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Clin Cancer Res. 2019 May 1;25(9):2860-2873. doi: 10.1158/1078-0432.CCR-18-0716. Epub 2019 Feb 5.

Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer.

Author information

1
Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
2
miRecule, Inc. Rockville, Maryland.
3
RNAi Screening Facility, National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
4
Molecular Characterization & Clinical Assay Development Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
5
Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
6
Department of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
7
Vavilov Institute of General Genetics Russian Academy of Science, Moscow, Russia.
8
Department of Pathology, Einstein School of Medicine, Bronx, New York.
9
Department of Otorhinolaryngology-Head and Neck Surgery, Montefiore Medical Center, Bronx, New York.
10
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
11
Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
12
Departments of Oncology and Otolaryngology at the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown, Washington DC.
13
Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, Maryland. vanwaesc@nidcd.nih.gov chenz@nidcd.nih.gov.

Abstract

PURPOSE:

To identify deregulated and inhibitory miRNAs and generate novel mimics for replacement nanomedicine for head and neck squamous cell carcinomas (HNSCC).

EXPERIMENTAL DESIGN:

We integrated miRNA and mRNA expression, copy number variation, and DNA methylation results from The Cancer Genome Atlas (TCGA), with a functional genome-wide screen.

RESULTS:

We reveal that the miR-30 family is commonly repressed, and all 5 members sharing these seed sequence similarly inhibit HNSCC proliferation in vitro. We uncover a previously unrecognized inverse relationship with overexpression of a network of important predicted target mRNAs deregulated in HNSCC, that includes key molecules involved in proliferation (EGFR, MET, IGF1R, IRS1, E2F7), differentiation (WNT7B, FZD2), adhesion, and invasion (ITGA6, SERPINE1). Reexpression of the most differentially repressed family member, miR-30a-5p, suppressed this mRNA program, selected signaling proteins and pathways, and inhibited cell proliferation, migration, and invasion in vitro. Furthermore, a novel miR-30a-5p mimic formulated into a targeted nanomedicine significantly inhibited HNSCC xenograft tumor growth and target growth receptors EGFR and MET in vivo. Significantly decreased miR-30a/e family expression was related to DNA promoter hypermethylation and/or copy loss in TCGA data, and clinically with decreased disease-specific survival in a validation dataset. Strikingly, decreased miR-30e-5p distinguished oropharyngeal HNSCC with poor prognosis in TCGA (P = 0.002) and validation (P = 0.007) datasets, identifying a novel candidate biomarker and target for this HNSCC subset.

CONCLUSIONS:

We identify the miR-30 family as an important regulator of signal networks and tumor suppressor in a subset of HNSCC patients, which may benefit from miRNA replacement nanomedicine therapy.

PMID:
30723145
PMCID:
PMC6497577
[Available on 2020-05-01]
DOI:
10.1158/1078-0432.CCR-18-0716

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