Functional and Potential Therapeutic Implication of MicroRNAs in Pancreatic Cancer.

The alarmingly low five-year survival rate for pancreatic cancer presents a global health challenge, contributing to about 7% of all cancer-related deaths. Late-stage diagnosis and high heterogeneity are the biggest hurdles in treating pancreatic cancer. Thus, there is a pressing need to discover novel biomarkers that could help in early detection as well as improve therapeutic strategies. MicroRNAs (miRNAs), a class of short non-coding RNA, have emerged as promising candidates with regard to both diagnostics and therapeutics. Dysregulated miRNAs play pivotal roles in accelerating tumor growth and metastasis, orchestrating tumor microenvironment, and conferring chemoresistance in pancreatic cancer. The differential expression profiles of miRNAs in pancreatic cancer could be utilized to explore novel therapeutic strategies. In this review, we also covered studies on recent advancements in various miRNA-based therapeutics such as restoring miRNAs with a tumor-suppressive function, suppressing miRNA with an oncogenic function, and combination with chemotherapeutic drugs. Despite several challenges in terms of specificity and targeted delivery, miRNA-based therapies hold the potential to revolutionize the treatment of pancreatic cancer by simultaneously targeting multiple signaling pathways.

Development of gemcitabine-modified miRNA mimics as cancer therapeutics for pancreatic ductal adenocarcinoma.

Despite the recent advancement in diagnosis and therapy, pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is still the most lethal cancer with a low five-year survival rate. There is an urgent need to develop new therapies to address this issue. In this study, we developed a treatment strategy by modifying tumor suppressor miRNAs, miR-15a and miR-194, with the chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics, Gem-miR-15a and Gem-miR-194, respectively. In a panel of PDAC cell lines, we found that Gem-miR-15a and Gem-miR-194 induce cell-cycle arrest and apoptosis, and these mimics are potent inhibitors with IC50 values up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a and Gem-miR-194 retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a, and FOXA1 for Gem-miR-194. We also found that our Gem-modified miRNA mimics exhibit an enhanced efficacy compared to Gem in patient-derived PDAC organoids. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of Gem-modified miRNAs as a treatment strategy for PDAC.

Correction: Soung et al. Therapeutic Potential of Chemically Modified MiR-489 in Triple-Negative Breast Cancers. Cancers 2020, 12, 2209.

In the original publication [...].

The Sensitization of Triple-Negative Breast Cancers to Poly ADP Ribose Polymerase Inhibition Independent of BRCA1/2 Mutation Status by Chemically Modified microRNA-489.

Chemoresistance and inefficient therapeutic efficacies in triple-negative breast cancers (TNBCs) are among the major clinical problems in breast cancers. A potential new method to sensitize these tumors to current treatment options is, therefore, urgent and necessary. Our previous studies demonstrated that miR-489 serves as one of the top tumor-suppressing miRs and features downregulated expression in metastatic TNBCs and that the restoration of miR-489 expression in TNBCs effectively inhibits the metastatic potentials of TNBCs both in vitro and in vivo. The chemical modification of miR-489 (CMM489) through the replacement of uracil with 5-FU further enhances the therapeutic potential of miR-489. In the present study, we tested the effects of CMM489 in synergizing DNA damage response (DDR) inhibitors such as PARP inhibitors. CMM489 is particularly effective in sensitizing TNBC cell lines with inherent resistance to PARP inhibitors regardless of BRCA mutation status. One of the anti-cancer mechanisms through which CMM489 synergizes with PARP inhibitors is the blockade of homologous recombination (HR) in TNBC cells upon DNA damage. The results of this study highlight the potential use of CMM489 in combination treatments with PARP inhibitors in TNBCs.