Multi-modal effects of 1B3, a novel synthetic miR-193a-3p mimic, support strong potential for therapeutic intervention in oncology.

Bryony J Telford,Marieke Stegink,Sanaz Yahyanejad,Michel Janicot,Harm C Den Boer,Mir Farshid Alemdehy,Laurens Ah Van Pinxteren,Marion Tj Van Den Bosch,Rogier M Vos,Roel Qj Schaapveld,Thijs De Gunst

doi:10.18632/oncotarget.27894

Abstract

Compelling evidence demonstrates that miR-193a-3p is a tumor suppressor microRNA in many cancer types, and its reduced expression is linked to cancer initiation and progression, metastasis, and therapy resistance. However, its mechanism of action is not consistently described between studies, and often contradicts the pleiotropic role of a microRNA in manipulating several different mRNA targets. We therefore comprehensively investigated miRNA-193a-3p's mode of action in a panel of human cancer cell lines, with a variety of genetic backgrounds, using 1B3, a synthetic microRNA mimic. Interestingly, the exact mechanism through which 1B3 reduced cell proliferation varied between cell lines. 1B3 efficiently reduced target gene expression, leading to reduced cell proliferation/survival, cell cycle arrest, induction of apoptosis, increased cell senescence, DNA damage, and inhibition of migration. SiRNA silencing of 1B3 target mRNAs further highlighted the advantage of the pleiotropic mechanism of 1B3 action, as repression of individual targets did not achieve the same robust effect on cell proliferation in all cell lines. Importantly, a novel lipid nanoparticle-based formulation of 1B3, INT-1B3, demonstrated marked anti-tumor activity as a single agent following systemic administration in tumor-bearing mice. Together, these data strongly support the development of 1B3 as a novel therapeutic agent for treatment of human cancer.

Highlights

Despite decades of research and an unprecedented advancement of therapeutic options [1], cancer accounts for one in every six deaths worldwide, with ~18,000,000 new cases diagnosed in 2018 and expected to grow to ~30,000,000 by 20401
MiRNA therapeutics face challenges, in ensuring the molecule is stable in the bloodstream and effectively delivered to the tumor tissue [12]
The selected cancer cell lines had a variety of genetic backgrounds including Tumor protein p53 (TP53) deletion or loss of function (Hep3B, SNU-449, H1299, H1975, A2058, PANC-1, and BT-549) and KRAS Proto-Oncogene (KRAS) activating mutations (HCT116, A549, H460, and PANC-1)

Summary

Introduction

Despite decades of research and an unprecedented advancement of therapeutic options [1], cancer accounts for one in every six deaths worldwide, with ~18,000,000 new cases diagnosed in 2018 and expected to grow to ~30,000,000 by 20401. MicroRNAs (miRNAs) are naturally occurring short (~22 nucleotide) double stranded RNA molecules with a unique nucleotide sequence (seed sequence) that binds, at least partially, to complementary mRNA sequences This leads to mRNA degradation or suppressed translation which silences gene expression [4, 5]. As clinicians look more towards drug combinations for cancer treatment, antagomiRs and miRNA mimics represent obvious drug candidates for an all-in-one combination therapy. Despite this promise, miRNA therapeutics face challenges, in ensuring the molecule is stable in the bloodstream and effectively delivered to the tumor tissue [12]. No miRNA mimic therapy has been approved by the FDA, a few candidates are in preclinical and clinical development [13]

Methods

Results

Conclusion