# MicroRNAs Let-7b-5p and miR-24-3p as Potential Therapeutic Agents Targeting Pancreatic Cancer Stem Cells

## TL;DR

This study identifies two microRNAs, let-7b-5p and miR-24-3p, that could help treat pancreatic cancer by targeting cancer stem cells and improving drug response.

## Contribution

The study discovers and validates two novel miRNAs that target pancreatic cancer stem cells and enhance chemosensitivity.

## Key findings

- Let-7b-5p and miR-24-3p inhibit key pluripotency pathways in pancreatic cancer stem cells.
- Overexpression of these miRNAs reduces sphere formation and increases gemcitabine sensitivity.
- The miRNAs induce differentiation and suppress tumorigenicity in vivo.

## Abstract

Pancreatic cancer poses a major clinical challenge due to its aggressiveness, frequent recurrence, and limited response to current chemotherapeutic approaches. Cancer stem cells (CSCs), particularly pancreatic CSCs (PCSCs), are key drivers of tumor initiation, therapeutic resistance, and disease relapse. MicroRNAs (miRNAs) have emerged as critical regulators of CSC biology and influence self-renewal, pluripotency, and drug resistance through key signaling pathways. To identify PCSC-specific miRNAs, we enriched these cells using the pancreosphere culture method and isolated PCSC+ and PCSC− populations using FACS based on their expression of CD44, CD24, and CD133 surface markers. MicroRNA microarray analysis revealed 31 differentially expressed miRNAs (DEmiRNAs), of which 10 downregulated miRNAs were involved in pathways regulating pluripotency, including the Wnt/β-catenin, TGF-β, MAPK, and PI3K/AKT pathways. Then, 2 of these 10 DEmiRNAs, let-7b-5p and miR-24-3p, were selected for experimental validation. Their overexpression in PCSC+ cells inhibited these pathways, downregulated pluripotency factors, and induced differentiation into endocrine and exocrine phenotypes, as confirmed by RT-qPCR, Western blot, and RNA-seq. Functionally, each miRNA reduced sphere formation, increased gemcitabine sensitivity, and suppressed tumorigenicity in vivo, highlighting their potential as therapeutic candidates. Restoring tumor-suppressive miRNA expression may offer a novel strategy to overcome chemoresistance and improve outcomes in pancreatic cancer.