MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma

Adrenocortical carcinoma (ACC) has a poor prognosis with significant unmet clinical need due to late diagnosis, high rates of recurrence/metastasis and poor response to conventional treatment. Replacing tumor suppressor microRNAs (miRNAs) offer a novel therapy, however systemic delivery remains chal...

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Published inOncotarget Vol. 6; no. 34; pp. 36675 - 36688
Main Authors Glover, Anthony R, Zhao, Jing Ting, Gill, Anthony J, Weiss, Jocelyn, Mugridge, Nancy, Kim, Edward, Feeney, Alex L, Ip, Julian C, Reid, Glen, Clarke, Stephen, Soon, Patsy S H, Robinson, Bruce G, Brahmbhatt, Himanshu, MacDiarmid, Jennifer A, Sidhu, Stan B
Format Journal Article
LanguageEnglish
Published United States Impact Journals LLC 03.11.2015
Subjects
Adrenal Cortex Neoplasms - genetics
Adrenal Cortex Neoplasms - therapy
Adrenocortical Carcinoma - genetics
Adrenocortical Carcinoma - therapy
Animals
Cell Line, Tumor
Cell Proliferation
Female
Genetic Therapy - methods
Humans
Immunohistochemistry
Mice
Mice, Nude
MicroRNAs - administration & dosage
MicroRNAs - genetics
Prognosis
Random Allocation
Research Paper
RNA, Untranslated - genetics
Transfection - methods
Xenograft Model Antitumor Assays
miR-7
noncoding RNA
adrenal cancer
nanoparticle therapy
Online AccessGet full text

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Abstract Adrenocortical carcinoma (ACC) has a poor prognosis with significant unmet clinical need due to late diagnosis, high rates of recurrence/metastasis and poor response to conventional treatment. Replacing tumor suppressor microRNAs (miRNAs) offer a novel therapy, however systemic delivery remains challenging. A number of miRNAs have been described to be under-expressed in ACC however it is not known if they form a part of ACC pathogenesis. Here we report that microRNA-7-5p (miR-7) reduces cell proliferation in vitro and induces G1 cell cycle arrest. Systemic miR-7 administration in a targeted, clinically safe delivery vesicle (EGFREDVTM nanocells) reduces ACC xenograft growth originating from both ACC cell lines and primary ACC cells. Mechanistically, miR-7 targets Raf-1 proto-oncogene serine/threonine kinase (RAF1) and mechanistic target of rapamycin (MTOR). Additionally, miR-7 therapy in vivo leads to inhibition of cyclin dependent kinase 1 (CDK1). In patient ACC samples, CDK1 is overexpressed and miR-7 expression inversely related. In summary, miR-7 inhibits multiple oncogenic pathways and reduces ACC growth when systemically delivered using EDVTM nanoparticles. This data is the first study in ACC investigating the possibility of miRNAs replacement as a novel therapy.
AbstractList Adrenocortical carcinoma (ACC) has a poor prognosis with significant unmet clinical need due to late diagnosis, high rates of recurrence/metastasis and poor response to conventional treatment. Replacing tumor suppressor microRNAs (miRNAs) offer a novel therapy, however systemic delivery remains challenging. A number of miRNAs have been described to be under-expressed in ACC however it is not known if they form a part of ACC pathogenesis. Here we report that microRNA-7–5p (miR-7) reduces cell proliferation in vitro and induces G 1 cell cycle arrest. Systemic miR-7 administration in a targeted, clinically safe delivery vesicle ( EGFR EDV TM nanocells) reduces ACC xenograft growth originating from both ACC cell lines and primary ACC cells. Mechanistically, miR-7 targets Raf-1 proto-oncogene serine/threonine kinase (RAF1) and mechanistic target of rapamycin (MTOR). Additionally, miR-7 therapy in vivo leads to inhibition of cyclin dependent kinase 1 (CDK1). In patient ACC samples, CDK1 is overexpressed and miR-7 expression inversely related. In summary, miR-7 inhibits multiple oncogenic pathways and reduces ACC growth when systemically delivered using EDV TM nanoparticles. This data is the first study in ACC investigating the possibility of miRNAs replacement as a novel therapy.
Adrenocortical carcinoma (ACC) has a poor prognosis with significant unmet clinical need due to late diagnosis, high rates of recurrence/metastasis and poor response to conventional treatment. Replacing tumor suppressor microRNAs (miRNAs) offer a novel therapy, however systemic delivery remains challenging. A number of miRNAs have been described to be under-expressed in ACC however it is not known if they form a part of ACC pathogenesis. Here we report that microRNA-7-5p (miR-7) reduces cell proliferation in vitro and induces G1 cell cycle arrest. Systemic miR-7 administration in a targeted, clinically safe delivery vesicle (EGFREDVTM nanocells) reduces ACC xenograft growth originating from both ACC cell lines and primary ACC cells. Mechanistically, miR-7 targets Raf-1 proto-oncogene serine/threonine kinase (RAF1) and mechanistic target of rapamycin (MTOR). Additionally, miR-7 therapy in vivo leads to inhibition of cyclin dependent kinase 1 (CDK1). In patient ACC samples, CDK1 is overexpressed and miR-7 expression inversely related. In summary, miR-7 inhibits multiple oncogenic pathways and reduces ACC growth when systemically delivered using EDVTM nanoparticles. This data is the first study in ACC investigating the possibility of miRNAs replacement as a novel therapy.
Author Weiss, Jocelyn
Zhao, Jing Ting
Mugridge, Nancy
Ip, Julian C
Sidhu, Stan B
Kim, Edward
Gill, Anthony J
Clarke, Stephen
Robinson, Bruce G
Feeney, Alex L
Glover, Anthony R
Brahmbhatt, Himanshu
Soon, Patsy S H
Reid, Glen
MacDiarmid, Jennifer A
AuthorAffiliation 1 Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia
7 Ingham Institute for Applied Medical Research, University of New South Wales, Liverpool, NSW, Australia
5 Asbestos Diseases Research Institute, University of Sydney, Concord, Sydney, NSW, Australia
2 Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia
9 University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Sydney, St Leonards, Sydney, NSW, Australia
8 Department of Endocrinology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
6 Department of Oncology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
3 Department of Anatomical Pathology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
4 EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia
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– name: 8 Department of Endocrinology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
– name: 3 Department of Anatomical Pathology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
– name: 4 EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia
– name: 1 Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia
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– sequence: 3
  givenname: Anthony J
  surname: Gill
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  organization: Department of Anatomical Pathology, Royal North Shore Hospital and University of Sydney, St Leonards, Sydney, NSW, Australia
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  organization: EnGeneIC Ltd, Lane Cove West, Sydney, NSW, Australia
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  surname: Feeney
  fullname: Feeney, Alex L
  organization: Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW, Australia
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  surname: Ip
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  organization: University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Sydney, St Leonards, Sydney, NSW, Australia
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Keywords miR-7
noncoding RNA
adrenal cancer
nanoparticle therapy
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Snippet Adrenocortical carcinoma (ACC) has a poor prognosis with significant unmet clinical need due to late diagnosis, high rates of recurrence/metastasis and poor...
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StartPage 36675
SubjectTerms Adrenal Cortex Neoplasms - genetics
Adrenal Cortex Neoplasms - therapy
Adrenocortical Carcinoma - genetics
Adrenocortical Carcinoma - therapy
Animals
Cell Line, Tumor
Cell Proliferation
Female
Genetic Therapy - methods
Humans
Immunohistochemistry
Mice
Mice, Nude
MicroRNAs - administration & dosage
MicroRNAs - genetics
Prognosis
Random Allocation
Research Paper
RNA, Untranslated - genetics
Transfection - methods
Xenograft Model Antitumor Assays
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Title MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma
URI https://www.ncbi.nlm.nih.gov/pubmed/26452132
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