Abstract
MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most upregulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 264-269 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 107 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2010 |
Fingerprint
Keywords
- AntagomiRs
- DDIT4
- Hepatocarcinogenesis
- MicroRNA
- Mouse model
ASJC Scopus subject areas
- General
Cite this
miR-221 overexpression contributes to liver tumorigenesis. / Pineau, Pascal; Volinia, Stefano; McJunkin, Katherine; Marchio, Agnès; Battiston, Carlo; Terris, Benoît; Mazzaferro, Vincenzo; Lowe, Scott W.; Croce, Carlo M.; Dejean, Anne.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 1, 2010, p. 264-269.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - miR-221 overexpression contributes to liver tumorigenesis
AU - Pineau, Pascal
AU - Volinia, Stefano
AU - McJunkin, Katherine
AU - Marchio, Agnès
AU - Battiston, Carlo
AU - Terris, Benoît
AU - Mazzaferro, Vincenzo
AU - Lowe, Scott W.
AU - Croce, Carlo M.
AU - Dejean, Anne
PY - 2010
Y1 - 2010
N2 - MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most upregulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.
AB - MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most upregulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.
KW - AntagomiRs
KW - DDIT4
KW - Hepatocarcinogenesis
KW - MicroRNA
KW - Mouse model
UR - http://www.scopus.com/inward/record.url?scp=76249128792&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=76249128792&partnerID=8YFLogxK
U2 - 10.1073/pnas.0907904107
DO - 10.1073/pnas.0907904107
M3 - Article
C2 - 20018759
AN - SCOPUS:76249128792
VL - 107
SP - 264
EP - 269
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 1
ER -