV-ACLF compared with surviving patients (P<0.05). OPN level positively correlated with total bilirubin (r=0.554, P<0.001), Model for End-Stage Liver Disease (MELD) score (r=0.234, P=0.038), MELD-Na score (r=0.379, P=0.005) and monocyte count (r=0.282, P=0.039), and OPN was an independent risk factor for 90-day mortality in ACLF (P=0.021, odds ratio=1.104, 95% confidence interval: 1.003-1.116). Furthermore, ACLF patients were stratified into three groups according to serum OPN levels (low mortality risk: <6,135 ng/ml; intermediate risk: 6,135-9,043 ng/ml; and high risk: >9,043 ng/ml), for which the 90-day mortality rates were 27.78 (5/18), 52.94 (9/17) and 73.68% (14/19), respectively, and those in the high risk had a poorer prognosis compared with the low risk group (P=0.009). In conclusion, serum OPN may be an independent risk factor associated with HBV-ACLF prognosis.

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Suppression of osteopontin inhibits chemically induced hepatic carcinogenesis by induction of apoptosis in mice

Cited by 19 publications

References 45 publications

Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor

Serum osteopontin is a predictor of prognosis for HBV‑associated acute‑on‑chronic liver failure

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