**5. Global miRNA expression profiling of HCC**

One of the most important findings of the analysis on the human genome is identification of a significant number of sequences encoding non-coding RNA molecules such as small nucleolar RNAs and microRNAs also known as miRNAs [55-56]. MicroRNAs, singlestranded RNAs typically 21-23 nucleotide long, are untranslated molecules that have capability to bind complementary sequences resulting in their silence, therefore, regulating the expression of their target genes. Some of these molecules have currently been intensely studied and their biogenesis, structure and function are now known and some other small regulatory RNAs are yet to be discovered. Among these different RNAs species, miRNAs holds special attention due to its properties and potential use as therapeutic targets for cancer. Currently around 6000 miRNAs from multiple species have been annotated in different databases. These miRNAs target and regulate around 30% of all protein coding genes in mammals. It has been shown that the miRNAs regulate processes essential to differentiation, apoptosis, cell growth, adhesion, and cell death [57-58]. Recently, due to its oncogenic and tumor suppression activities, these molecules exploited for various cancers, including HCC [59-63].

The genomic instability, transcriptional regulation, and epigenetic alteration have been identified to contribute to the abnormal expression of miRNAs in HCC. Furthermore, the aberrant expression of certain miRNAs is correlated with clinical features of HCC, indicating their potential to serve as diagnostic and prognostic biomarkers of HCC [64-65]. Some aberrantly expressed miRNAs may have a direct role in liver tumorigenesis, and could promote differentiation, cell cycle progression, angiogenesis and invasion, such as mir-221 and mir-21 [59]. Murakami *et al.* identified eight miRNAs with altered expression in HCC, which discriminated HCC samples from non-tumor with 97.8% accuracy [66]. Similarly, Huang *et al.* identified 24 abberrantly expressed miRNAs [67]. Toffanin *et al.* studied miRNA profiling of HCC samples that was previously profiled for mRNA and copy number (CN) changes [65]. The authors identified three subclasses of HCC based on miRNA profiles. The other studies identified miRNA signatures that predicted metastasis potential, recurrence and survival [64, 68-69]. Since the miRNAs are stable in blood, more recently, the circulating miRNAs have been reported as diagnostic markers for various cancers, including the HCC [70-72].Therefore, identification of miRNAs and their protein-coding target genes is important to understand the mechanisms of hepatocarcinogenesis, and reveals new biomarkers for diagnosis, prognosis and therapeutic targets.
