It has been shown in endothelial cells of different tumor models that siRNAs downregulating VEGFR-1 and VEGFR-2 could block angiogenesis. to the 5 end from the antisense strand. The cleaved mRNA fragments are released from RISC and degraded. RNAi technology has recently been developed as a potential therapeutic agent. Compared with antisense oligonucleotides, siRNAs are definitely more resistant to nuclease degradation and show a more prolonged therapeutic effect [6, 7]. RNAi works in both cell lines and various primary cells [8], if it is properly delivered. It is broadly, yet specifically, applicable to any target gene with which the sequence is known. The promise that siRNA can specifically downregulate undruggable gene products brings hope to the incurable diseases and ushers in a new era of pharmaceutical science [9]. This review summarizes different signaling pathways inhibited by siRNA and the advantages in the usage of targeted siRNA delivery systems. == 2 . siRNA to get cancer treatment == == 2 . 1 Inhibition of angiogenesis == Angiogenesis is a main element that regulates tumor growth, invasion and metastasis. The vascular endothelial growth element (VEGF) family members has been reported as a important mediator of those processes. VEGF, a glycoprotein, can trigger the signaling pathway to enhance endothelial cell growth, differentiation and migration and safeguard the pre-existing vasculature from death. Because shown inFigure 1, activation of VEGFR-1 or VEGFR-2 can lead to cell survival, proliferation or migration via several different pathways. 1st, Ras pathway is activated to activate cell proliferation and survival via the mitogen-activated protein-kinase (MAPK) cascade. Second of all, VEGF can also phosphorylate phospholipase C (PLC-), which activates protein kinase C and triggers the MAPK pathway [10]. Thirdly, the AKT pathway is phosphorylated through VEGFR activation in a PI3K-dependent manner. Finally, CSRM617 Hydrochloride focal adhesion CSRM617 Hydrochloride kinase (FAK) activation is mediated via the C-terminal tail of VEGFR-2 and is required for cell migration [11, 12]. == Physique 1 . Cellular signaling in tumor and endothelial cells. == Target CENPA genes to which siRNA continues to be used for downregulation are determined with a red star. siRNA, which downregulates VEGF expression, inhibits tumor growth in HeLa cells, ovarian carcinoma or melanoma cellsin vitro, as well as in a PtdCho-3 xenograft model [13]. Blocking VEGF receptor expression is another way to inhibit angiogenesis. It has been shown in endothelial cells of different tumor models that siRNAs downregulating VEGFR-1 and VEGFR-2 could block angiogenesis. The combination of anti-VEGF and anti-VEGFR siRNA improves therapeutic effect [1416]. == 2 . 2 Inhibition of tumor survival and induction of apoptosis == siRNAs targeting oncogenes that are involved in survival or antiapoptosis show great therapeutic potential for cancer therapy [17]. The Wnt pathway plays an important role in carcinogenesis. Wnt signaling is transduced through Wnt receptors to the beta-catenin-Tcf pathway, the c-Jun-N-terminal kinase (JNK) pathway or the Ca(2+)-releasing pathway. Wnt/beta-catenin signaling pathway is highly activated and leads to beta-catenin build up in a variety of human being cancers. Anti-Wnt-1 siRNA induced apoptosis in MCF-7 breast cancer cell range [18]. siRNAs blocking Wnt pathway have also been used to target cancerous stem cells in non-small cell lung cancer (NSCLC), which has limited response to single-agent chemotherapy [19]. These results suggest that siRNA inhibiting CSRM617 Hydrochloride Wnt pathway may serve as a potential anticancer agent. NF-B, a transcription factor which regulates various genes involved in different pathological states, continues to be related to oncogenesis and plays an important role in cell survival and antiapoptosis in response to chemotherapy. siRNA is currently used to inhibit the function of NF-B pathway. The combination of p65 siRNA and CPT-11, a topoisomerase I inhibitor, significantly delayed tumor growth and reduced tumor size in HCT116 xenograft models [20]. These studies demonstrate that siRNA targeting NF-B cannot only enhance apoptosis, but also increase sensitivity to radiation or chemotherapy in tumor cells [20, 21]. siRNA targeting heparin binding-epidermal growth factor-like growth factor (HB-EGF), a ligand of epidermal growth element receptor (EGFR), can inhibit every step involved in peritoneal dissemination in human ovarian cancerin vitroandin vivo[22]. EGFR, which is overexpressed in a variety of tumors, is related to tumor proliferation, anti-apoptosis, enhanced metastasis and drug resistance [23, 24]. Because shown inFigure 1, activation of EGFR results in homo/hetero-dimerization of the receptor and phosphorylation of specific tyrosine kinases, which induce.