Circulating miR-192 in liver fluke-associated cholangiocarcinoma patients: a prospective prognostic indicator

Silakit, Runglawan; Loilome, Watcharin; Yongvanit, Puangrat; Chusorn, Porncheera; Techasen, Anchalee; Boonmars, Thidarut; Khuntikeo, Narong; Chamadol, Nittaya; Pairojkul, Chawalit; Namwat, Nisana

doi:10.1002/jhbp.145

Cited by 72 publications

(43 citation statements)

References 37 publications

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“…We additionally showed that miR-192 can suppress expression of the bile acid and anticancer drug transporter OATP1B3 and the bile acid transporter OST␣/␤ in a FXR-dependent manner. It remains unclear whether restoration of miR-192 expression and the consequently diminished expression of FXR target genes would be beneficial for cancer patients, especially considering that miR-192 has been shown to possibly act as an oncogenic miRNA by downregulation of Smad interacting protein 1 in other inflammation-related cancers (21,26,35). Therefore, it can be speculated that diminished expression of the transport protein OST␣/OST␤, a heterodimer-forming bile acid transporter important for the excretion of bile acids from hepatocytes and enterocytes, may be a mechanism of intracellular bile acid accumulation promoting inflammation and/or cancer development in certain cases.…”

Section: Discussionmentioning

confidence: 99%

“…An important role of miR-192 targeting ZEB2 mRNA has also been found in HCC (13). In contrast, certain forms of cancer, such as cholangiocarcinoma and esophageal cancer, show increased miR-192 expression during carcinogenesis (21,26).…”

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confidence: 94%

“…Elevated serum levels of miR-192 have been detected in various liverassociated diseases, including drug-induced liver injury, nonalcoholic steatohepatitis, cholangiocarcinoma, and hepatitis B-related hepatocellular carcinoma and may serve as a biomarker (24,26,28,31,37). Thus several studies have hypothesized that tissue-specific chronic inflammation may trigger increases in miR-192 expression, as in nonalcoholic steatohepatitis (21,24,26). Because miR-192 shows an inverse correlation with the metastatic potential of colon cancer cells, miR-192 has been suggested to be a predictive biomarker for the risk of developing liver metastasis in colon carcinoma.…”

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confidence: 99%

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microRNA-192 suppresses the expression of the farnesoid X receptor

Krattinger

Boström

Schiöth

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Farnesoid X receptor (FXR, NR1H4) plays an important role in the regulation of bile acid homeostasis in liver and intestine and may exert protective effects against certain forms of cancer such as colon carcinoma. However, the role of FXR in cell growth regulation, apoptosis, and carcinogenesis is still controversial. Similar to FXR, microRNA-192 (miR-192) is mainly expressed in the liver and colon and plays an important role in the pathogenesis of colon carcinoma. In this study, we investigated the extent to which FXR is regulated by miR-192. Two in silico-predicted binding sites for miR-192-3p within the NR1H4-3' untranslated region (UTR) were examined in vitro by luciferase reporter assays. Wild-type and mutated forms of the NR1H4-3'UTR were subcloned into a pmirGLO vector and cotransfected into Huh-7 cells with miR-192-3p. To study the effects of miR-192 on the expression of FXR, FXR target genes and cell proliferation, Huh-7 and Caco-2 cells were transfected with miR-192-5p and -3p mimics or antagomirs. In addition, the correlation between FXR and miR-192 expression was studied by linear regression analyses in colonic adenocarcinoma tissue from 27 patients. MiR-192-3p bound specifically to the NR1H4-3'UTR and significantly decreased luciferase activity. Transfection with miR-192 led to significant decreases in NR1H4 mRNA and protein levels as well as the mRNA levels of the FXR-inducible bile acid transporters OSTα-OSTβ and OATP1B3. Significant inverse correlations were detected in colonic adenocarcinoma between NR1H4 mRNA and miR-192-3p expression. In summary, microRNA-192 suppresses the expression of FXR and FXR target genes in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

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confidence: 94%

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confidence: 99%

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microRNA-192 suppresses the expression of the farnesoid X receptor

Krattinger

Boström

Schiöth

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Much attention has been given to miR-192-5p as a serum-based biomarker. As an example, miR-192-5p levels were highly elevated in various liver diseases [8,9,12,14,15] as well as in patients with cancer, where elevated serum levels are associated with tumour metastasis and poor survival [17]. In the present study, we analysed the expression of miR-192-5p in ischaemia/reperfusion (I/R) and toxin-induced liver injury.…”

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confidence: 98%

Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury

et al. 2016

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miR-192-5p has gained increasing relevance in various diseases, however, its function in acute liver injury is currently unknown. We analysed miR-192-5p serum levels and hepatic miR-192-5p expression in mice after hepatic ischaemia and reperfusion (I/R) as well as in toxic liver injury. On a functional level, miRNA levels were analysed in the different hepatic cell-compartments and in the context of tumour necrosis factor (TNF)-dependent liver cell death. We detected increased serum levels of miR-192-5p after hepatic I/R- and carbon tetrachloride (CCl4)-induced liver injury. miR-192-5p levels correlated with the degree of liver damage and the presence of hepatic cell death detected by TUNEL stainings (terminal deoxynucleotidyltransferase-mediated dUTP biotin nick-end labelling stainings). Moreover, expression of miR-192-5p was increased in a hypoxia/reoxygenation (H/R) model of in vitro hepatocyte injury, supporting that the passive release of miR-192-5p represents a surrogate for hepatocyte death in liver injury. In critically ill patients, miR-192-5p levels were elevated selectively in patients with liver injury and closely correlated with the presence of hepatic injury. In contrast with up-regulated miR-192-5p in the serum, we detected a down-regulation of miR-192-5p in both injured mouse and human livers. Deregulation of miR-192-5p in livers was dependent on stimulation with TNF. Functional experiments confirmed a protective effect of down-regulation of miR-192-5p in hepatocytes, suggesting a role of miR-192-5p in limiting liver injury. Finally, we identified Zeb2, an important regulator of cell death, as a potential target gene mediating the function of miR-192-5p Our data suggest that miR-192-5p is involved in the regulation of liver cell death during acute liver injury and might represent a potent marker of hepatic injury.

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“…Moreover, elevated levels of circulating miR-26a correlated with the disease stage and were reported to be independent prognostic markers of overall and disease-free survival [70]. In a study from Thailand including patients with liver fluke-associated CCA, high levels of serum miR-192 were found to significantly correlate with lymph node metastasis and shorter overall survival [71]. However, most studies on the prognostic capabilities of miRNAs for CCA have analyzed tissue samples from tumor resection without considering serum analyses.…”

Section: Resultsmentioning

confidence: 99%

Circulating Biomarkers for Cholangiocarcinoma

Loosen

Vucur

Roderburg

et al. 2018

Dig Dis

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Background: Cholangiocarcinoma (CCA) represents the second most common primary liver malignancy. The incidence rate has constantly increased over the last decades and CCA patients face a dismal prognosis with a 5-year survival rate of less than 5% for advanced stage of disease. Surgical tumor resection has remained the only potentially curative treatment option in daily practice but is often not feasible due to advanced disease stage at initial diagnosis. Summary: The early detection of cholangiocarcinoma is essential to provide patients with a potentially curative treatment. Furthermore, prognostic biomarkers represent a valuable tool to offer patients a tailored therapeutic approach in accordance to their life expectancy. The clinically most established biomarker carbohydrate antigen 19–9 shows only a limited diagnostic and prognostic power, encouraging the evaluation of novel biomarkers for cholangiocarcinoma in the last years. Key Massage: In this review, we assess currently available and potential future biomarkers for the diagnosis and prognosis of cholangicarcinoma.

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Circulating miR-192 in liver fluke-associated cholangiocarcinoma patients: a prospective prognostic indicator

Abstract: This finding indicates that elevated levels of miR-192 may be involved in CCA genesis and have a potential utility as a noninvasive prognostic indicator for CCA patients.

Cited by 72 publications

References 37 publications

microRNA-192 suppresses the expression of the farnesoid X receptor

microRNA-192 suppresses the expression of the farnesoid X receptor

Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury

Circulating Biomarkers for Cholangiocarcinoma

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