To date only one study regarding

To date, only one study regarding the role of miRNAs during hepatic cyst formation has been published. While this is an older publication, published in 2008, the findings are worth discussing, based on the limited information on miRNAs during PLD. In whole liver sections from patients with PLD due to ARPKD or ADPKD, the expression of miR-15a was decreased in cholangiocytes lining cysts compared with normal human liver sections. Further analysis identified cell division cycle (CDC)25A, which plays a major role in alpha adrenergic blockers progression, as a target of miR-15a. To verify that CDC25A is a target of miR-15a, staining was performed in liver sections and the results revealed that cholangiocytes lining liver cysts in patients with ARPKD or ADPKD had increased expression of CDC25A compared with normal human liver. These findings suggest that suppression of miR-15a promotes hepatic cyst formation by increasing cholangiocyte proliferation via upregulated Cdc25A. Replenishing miR-15a biliary expression may decrease cyst growth in patients suffering from PLD. Further work regarding miRNA regulation of PLD is necessary.
Cholangiocarcinoma Cholangiocarcinoma (CCA) is the second most common liver cancer and arises from damaged cholangiocytes lining the intra- and/or extra-hepatic bile ducts. CCA is a devastating cancer that commonly has a poor prognosis and low five-year survival rate. While the diagnosis of CCA is fairly rare, its incidence has recently been rising. Men are 1.5 times more likely to be diagnosed than women, and Asians are almost twice as likely to be diagnosed. Risk factors known to increase the likelihood of developing CCA include PSC, liver fluke infestation, hepatolithiasis, choledochal cysts and chronic liver infection; however, these risk factors cannot explain the current rise in CCA incidence. Currently, surgical resection is the preferred method of treatment for patients with CCA; however, CCA patients who also have decreased liver function and/or underlying cirrhosis have poorer prognosis to this treatment. Based on the limited treatment options, it is imperative that new and effective treatment strategies are developed. While a large number of studies have been published on the role of miRNAs during CCA diagnosis, treatment and pathogenesis, this review will focus on those published within the past five years. N-myc downstream-regulated gene 2 (NDRG2) plays a major role in cell cycle, growth and proliferation, and is mainly recognized as a tumor suppressor during carcinogenesis. A recent study investigated the role of NDRG2 during CCA progression and its regulation by miR-181c. Human CCA tumor samples showed decreased NDRG2 levels but increased miR-181c expression compared with adjacent non-tumor liver samples. Binding between miR-181c and NDRG2 was confirmed by luciferase assay and site-directed mutagenesis in the 3′ UTR of NDRG2 in cultured human CCA cells. Additionally, NDRG2-linked reporter activity was repressed by miR-181c mimic treatment in a dose-dependent manner, but reporter activity was greatly increased following anti-miR-181c treatment. Furthermore, downregulation of NDRG2 coupled with upregulation of miR-181c was significantly associated with a poorer prognosis, and in vitro work conferred increased chemoresistance and metastatic potential. These results identify a novel pathway whereby miR-181c regulates NDRG2 to influence carcinogenesis and metastasis, and suggests the therapeutic potential of targeting miR-181c during CCA. Inflammation favors tumorigenesis through enhanced angiogenesis, DNA damage, maintenance of cancer stem cells and cell proliferation. Specifically, IL-6 has been recognized as a main cytokine produced by cholangiocytes during inflammatory processes such as cholangitis. One group studied miRNA and inflammatory differences between CCA tumors and adjacent non-tumor liver tissue. In CCA samples, miR-122, miR-32, miR-101, let-7c, miR-99a and miR-125b were significantly downregulated, whereas miR-200c, miR-21 and miR-221 were significantly upregulated compared with adjacent non-tumor samples. To investigate whether these deregulated miRNAs played a role in CCA inflammation, predicted targeting relationships between these miRNAs and selected cytokines that are most commonly associated with CCA (IL-6, IL-8, insulin-like growth factor [IGF]-1, transforming growth factor [TGF]-β1 and vascular endothelial growth factor [VEGF]) was performed using Starbase v2.0. The results demonstrated that miR-99a, let-7c and miR-125b (all of which were decreased in CCA) could regulate all of the aforementioned CCA-associated cytokines. Interestingly, these three miRNAs are found on the same cluster on chromosome 21q21, and it was hypothesized that the clustering of these three miRNAs could synergistically influence CCA-associated inflammatory processes. In vitro, reintroduction of miR-99a, let-7c or miR-125b inhibited human CCA cell migration and invasion, and reintroduction of the entire cluster significantly decreased human CCA cell ability to form cancer stem cell-like spheroids. These results indicate that targeting miR-99a, let-7c and/or miR-125b may be a potential treatment strategy for targeting inflammation, cytokine production, metastasis, and cancer stem cell-like properties in CCA.