TY - JOUR
T1 - Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and potential therapeutic nanomedicine in head and neck cancer
AU - Saleh, Anthony D.
AU - Cheng, Hui
AU - Martin, Scott E.
AU - Si, Han
AU - Ormanoglu, Pinar
AU - Carlson, Sophie
AU - Clavijo, Paul E.
AU - Yang, Xinping
AU - Das, Rita
AU - Cornelius, Shaleeka
AU - Couper, Jamie
AU - Chepeha, Douglas
AU - Danilova, Ludmila
AU - Harris, Thomas M.
AU - Prystowsky, Michael B.
AU - Childs, Geoffrey J.
AU - Smith, Richard V.
AU - Gordon Robertson, A.
AU - Jones, Steven J.M.
AU - Cherniack, Andrew D.
AU - Kim, Sang S.
AU - Rait, Antonina
AU - Pirollo, Kathleen F.
AU - Chang, Esther H.
AU - Chen, Zhong
AU - Van Waes, Carter
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-0716
DO - 10.1158/1078-0432.CCR-18-0716
M3 - Article
C2 - 30723145
AN - SCOPUS:85065532119
SN - 1078-0432
VL - 25
SP - 2860
EP - 2873
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -