they play in carcinogenesis. miRNA MiRNAs play critical roles in many biological processes including cancer by directly interacting with specific messenger RNAs through base pairing and then inhibiting expression of the target genes through a variety of molecular mechanisms. AZD8931 MiRNAs can undergo aberrant regulation during carcinogenesis, and they can act as oncogenes or tu mor suppressor genes. Disruption of miRNA expres sion levels in tumor cells may result from distorted epigenetic regulation of miRNA expression, abnor malities in miRNA processing genes and proteins, and the location of miRNAs at cancer associated ge nomic regions. Consequently, abnormal miRNA ex pression is a ubiquitous feature of solid tumors in cluding HCC.
In liver carcinogenesis, PS-341 miRs have been found to have both tumor suppressive and oncogenic activity. Clearly, miRNAs play a critical role in carcinogenesis and oncogenesis. Emerging evidence suggests that certain abnormal miRNA expression induces CSC dysregulation, re sulting in unlimited self renewal and cancer progres sion. Therefore, miRNA expression is a vital key to CSC dysregulation. Lin28 and let 7 signaling Lin28 was first characterized in the nematode Caenorhabditis elegans as an important regulator of developmental timing. Recently, Lin28 was used together with OCT4, NANOG and SOX2 to re program human somatic fibroblasts to pluripotency. Overexpression of these stem cell factors has been reported to promote oncogenesis by driving self renewal and proliferation.
Moreover, poorly differentiated, aggressive human tumors have re cently been shown to have an embryonic stem cell like gene expression signature, these stem cell factors have also been reported to have roles in tumor progression. LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines . The mammalian homologs of lin 28, Lin28 and Lin28b, bind to the terminal loop of the precursors of let 7 family miRNAs and block their processing into mature miRNAs. In HCC, LIN28B expressing tumors are associated with ad vanced stage. Moreover, LIN28B expression was associated with a significantly increased incidence of early recurrence. LIN28 is associated with an ad vanced disease and poor clinical outcome in HCC. The initiation of hepatocarcinogenesis is linked to chronic inflammation clinically and epi demiologically.
The positive feedback loop involving NF ?B, Lin28B, let 7, and IL 6 is required for mainte nance of the transformed phenotype and stem cell population . miR 181 Mir 181 was first characterized in the patients with acute myeloid leukemia as a predictor of prog nosis. Recently, we have identified a subset of highly EpCAM HCC cells from AFP tumors with cancer stem progenitor cell features. MiR 181 family members are up regulated in EpCAMAFP HCC cells. Moreover, miR 181 family members were highly expressed in embryogenic livers and isolated hepatic stem cells. Forced expression of miR 18