miRNA-211 maintains metabolic homeostasis in medulloblastoma through its target gene long-chain acyl-CoA synthetase 4

Menglang Yuan; Iqbal Mahmud; Keisuke Katsushima; Kandarp Joshi; Olivier Saulnier; Rudramani Pokhrel; Bongyong Lee; Wathsala Liyanage; Haritha Kunhiraman; Stacie Stapleton; Ignacio Gonzalez-Gomez; Rangaramanujam M Kannan; Tanja Eisemann; Elayaraja Kolanthai; Sudipta Seal; Timothy J Garrett; Saed Abbasi; Kimberly Bockley; Justin Hanes; Prem Chapagain; George Jallo; Robert J Wechsler-Reya; Michael D Taylor; Charles G Eberhart; Animesh Ray; Ranjan J Perera

doi:10.1186/s40478-023-01684-w

miRNA-211 maintains metabolic homeostasis in medulloblastoma through its target gene long-chain acyl-CoA synthetase 4

Acta Neuropathol Commun. 2023 Dec 19;11(1):203. doi: 10.1186/s40478-023-01684-w.

Authors

Menglang Yuan^{1

2}, Iqbal Mahmud³, Keisuke Katsushima^{1

2}, Kandarp Joshi^{1

2}, Olivier Saulnier⁴, Rudramani Pokhrel^{1

2}, Bongyong Lee^{1

2}, Wathsala Liyanage⁵, Haritha Kunhiraman^{1

2}, Stacie Stapleton², Ignacio Gonzalez-Gomez², Rangaramanujam M Kannan^{5

6}, Tanja Eisemann⁷, Elayaraja Kolanthai⁸, Sudipta Seal⁸, Timothy J Garrett⁹, Saed Abbasi^{5

10}, Kimberly Bockley^{5

11}, Justin Hanes^{5

10

11}, Prem Chapagain¹², George Jallo², Robert J Wechsler-Reya¹³, Michael D Taylor^{4

14

15}, Charles G Eberhart¹⁶, Animesh Ray^{17

18}, Ranjan J Perera^{19

20}

Affiliations

¹ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA.
² Johns Hopkins All Children's Hospital, 600 5th St. South, St. Petersburg, FL, 33701, USA.
³ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁴ The Arthur and Sonia Labatt Brain Tumour Research Centre and the Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
⁶ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁷ National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
⁸ Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center, Materials Science and Engineering, College of Medicine, University of Central Florida, Orlando, FL, 32826, USA.
⁹ Department Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
¹⁰ Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
¹¹ Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, 21205, USA.
¹² Department of Physics, Florida International University, Miami, FL, 33199, USA.
¹³ Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA.
¹⁴ Texas Children's Cancer Center, Hematology-Oncology Section, Houston, TX, 77030, USA.
¹⁵ Department of Pediatrics-Hematology/Oncology and Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA.
¹⁶ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
¹⁷ Riggs School of Applied Life Sciences, Keck Graduate Institute, Claremont, CA, 91711, USA.
¹⁸ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
¹⁹ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, 1650 Orleans St., Baltimore, MD, 21231, USA. jperera2@jh.edu.
²⁰ Johns Hopkins All Children's Hospital, 600 5th St. South, St. Petersburg, FL, 33701, USA. jperera2@jh.edu.

Abstract

The prognosis of childhood medulloblastoma (MB) is often poor, and it usually requires aggressive therapy that adversely affects quality of life. microRNA-211 (miR-211) was previously identified as an important regulator of cells that descend from neural cells. Since medulloblastomas primarily affect cells with similar ontogeny, we investigated the role and mechanism of miR-211 in MB. Here we showed that miR-211 expression was highly downregulated in cell lines, PDXs, and clinical samples of different MB subgroups (SHH, Group 3, and Group 4) compared to normal cerebellum. miR-211 gene was ectopically expressed in transgenic cells from MB subgroups, and they were subjected to molecular and phenotypic investigations. Monoclonal cells stably expressing miR-211 were injected into the mouse cerebellum. miR-211 forced expression acts as a tumor suppressor in MB both in vitro and in vivo, attenuating growth, promoting apoptosis, and inhibiting invasion. In support of emerging regulatory roles of metabolism in various forms of cancer, we identified the acyl-CoA synthetase long-chain family member (ACSL4) as a direct miR-211 target. Furthermore, lipid nanoparticle-coated, dendrimer-coated, and cerium oxide-coated miR-211 nanoparticles were applied to deliver synthetic miR-211 into MB cell lines and cellular responses were assayed. Synthesizing nanoparticle-miR-211 conjugates can suppress MB cell viability and invasion in vitro. Our findings reveal miR-211 as a tumor suppressor and a potential therapeutic agent in MB. This proof-of-concept paves the way for further pre-clinical and clinical development.

Keywords: Medulloblastoma; Metabolism; Nanoparticles; Therapeutics; miRNA-211.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms* / metabolism
Gene Expression Regulation, Neoplastic
Homeostasis
Humans
Ligases / genetics
Ligases / metabolism
Medulloblastoma* / metabolism
Mice
MicroRNAs* / genetics
MicroRNAs* / metabolism
Quality of Life

Substances

Ligases
MicroRNAs
MIRN211 microRNA, human
long-chain-fatty-acid-CoA ligase

Abstract

MeSH terms

Substances

Grants and funding