Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and potential therapeutic nanomedicine in head and neck cancer

Anthony D. Saleh, Hui Cheng, Scott E. Martin, Han Si, Pinar Ormanoglu, Sophie Carlson, Paul E. Clavijo, Xinping Yang, Rita Das, Shaleeka Cornelius, Jamie Couper, Douglas Chepeha, Ludmila Danilova, Thomas M. Harris, Michael B. Prystowsky, Geoffrey J. Childs, Richard V. Smith, A. Gordon Robertson, Steven J.M. Jones, Andrew D. CherniackSang S. Kim, Antonina Rait, Kathleen F. Pirollo, Esther H. Chang, Zhong Chen, Carter Van Waes

Research output: Contribution to journalArticle

6 Scopus citations

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, SER-PINE1). 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 ¼ 0.002) and validation (P ¼ 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.

Original languageEnglish (US)
Pages (from-to)2860-2873
Number of pages14
JournalClinical Cancer Research
Volume25
Issue number9
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Saleh, A. D., Cheng, H., Martin, S. E., Si, H., Ormanoglu, P., Carlson, S., Clavijo, P. E., Yang, X., Das, R., Cornelius, S., Couper, J., Chepeha, D., Danilova, L., Harris, T. M., Prystowsky, M. B., Childs, G. J., Smith, R. V., Gordon Robertson, A., Jones, S. J. M., ... Van Waes, C. (2019). Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and potential therapeutic nanomedicine in head and neck cancer. Clinical Cancer Research, 25(9), 2860-2873. https://doi.org/10.1158/1078-0432.CCR-18-0716