MiR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2.

Lidia Villanova,Ruggero De Maria,Cristina Piccolo,Alessandra Boe,Micol Eleonora Fiori,Chiara Barbini

doi:10.3390/ijms21072423

Abstract

MicroRNAs are tiny but powerful regulators of gene expression at the post-transcriptional level. Aberrant expression of oncogenic and tumor-suppressor microRNAs has been recognized as a common feature of human cancers. Colorectal cancer represents a major clinical challenge in the developed world and the design of innovative therapeutic approaches relies on the identification of novel biological targets. Here, we perform a functional screening in colorectal cancer cells using a library of locked nucleic acid (LNA)-modified anti-miRs in order to unveil putative oncogenic microRNAs whose inhibition yields a cytotoxic effect. We identify miR-1285-3p and further explore the effect of its targeting in both commercial cell lines and primary colorectal cancer stem cells, finding induction of cell cycle arrest and apoptosis. We show that DAPK2, a known tumor-suppressor, is a novel miR-1285 target and mediates both the anti-proliferative and the pro-apoptotic effects of miR-1285 depletion. Altogether, our findings uncover a novel oncogenic microRNA in colorectal cancer and lay the foundation for further studies aiming at the development of possible therapeutic strategies based on miR-1285 targeting.

Highlights

Colorectal cancer (CRC) is the third leading cause of cancer death in developed countries [1]
We discovered a novel oncogenic microRNA in colorectal cancer and showed that Locked nucleic acid (LNA)-mediated targeting of miR-1285 triggers a powerful cytotoxic effect
By hitting a single microRNA we may concurrently overcome multiple escape strategies developed by transformed cells and hijack the miR-mediated machinery to push cancer cells toward non-tumoral settings

Summary

Introduction

Colorectal cancer (CRC) is the third leading cause of cancer death in developed countries [1]. Several therapeutic approaches are currently available, ranging from conventional chemotherapy and radiotherapy to the more recent targeted therapies, the prognosis of patients with metastatic colorectal cancer remains poor. MicroRNAs (miRNAs) are small evolutionarily conserved non-coding RNAs (~22 nt in length) that act as post-transcriptional regulators of gene expression [2]. MiRNA expression is dysregulated in cancer owing to chromosomal rearrangements, point mutations, epigenetic alterations, changes in transcription factors activity or abnormalities in the miRNA biogenesis machinery [3]. Among the microRNA-based anti-cancer therapies, chemically modified antisense oligonucleotides (anti-miRs) are designed to bind directly to the mature strand of the targeted miRNA and represent the most successful strategy to induce a functional blockade of oncogenic miRNAs [5]. Locked nucleic acid (LNA)-modified anti-miRs are chemically locked by a bridge that connects the 2 -oxygen and 4 -carbon in a ribonucleotide, conferring an unprecedented hybridization affinity and stability to nuclease degradation

Methods

Results

Conclusion