45 Moreover, silencing of PTEN or TIMP3 phenocopied the effects of miR-221-222 cluster on TRAIL resistance and was accompanied by a reduction of caspases activation and poly (ADP-ribose) polymerase (PARP) cleavage.45 This further corroborated the anti-apoptotic role of miR-221-222. selleck chemicals llc Several miRNAs have been reported to play a role in the control of cell cycle (Fig. 3), in particular at the G1/S checkpoint. MiR-26a targets G1/S cyclins (both cyclin D2 and E2) in murine liver cancer,59 whereas miR-195 targets multiple genes (including cyclin D1, CDK6, and E2F3) of the G1/S transition in primary HCC.56 Both miR-26a and miR-195 have been found to be

frequently downregulated in HCC, where they have been shown to cooperate in overcoming the G1/S cell cycle blockade through repression of E2F transcription.56,59 In addition, miR-221 in HCC has also been reported to target CDKN1B/p27/Kip1 and CDKN1C/p57/Kip2, both of which are CDK inhibitors.46 Taken together with the above described anti-apoptotic properties,45,47 these findings indicate that miR-221 can simultaneously affect multiple oncogenic pathways in HCC. Intriguingly, both miR-106b and miR-93 can also target E2F1.33 While this may seemingly contradict the oncogenic property of miR-106b-25 cluster in HCC, it is plausible

that since high levels of E2F1 can cause apoptosis,60 upregulation of miR-106b and miR-93 may serve to prevent excessive accumulation of E2F1. Thus, together with Doramapimod datasheet miR-25 targeting of pro-apoptotic Bim protein,33 members of the miR-106b-25 cluster might coordinate the curtailment

of apoptosis in HCC. medchemexpress Our previous work demonstrated that miR-223 is commonly downregulated in HCC.30 Re-expression of miR-223 revealed a consistent inhibitory effect on cell viability. We also showed that miR-223 could target stathmin1 (STMN1), which is a microtubule destabilizer that sequesters tubulin for depolymerization and affects microtubule assembly.30 As microtubules have an important role in the segregation of metaphase chromosomes during mitosis, it is probable that miR-223 has a function in regulating the G2/M transition. Receptor tyrosine kinases are cell surface receptors that transmit extracellular stimuli to intracellular signaling responses. RTK transduction activates a series of proteins and elicits downstream signaling cascades that eventually alter transcription of a myriad of genes involved in cellular processes, such as proliferation, apoptosis and survival (Fig. 4). Hepatocyte growth factor receptor (HGFR; also known as c-Met) is a RTK, whose oncogenic function has been extensively documented in HCC.61,62 It has been shown that c-Met can be regulated by a number of miRNAs.