Featured Review Cellscience Reviews Vol 4 No 1 ISSN 1742-8130

RNA interference: Relevance in Targeting Ras and Ras-signaling Pathways in Human Cancer

RNA interference (RNAi) describes the phenomenon of sequence specific degradation of mRNA by 21-23 bp dsRNAs (small interfering RNA, or siRNA) through Watson-Crick base pair complementation. siRNAs have become indispensable tools for the study of gene function since their validation in mammalian cells some 6 years ago. There have also been intense interests in considering the clinical applicability of siRNA-based targeted cancer therapy. Aberrant mRNA translation of mutant oncogenes and tumor suppressor genes has been shown to be critical for oncogenesis. Hence the use of siRNA to knockdown offending oncogenic activity has immediate relevance, particularly in light of the exquisite specificity of siRNAs in distinguishing single nucleotide differences between mutant and wild type genotypes, and the markedly improved efficacy of siRNAs as compared with antisense oligonucletotides or ribozymes as seen in preclinical studies. The MAPK (mitogen-activated protein kinase) cascade, the PI3K/Akt (phosphoinositide 3-kinases) and the protein kinase C (PKC) pathway are considered to be the three most important signaling pathways for tumor transformation. The proto-oncogene Ras is a critical node for relaying tyrosine kinase receptor (Her2/neu and other EGFRs) activating signals to these pathways. Mutations of Ras, commonly found in human cancers, also lead to the activation of downstream oncogenes and transcription factors including Akt, PKC (protein kinase C), mTOR (mammalian target of rapamycin), MDM2 (mouse double minute 2 homolog), GSK-3 (glycogen synthase kinase-3), c-MYC (myelocytomatosis viral oncogene), and TIAM1 (T-lymphoma invasion and metastasis related gene), with proliferative, anti-apoptotic, and angiogenic consequences. We review current literature findings on the antitumor outcome by siRNAs directed against oncogenic Ras and Ras-related signaling pathways, and discuss their clinical applicability for the development of RNAi-based cancer therapeutics.

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