58). Reporter assay readouts later confirmed estrogen receptor-α

(ERα) as a target of miR-18a. Since it is known that estrogen protects females from the development of HCC, it is plausible that miR-18a weakens the protective effects of estrogen by suppressing the translation of ERα, thereby increasing the risk of HCC development in women.24 Chronic heavy alcohol consumption is another risk factor in the development of HCC. In a miRNA microarray study, miR-126* was shown to be specifically downregulated in alcohol-related HCC.25 This downregulation, however, was not evident in non-tumoral tissues, implicating that miR-126* repression might be directly linked to alcohol-induced hepatocarcinogenesis.25 Obesity is becoming an important risk factor for HCC in recent years. Obese patients are prone to develop non-alcoholic Ibrutinib supplier fatty liver disease (NAFLD), which is deposition of fat in liver cells

unrelated to alcohol consumption. The spectrum of NAFLD ranges from fatty liver, to non-alcoholic steatohepatitis (NASH), and finally cirrhosis, which predisposes to HCC development. MiRNAs have been shown to be involved in the pathogenesis of NASH. Unsaturated fatty acids have been shown to increase miR-21 expression, which affects phosphatase and tensin homolog (PTEN) expression and consequentially induces steatosis.26 The pathophysiological relevance of this phenomenon was further verified by the observation of an increased selleck inhibitor miR-21 level and PTEN downregulation in the livers of Wistar rats fed with a high-fat diet, and in human liver biopsies of patients with steatosis.26 In mice administered a choline-deficient and amino acid-defined (CDAA) diet that promoted NASH-induced hepatocarcinogenesis, microarray analysis identified 30 differential expressed miRNAs.27 Among these, miR-155 was consistently upregulated during Dapagliflozin the course of CDAA intake. In RAW 264.7 cells, miR-155 was reported to target CCAAT/enhancer binding protein beta (C/EBPβ),28 a transcription

factor with tumor suppressive activity. Transfection of miR-155 readily decreased C/EBPβ expression and promoted cell viability in Hep3B and HepG2 cells.27 The results of these studies imply considerable importance for both miR-155 and miR-21 in NASH-associated HCC. MiRNAs may also potentiate the actions of hepato-carcinogens. For instance, tamoxifen, an estrogen receptor antagonist commonly used in the clinical treatment of breast cancer, has been shown to induce HCC in rats.29 Long-term exposure of tamoxifen to female rodents perturbed miRNA expression and induced oncogenic miRNAs expression, including miR-17-92 cluster, miR-106a, and miR-34. These changes in miRNA could have predisposed to malignant liver transformation.29 Under normal physiological conditions, the balance between cell proliferation and programmed cell death is tightly regulated in order to maintain tissue homeostasis.