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Global Translational Medicine Small RNA therapy for pancreatic cancer

MRP5 are major transporters of gemcitabine efflux, and In this review, 15 miRNA targets for PC are summarized
their expression is induced by gemcitabine in a time- and in Table 3. These targets can be categorized into two major
dose-dependent manner in PDAC cell lines. 37 groups based on their expression levels in PC.

In addition to gemcitabine, another commonly One group includes eight miRNAs whose expression
used chemotherapy agent is 5-FU. By incorporation of was downregulated. Li et al. identified the role of the
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DNA, RNA, or both, 5-FU accumulates in cells, leading entire miR-200 miRNA family in gemcitabine-resistant
to increased cytotoxicity and, eventually, cell death. PDAC cells, primarily through the reversal of epithelial-
However, due to its low intracellular stability, most mesenchymal transition. In addition, it was proposed
5-FU is easily broken down into dihydrofluorouracil by that upregulation of miR-34 might partially restore the
dihydropyrimidine dehydrogenase (DPD) in the liver, tumor-suppressive function of p53 in p53-deficient
which affects drug sensitivity and resistance. Therefore, human PC cells. Overexpression of miR-143 or miR-145
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DPD may be a potential therapeutic target. The downregulated KRAS and RREB1, as well as a series of
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combination of cisplatin with other nucleophiles in vivo can genes in the MAPK signaling cascade, thereby achieving
lead to drug resistance, but the mechanism of oxaliplatin an inhibitory effect on PC. The persistent activation
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resistance remains unclear. In this review, small RNA drugs of NF-κB, a key regulator of important genes that
may target enzymes that cause chemical resistance, and influence various cellular processes, was also recognized
their combination with chemical drugs may help improve as a contributor to the aggressive behavior of PC.
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this resistance. However, the combination of the two drugs Previous studies showed that overexpression of miR-
may lead to drug interactions, toxic side effects, and other 146a diminished the invasiveness of PC cells, which was
potential risks. Further research is needed to overcome accompanied by a reduction in NF-κB expression. In
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these challenges. primary PC, STAT3 is activated and plays a role in several
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The last group of genetic factors is related to improving physiological processes. Yan et al. demonstrated that
the tumor microenvironment. One of the biggest challenges miR-20a modulated STAT3 at the post-transcriptional
in the development of new drugs for PC is the complexity level, leading to a reduction in cell proliferation and
of its tumor microenvironment. PC is characterized by a invasion in pancreatic carcinoma. In addition, dual-
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dense stroma, hypoxia, limited blood vessels, and strong luciferase assays demonstrated that miR-130b directly
immunosuppressive activity. Composed of pancreatic targeted STAT3, a result that was further confirmed by
stellate cells, cancer-associated fibroblasts, immune cells, the inverse expression of miR-130b and STAT3 in PC
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and extracellular matrix components, this environment specimens. Zou et al. found that overexpression of
not only promotes tumor growth and invasion but also miR-29c could inhibit hepatic metastasis of PC in the
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contributes to resistance against chemotherapy and other nude mouse orthotopic transplantation model. Xu et al.
anticancer treatments. The dense fibrotic reaction in the studied gemcitabine-resistant PC cells and found that miR-
stroma and changes in the tumor’s immune environment 497 inhibited cell proliferation, decreased the percentage of
are considered the main reasons for the failure of cells in the S-phase, and targeted fibroblast growth factor-2
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current PC treatments. However, a recent study from and its receptor-1. Overexpression of miR-497 inhibited
the University of Rome in Italy found that the increased tumor growth in vivo. miR-137 is also a tumor suppressor
invasiveness of PDAC linked to metabolic disorders that inhibits the proliferation and invasion of cancer cells
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is associated with the accumulation of collagen fibers, through targeting multiple oncogenes.
driven by the enhanced activity of Prolyl 4-hydroxylase The second group of miRNAs had abnormally elevated
subunit alpha-1 (P4HA1). Under conditions of metabolic expression in PC. As early as 2008, some researchers used
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imbalance, P4HA1 promotes the hydroxylation of collagen miRNA gene chips to screen the differentially expressed
proline, strengthens collagen contraction, and inhibits miRNAs in pancreatic tumor tissues and normal pancreatic
the infiltration of PDAC. This suggests that P4HA1 tissues, as well as in PC cells and normal pancreatic cells
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plays a role in matrix deposition during PC development and found that miR-181 and miR-214 were specifically
and could serve as a potential target for small RNA drug expressed in PC. In addition, miR-21, as an oncogene in
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development. human cancer, promoted cancer progression by enabling
evasion of host immune surveillance in PC. Wang et al.
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3.2. miRNAs involved in the development of PC also found that the expression of miR-155 in tumor tissues
Previous studies have shown that some miRNAs are of PC patients was higher than in the adjacent normal
abnormally expressed under disease conditions and become tissues. Furthermore, miRNAs with abnormally elevated
important factors in disease occurrence and development. expression in PC include miR-221/miR-222, miR-29a,
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Volume 4 Issue 2 (2025) 16 doi: 10.36922/gtm.8247