MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma

H. J. Bae; J. H. Noh; J. K. Kim; J. W. Eun; K. H. Jung; M. G. Kim; Y. G. Chang; Q. Shen; S. J. Kim; W. S. Park; J. Y. Lee; S. W. Nam

doi:10.1038/onc.2013.216

MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma

H. J. Bae
, J. H. Noh
, J. K. Kim
, J. W. Eun
, K. H. Jung
, M. G. Kim
, Y. G. Chang
, Q. Shen
, S. J. Kim
, W. S. Park
, J. Y. Lee
, S. W. Nam

Department of Pathology

The Catholic University of Korea

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

132 Scopus citations

Abstract

Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3′-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.

Original language	English
Pages (from-to)	2557-2567
Number of pages	11
Journal	Oncogene
Volume	33
Issue number	20
DOIs	https://doi.org/10.1038/onc.2013.216
State	Published - 15 May 2014

Bibliographical note

Funding Information:
A total of 60 HCCs and 60 non-cancerous liver tissue samples were obtained from the Liver Cancer Specimen Bank of the National Research Resource Bank Program of the Korea Science and Engineering Foundation of the Ministry of Science, and Seoul National University, School of Medicine, Seoul, Korea, and this study was approved by the Institutional Review of Board (IRB) of the Songeui Campus, College of Medicine, Catholic University of Korea (IRB approval number; CUMC09U115).

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST; Grant No. 2011-0010705 and No. 2012M3A9D1054476), and by the Korean Science and Engineering Foundation via the ‘Cancer Evolution Research Center’ at the Catholic University of Korea.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

SIRT1
cell cycle
hepatocellular carcinoma
miR-29c
tumor suppressor

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10.1038/onc.2013.216

Cite this

@article{a89777b6e26f4ba5ae14cf20a8131b64,

title = "MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma",

abstract = "Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3′-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.",

keywords = "SIRT1, cell cycle, hepatocellular carcinoma, miR-29c, tumor suppressor",

author = "Bae, \{H. J.\} and Noh, \{J. H.\} and Kim, \{J. K.\} and Eun, \{J. W.\} and Jung, \{K. H.\} and Kim, \{M. G.\} and Chang, \{Y. G.\} and Q. Shen and Kim, \{S. J.\} and Park, \{W. S.\} and Lee, \{J. Y.\} and Nam, \{S. W.\}",

note = "Funding Information: A total of 60 HCCs and 60 non-cancerous liver tissue samples were obtained from the Liver Cancer Specimen Bank of the National Research Resource Bank Program of the Korea Science and Engineering Foundation of the Ministry of Science, and Seoul National University, School of Medicine, Seoul, Korea, and this study was approved by the Institutional Review of Board (IRB) of the Songeui Campus, College of Medicine, Catholic University of Korea (IRB approval number; CUMC09U115). Funding Information: This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST; Grant No. 2011-0010705 and No. 2012M3A9D1054476), and by the Korean Science and Engineering Foundation via the {\textquoteleft}Cancer Evolution Research Center{\textquoteright} at the Catholic University of Korea.",

year = "2014",

month = may,

day = "15",

doi = "10.1038/onc.2013.216",

language = "English",

volume = "33",

pages = "2557--2567",

journal = "Oncogene",

issn = "0950-9232",

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T1 - MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma

AU - Bae, H. J.

AU - Noh, J. H.

AU - Kim, J. K.

AU - Eun, J. W.

AU - Jung, K. H.

AU - Kim, M. G.

AU - Chang, Y. G.

AU - Shen, Q.

AU - Kim, S. J.

AU - Park, W. S.

AU - Lee, J. Y.

AU - Nam, S. W.

N1 - Funding Information: A total of 60 HCCs and 60 non-cancerous liver tissue samples were obtained from the Liver Cancer Specimen Bank of the National Research Resource Bank Program of the Korea Science and Engineering Foundation of the Ministry of Science, and Seoul National University, School of Medicine, Seoul, Korea, and this study was approved by the Institutional Review of Board (IRB) of the Songeui Campus, College of Medicine, Catholic University of Korea (IRB approval number; CUMC09U115). Funding Information: This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST; Grant No. 2011-0010705 and No. 2012M3A9D1054476), and by the Korean Science and Engineering Foundation via the ‘Cancer Evolution Research Center’ at the Catholic University of Korea.

PY - 2014/5/15

Y1 - 2014/5/15

N2 - Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3′-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.

AB - Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3′-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.

KW - SIRT1

KW - cell cycle

KW - hepatocellular carcinoma

KW - miR-29c

KW - tumor suppressor

UR - https://www.scopus.com/pages/publications/84901193349

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DO - 10.1038/onc.2013.216

M3 - Article

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AN - SCOPUS:84901193349

SN - 0950-9232

VL - 33

SP - 2557

EP - 2567

JO - Oncogene

JF - Oncogene

IS - 20

ER -

MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma

Abstract

Bibliographical note

UN SDGs

Keywords

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