Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Janaiah Kota; Raghu R. Chivukula; Kathryn A. O'Donnell; Erik A. Wentzel; Chrystal L. Montgomery; Hun Way Hwang; Tsung Cheng Chang; Perumal Vivekanandan; Michael Torbenson; K. Reed Clark; Jerry R. Mendell; Joshua T. Mendell

doi:10.1016/j.cell.2009.04.021

Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Janaiah Kota, Raghu R. Chivukula, Kathryn A. O'Donnell, Erik A. Wentzel, Chrystal L. Montgomery, Hun Way Hwang, Tsung Cheng Chang, Perumal Vivekanandan, Michael Torbenson, K. Reed Clark, Jerry R. Mendell, Joshua T. Mendell

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

1402 Scopus citations

Abstract

Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.

Original language	English (US)
Pages (from-to)	1005-1017
Number of pages	13
Journal	Cell
Volume	137
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2009.04.021
State	Published - Jun 12 2009

Keywords

HUMDISEASE
RNA

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2009.04.021

Cite this

@article{b8a4ed2937af46f3945f10017f9a5390,

title = "Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model",

abstract = "Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.",

keywords = "HUMDISEASE, RNA",

author = "Janaiah Kota and Chivukula, {Raghu R.} and O'Donnell, {Kathryn A.} and Wentzel, {Erik A.} and Montgomery, {Chrystal L.} and Hwang, {Hun Way} and Chang, {Tsung Cheng} and Perumal Vivekanandan and Michael Torbenson and Clark, {K. Reed} and Mendell, {Jerry R.} and Mendell, {Joshua T.}",

note = "Funding Information: We thank Michael Bishop for tet-o- MYC mice, Terri Shaffer and Lucia Rosas for help with virus administration, and the staff at Nationwide Children's Hospital Viral Vector Core facility. This work was supported by US National Institutes of Health grant R01CA120185 (to J.T.M.), the Sol Goldman Center for Pancreatic Cancer Research (J.T.M.), and the Research Institute at Nationwide Children's Hospital (J.R.M.). J.T.M. is a Rita Allen Foundation Scholar and a Leukemia and Lymphoma Society Scholar. K.A.O. is a fellow of the Damon Runyon Cancer Research Foundation (DRG-1918-06). R.R.C. is supported by the Medical Scientist Training Program. ",

year = "2009",

month = jun,

day = "12",

doi = "10.1016/j.cell.2009.04.021",

language = "English (US)",

volume = "137",

pages = "1005--1017",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "6",

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TY - JOUR

T1 - Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

AU - Kota, Janaiah

AU - Chivukula, Raghu R.

AU - O'Donnell, Kathryn A.

AU - Wentzel, Erik A.

AU - Montgomery, Chrystal L.

AU - Hwang, Hun Way

AU - Chang, Tsung Cheng

AU - Vivekanandan, Perumal

AU - Torbenson, Michael

AU - Clark, K. Reed

AU - Mendell, Jerry R.

AU - Mendell, Joshua T.

N1 - Funding Information: We thank Michael Bishop for tet-o- MYC mice, Terri Shaffer and Lucia Rosas for help with virus administration, and the staff at Nationwide Children's Hospital Viral Vector Core facility. This work was supported by US National Institutes of Health grant R01CA120185 (to J.T.M.), the Sol Goldman Center for Pancreatic Cancer Research (J.T.M.), and the Research Institute at Nationwide Children's Hospital (J.R.M.). J.T.M. is a Rita Allen Foundation Scholar and a Leukemia and Lymphoma Society Scholar. K.A.O. is a fellow of the Damon Runyon Cancer Research Foundation (DRG-1918-06). R.R.C. is supported by the Medical Scientist Training Program.

PY - 2009/6/12

Y1 - 2009/6/12

N2 - Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.

AB - Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.

KW - HUMDISEASE

KW - RNA

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JO - Cell

JF - Cell

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ER -

Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Abstract

Keywords

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