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Global Translational Medicine Small RNA therapy for pancreatic cancer

Figure 1. The number of research papers published from 2005 to 2025, retrieved from the Web of Science database using the keyword “Pancreatic cancer”
and “microRNA”

binding to an Argonaute (AGO) protein, which serves binding affinity to the target RNA and improve resistance
as the central component of the RNA-induced silencing against enzymatic degradation. Notably, most drugs
complex (RISC). Once incorporated into the AGO protein, approved by the U.S. FDA exert their antisense effects
the miRNA guides RISC to bind a complementary target through RNase-mediated mechanisms. 64
mRNA, resulting in translational repression or degradation The second mechanism of action of ASOs is based
of the targeted mRNA. In addition to binding to the 3’ UTR, on steric hindrance, which blocks key regions of mRNA,
miRNAs can also inhibit protein expression by interacting thereby affecting its maturation or translation into proteins.
with coding sequences or the 5’UTR of mRNAs. For example, Bennett and Swayze. found that an ASO
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RNA interference (RNAi) is a natural process that targeting the mRNA sequence leads to translational arrest
promotes the degradation of target mRNA, thereby by either inhibiting its interaction with the 40S ribosomal
silencing gene expression (Figure 2B). When long-chain subunit or preventing the assembly of the 40S and 60S
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double-stranded RNA is cleaved by Dicer, a member of ribosomal subunits (Figure 2C).
the ribonuclease (RNase) III family, siRNA duplexes are The third mechanism of action of ASOs involves
produced. Subsequently, the siRNA is incorporated into the blocking alternative splicing (Figure 2C). Dhuri et al.
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RISC. Inside the RISC, the siRNA interacts with the AGO2 found that ASOs can target the splicing regulatory regions
component, causing the duplex to unwind and leading to of pre-mRNA and bind to them in a complementary
the degradation of the sense strand. The antisense strand, manner. After binding, steric hindrance is generated,
which is complementary to the target mRNA, then guides which inhibits or promotes the binding of splicing factors
the RISC complex to the target mRNA. to regulatory regions, thereby affecting spliceosome
ASO is a single-stranded oligonucleotide with assembly and generating different mRNA isoforms.
three mechanisms of action. The first is based on the Aptamers are structured oligonucleotide sequences
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RNase H1-mediated mRNA degradation mechanism. (RNA or DNA) obtained through an in vitro screening
ASO specifically targets RNA molecules, leading to the technique called Systematic Evolution of Ligands by
formation of ASO-RNA heteroduplexes, which serve as Exponential Enrichment. Due to their unique tertiary
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substrates for RNase enzymes in the cytoplasm, as depicted structures, aptamers can recognize target molecules
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in Figure 2C. Once the ASO-RNA heteroduplexes are through their three-dimensional conformations and
formed, RNases initiate RNA degradation within these exhibit high binding affinities (Figure 2D). The small
structures. The design of gapmer ASOs is particularly and flexible structures of aptamers enable them to bind
innovative. It features a central region composed of to smaller targets or hidden domains that antibodies
unmodified nucleotides, which plays a crucial role in cannot access. The applications of aptamers have been
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facilitating RNase H1 activity. Meanwhile, the flanking extensively described. Interested readers are encouraged to
regions consist of modified nucleotides that enhance ASO refer to relevant literature. 68,69

Volume 4 Issue 2 (2025) 18 doi: 10.36922/gtm.8247