MicroRNA-138 suppresses glioblastoma proliferation through downregulation of CD44

Margaret Yeh,Yin-Ying Wang,Zhongming Zhao,Christina Oh,Eunhee Kim,Young-Jun Jeon,Jin Muk Kang,Sangwoon Chung,George A Calin,Eun S Park,Tae Jin Lee,Balveen Kaur,Ji Young Yoo,Yoshihiro Otani

doi:10.1038/s41598-021-88615-8

Abstract

Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to determine the therapeutic potential of putative tumor suppressive miRNA, miR-138, against glioblastoma (GBM). Whole transcriptome and miRNA expression profiling analyses on human GBM patient tissues identified miR-138 as one of the significantly downregulated miRNAs with an inverse correlation with CD44 expression. Transient overexpression of miR-138 in GBM cells inhibited cell proliferation, cell cycle, migration, and wound healing capability. We unveiled that miR-138 negatively regulates the expression of CD44 by directly binding to the 3′ UTR of CD44. CD44 inhibition by miR-138 resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In conclusion, we demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 for the treatment of primary GBM.

Highlights

Tumor suppressive microRNAs are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells
This study found from whole transcriptome and miRNA expression profiling analyses that miR-138 is downregulated in human primary GBM tissues and primary GBM cells derived from human patients with an inverse correlation with the expression of CD44
Total of 827 miRNAs were detected and the miRNA expression profiles were subjected to principal component analysis (PCA) for quality control, which clearly classified the samples into two groups (Fig. 1A)

Summary

Introduction

Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. In order to prime the tumor cells in GBM patients to become responsive to current treatment options or even new therapeutics, tumor cells need to be reprogrammed by reversing the aberrantly dysregulated gene expressions across various signaling pathways. This study found from whole transcriptome and miRNA expression profiling analyses that miR-138 is downregulated in human primary GBM tissues and primary GBM cells derived from human patients with an inverse correlation with the expression of CD44. Ectopic restoration of miR-138 negatively modulated the expression of CD44 in GBM cells leading to the inhibition of cell proliferation and increased survival rate in orthotopic xenograft mouse model. Our data strongly suggest that inhibition of CD44 signaling pathway through the restoration of miR-138 can benefit therapeutic outcomes in clinical settings for GBM patients

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