MicroRNAs as Potential Therapeutic Targets for Pancreatic Cancer
Pancreatic cancer remains one of the most aggressive and devastating malignancies, with a notoriously poor prognosis. The high mortality rate is primarily attributed to the late diagnosis, aggressive nature of the disease, and the limited efficacy of current therapeutic strategies. Despite advances in surgical techniques and chemotherapy, the five-year survival rate for pancreatic cancer patients remains alarmingly low. This underscores the urgent need for novel therapeutic approaches to improve patient outcomes. In recent years, microRNAs (miRNAs) have emerged as promising therapeutic targets due to their critical regulatory roles in cancer development and progression. This article provides a comprehensive overview of the role of miRNAs in pancreatic cancer, their potential as therapeutic targets, and the challenges and future prospects of miRNA-based therapies.
Introduction to Pancreatic Cancer and miRNAs
Pancreatic cancer is a highly lethal disease characterized by rapid progression, early metastasis, and resistance to conventional therapies. The standard treatment for pancreatic cancer involves surgical resection combined with perioperative chemotherapy. However, the dense fibrotic stroma and immunosuppressive microenvironment of pancreatic tumors limit the delivery and efficacy of chemotherapeutic agents. Consequently, there is a pressing need to explore alternative therapeutic strategies that target the molecular mechanisms driving pancreatic cancer.
MicroRNAs (miRNAs) are small, non-coding RNA molecules consisting of 19 to 23 nucleotides that regulate gene expression at the post-transcriptional level. By binding to the 3′ untranslated region (UTR) of target messenger RNAs (mRNAs), miRNAs can induce mRNA degradation or translational repression. It is estimated that miRNAs regulate approximately 60% of human protein-coding genes, making them critical players in various biological processes, including cell proliferation, apoptosis, and differentiation. In cancer, miRNAs can act as either oncogenes or tumor suppressors, depending on their target genes. Dysregulation of miRNA expression is frequently observed in pancreatic cancer, where they contribute to tumor initiation, progression, and metastasis.
The Role of miRNAs in Pancreatic Cancer
Tumor Suppressor miRNAs
Tumor suppressor miRNAs are downregulated in pancreatic cancer, and their overexpression can inhibit tumor progression by targeting oncogenic pathways. Several tumor suppressor miRNAs have been identified in pancreatic cancer, each with distinct mechanisms of action. For example, miR-455-3p suppresses pancreatic cancer progression by inhibiting the Wnt/β-catenin signaling pathway and promoting apoptosis through the regulation of Bcl-2 and Bax expression. Similarly, miR-373-3p enhances chemosensitivity to gemcitabine by downregulating Cyclin D2, thereby inhibiting the growth of gemcitabine-resistant pancreatic cancer cells.
miR-145 is another tumor suppressor miRNA that targets multiple genes involved in pancreatic cancer progression. It inhibits the TGF-β signaling pathway by downregulating TGF-β receptor and SMAD2, suppresses mucin 13 expression, and targets NEDD9 to inhibit cancer cell proliferation, migration, and invasion. Additionally, miR-145 enhances chemosensitivity to gemcitabine and inhibits angiogenesis by downregulating angiopoietin-2 (Ang-2).
Other notable tumor suppressor miRNAs include let-7, which inhibits pancreatic cancer progression by enhancing the expression of suppressor of cytokine signaling 3 (SOCS3) and suppressing STAT3 phosphorylation. miR-708 inhibits cancer cell proliferation and chemoresistance by targeting survivin, while miR-34a induces apoptosis and suppresses migration and invasion by regulating Snail1 and Notch1. miR-203a-3p also inhibits epithelial-mesenchymal transition (EMT) and proliferation by downregulating Slug.
Oncogenic miRNAs
Oncogenic miRNAs, which are overexpressed in pancreatic cancer, promote tumor progression by targeting tumor suppressor genes. Inhibition of these miRNAs can exert anti-cancer effects. For instance, miR-21 is a well-known oncogenic miRNA that enhances drug resistance and promotes cancer cell proliferation by downregulating PTEN and PDCD4. It also activates the MAPK/ERK and PI3K/AKT signaling pathways, contributing to tumor growth and survival. miR-155 is another oncogenic miRNA that promotes pancreatic cancer progression by targeting Foxo3a and suppressing SOCS1 and SOCS3, leading to increased STAT3 activation.
miR-203 has dual roles in pancreatic cancer, acting as both an oncogene and a tumor suppressor depending on the context. In some studies, miR-203 promotes cancer cell proliferation and invasion by targeting salt-inducible kinase 1 (SIK1) and SOCS3. In contrast, other studies have shown that miR-203 inhibits cancer cell proliferation and induces apoptosis by targeting survivin and DJ-1, highlighting the complexity of miRNA regulation in pancreatic cancer.
miRNA-Based Therapeutic Strategies for Pancreatic Cancer
The discovery of miRNAs as key regulators of pancreatic cancer progression has opened new avenues for therapeutic intervention. Both tumor suppressor miRNAs and oncogenic miRNAs can be targeted to inhibit tumor growth and enhance chemosensitivity. However, the clinical application of miRNA-based therapies faces several challenges, including the need for effective delivery systems to ensure targeted and sustained miRNA delivery to tumor cells.
Viral Vectors for miRNA Delivery
Viral vectors, such as adenoviruses and lentiviruses, have been widely used for miRNA delivery due to their high transduction efficiency. For example, intra-tumoral injection of an adenovirus vector carrying miR-143 has been shown to significantly inhibit tumor progression in xenograft models. Similarly, lentivirus vectors (LVs) have been used to deliver anti-miR-21, resulting in dose-dependent inhibition of pancreatic cancer cell proliferation. However, viral vectors carry risks of genotoxicity and immune activation, which limit their clinical application.
Nanoparticles and Liposome Carriers
Non-viral delivery systems, such as nanoparticles and liposomes, offer safer and more efficient alternatives for miRNA delivery. Nanoparticles can be designed to selectively deliver miRNAs to tumor sites, enhancing therapeutic efficacy while minimizing off-target effects. For instance, iRGD-TPN-21, a targeted nanoparticulate carrier coated with anti-miR-21, has been shown to inhibit tumor progression in a dose- and time-dependent manner. Liposome-based systems, such as cationic liposomes coated with albumin, can effectively deliver anti-miRNAs to pancreatic cancer cells, suppressing the expression of oncogenic miRNAs like miR-21, miR-10b, miR-221, and miR-222.
Exosomes, which are naturally occurring nanoparticles, have also emerged as promising miRNA delivery vehicles. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) can deliver miR-145-5p to pancreatic cancer cells, inhibiting proliferation and promoting apoptosis. Similarly, exosomes coated with miR-34a have been shown to inhibit pancreatic cancer progression in vitro and in vivo. Exosomes offer advantages such as natural stability, immunocompatibility, and specific targeting ability, making them ideal candidates for miRNA-based therapies.
Combination Therapies
Given the complexity of pancreatic cancer, combination therapies that target multiple pathways are likely to be more effective than single-agent treatments. For example, the combination of anti-miR-21 oligonucleotides and the chemotherapeutic agent sunitinib has been shown to significantly reduce pancreatic cancer cell viability compared to either treatment alone. Similarly, co-delivery of miR-345 and gemcitabine using a nanoscale device has been shown to suppress tumor progression and metastasis. Other combination strategies include the co-delivery of miR-205 and gemcitabine using EGFR-targeted micelles, which reverse gemcitabine resistance and inhibit tumor growth.
Clinical Trials of miRNA-Based Therapies for Pancreatic Cancer
The potential of miRNA-based therapies has been explored in clinical trials, with promising results. The first phase I clinical trial of miRNA-based cancer therapy (MRX34) involved the use of a liposomal formulation of miR-34a in patients with refractory advanced solid tumors, including pancreatic cancer. The trial demonstrated that MRX34 was effective and tolerable, with some patients achieving stable disease or partial responses. However, the trial was terminated prematurely due to severe immune-mediated adverse reactions, highlighting the need for improved delivery systems to minimize toxicity.
Another clinical trial investigated the use of siRNA against KRAS(G12D) in combination with gemcitabine for the treatment of inoperable locally advanced pancreatic cancer. The trial showed that intratumoral injection of siRNA was well tolerated and resulted in stable disease in most patients. These findings underscore the potential of miRNA-based therapies in pancreatic cancer treatment, but further research is needed to optimize delivery systems and minimize adverse effects.
Challenges and Future Prospects
Despite the promising potential of miRNA-based therapies, several challenges remain to be addressed. One major challenge is the development of effective delivery systems that can overcome the dense fibrotic stroma and immunosuppressive microenvironment of pancreatic tumors. Additionally, the off-target effects and potential immunostimulatory effects of miRNAs must be carefully evaluated to ensure safety and efficacy.
Future research should focus on identifying cancer-specific miRNAs and optimizing delivery systems to achieve targeted and sustained miRNA delivery. Combination therapies that target multiple pathways are likely to be more effective than single-agent treatments, and the development of novel co-delivery systems could enhance therapeutic outcomes. Furthermore, the integration of miRNA-based therapies with precision medicine approaches could pave the way for personalized treatment strategies for pancreatic cancer patients.
Conclusion
MicroRNAs play a critical role in the progression of pancreatic cancer, making them promising therapeutic targets. The development of effective delivery systems and combination therapies holds great potential for improving the treatment of pancreatic cancer. While challenges remain, continued research into the mechanisms of miRNA regulation and the optimization of delivery systems will be essential for translating miRNA-based therapies from the laboratory to the clinic. The integration of miRNAs into precision medicine approaches offers hope for improving the prognosis of pancreatic cancer patients in the future.
doi.org/10.1097/CM9.0000000000001826
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