The Journal
Reportedly , thecurrent oral cancer therapies are frequently encountered with numerous challenges like inadequate drug concentration reaching the target , nonspecific distribution of antitumor agents , inability to prevent the progression and recurrence of the cancer cells . However with RNAi therapy we can efficiently overcome some of the major adversities thus associated with the treatment methodologies as RNAi directly targets the cancerous cells at molecular scale . By understanding the mechanisms by which RNAi regulates gene expression , this powerfultool can be exploited as an adjunct to the multimodality therapy of various other malignancies too ( 2 ).
Mechanism of RNA interference ( RNAi )
RNAi is a naturally existing molecular technique to combat viral infections and regulate gene expressions in our cells ( 3 ). Its molecular mechanism can be explained as follows :
Step 1 - On entering the cell , endogenously transcribed or exogenously introduced long dsRNA acts as a trigger of the RNAi process . Step 2 - It is first processed by the RNase III enzyme Dicer in an ATP-dependent reaction . Step 3 - Dicer processes long dsRNA into 21-23 nucleotide long siRNA . Step 4 - The siRNA are incorporated into the RISC ( RNA induced silencing complex ) complex which consists of an Argonaute ( Ago ) protein as one of its main components . Ago cleaves and discards the passenger ( sense ) strand of the siRNA duplex leading to an active RISC . Step 5 - The remaining ( antisense ) strand of the siRNA duplex serves as the guide strand and guides the RISC to its homologous mRNA . Step 6-This results in the endonucleolytic cleavage of the target mRNA .
RNAi therapy for the treatment of oral cancer - The prime goal for RNAi approaches for cancer therapy is to knock out the expression of a cell cycle gene and / or an anti-apoptotic gene in the cancer cells thereby stopping tumor growth and killing the cancer cells selectively without damaging normal cells . Followings are some of the recent work on the role of RNAi in the treatment of oral cancer .
Plasmid-based shRNA constructs for inducing RNA interference
Recently scientists at Manitoba University have developed plasmid-based shRNA constructs for inducing RNA interference in order to treat epithelial oral cancer . By this mean they we successful in silencing decorin , a proteoglycan abnormally expressed in cancerous cells ( 4 ). They also found a decreased gene expression of other immune and angiogenesis related genes , Toll-like receptor 5 ( TLR-5 ) as well as Interleukin-8 ( IL-8 ) in decorin silenced oral epithelial cell lines . Moreover , Angiopoietin-1 ( Ang-1 ) -a tie2 receptor ligand expression was also reduced in decorin silenced cell lines . There work has confirmed that decorin function in dysplastic and malignant oral epithelia and validates it as a novel and specific immunotherapeutic target in progression of oral cancer amenable for RNAi therapeutics . Hence it has been proved that by targeting the nuclear decorin we can inhibit the progression of oral cancer .
31 Vol . 14 No . 1 Jan-Apr 2018