MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3

Florin M. Selaru, Alexandru V. Olaru, Takatsugu Kan, Stefan David, Yulan Cheng, Yuriko Mori, Jian Yang, Bogdan Paun, Zhe Jin, Rachana Agarwal, James P. Hamilton, John Abraham, Christos Georgiades, Hector Alvarez, Perumal Vivekanandan, Wayne Yu, Anirban Maitra, Michael Torbenson, Paul J. Thuluvath, Gregory James GoresNicholas F La Russo, Ralph Hruban, Stephen J. Meltzer

Research output: Contribution to journalArticle

208 Citations (Scopus)

Abstract

Cholangiocarcinomas (CCAs) are aggressive cancers, with high mortality and poor survival rates. Only radical surgery offers patients some hope of cure; however, most patients are not surgical candidates because of late diagnosis secondary to relatively poor accuracy of diagnostic means. MicroRNAs (miRs) are involved in every cancer examined, but they have not been evaluated in primary CCA. In this study, miR arrays were performed on five primary CCAs and five normal bile duct specimens (NBDs). Several miRs were dysregulated and miR-21 was overexpressed in CCAs. miR-21 differential expression in these 10 specimens was verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). To validate these findings, qRT-PCR for miR-21 was then performed on 18 additional primary CCAs and 12 normal liver specimens. MiR-21 was 95% sensitive and 100% specific in distinguishing between CCA and normal tissues, with an area under the receiver operating characteristic curve of 0.995. Inhibitors of miR-21 increased protein levels of programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinases 3 (TIMP3). Notably, messenger RNA levels of TIMP3 were significantly lower in CCAs than in normals. Conclusions: MiR-21 is overexpressed in human CCAs. Furthermore, miR-21 may be oncogenic, at least in part, by inhibiting PDCD4 and TIMP3. Finally, these data suggest that TIMP3 is a candidate tumor suppressor gene in the biliary tree.

Original languageEnglish (US)
Pages (from-to)1595-1601
Number of pages7
JournalHepatology
Volume49
Issue number5
DOIs
StatePublished - May 2009

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Tissue Inhibitor of Metalloproteinase-3
Cholangiocarcinoma
MicroRNAs
Cell Death
Reverse Transcriptase Polymerase Chain Reaction
Apoptosis Regulatory Proteins
Delayed Diagnosis
Biliary Tract
Bile Ducts
Tumor Suppressor Genes
ROC Curve
Neoplasms
Survival Rate
Messenger RNA

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3. / Selaru, Florin M.; Olaru, Alexandru V.; Kan, Takatsugu; David, Stefan; Cheng, Yulan; Mori, Yuriko; Yang, Jian; Paun, Bogdan; Jin, Zhe; Agarwal, Rachana; Hamilton, James P.; Abraham, John; Georgiades, Christos; Alvarez, Hector; Vivekanandan, Perumal; Yu, Wayne; Maitra, Anirban; Torbenson, Michael; Thuluvath, Paul J.; Gores, Gregory James; La Russo, Nicholas F; Hruban, Ralph; Meltzer, Stephen J.

In: Hepatology, Vol. 49, No. 5, 05.2009, p. 1595-1601.

Research output: Contribution to journalArticle

Selaru, FM, Olaru, AV, Kan, T, David, S, Cheng, Y, Mori, Y, Yang, J, Paun, B, Jin, Z, Agarwal, R, Hamilton, JP, Abraham, J, Georgiades, C, Alvarez, H, Vivekanandan, P, Yu, W, Maitra, A, Torbenson, M, Thuluvath, PJ, Gores, GJ, La Russo, NF, Hruban, R & Meltzer, SJ 2009, 'MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3', Hepatology, vol. 49, no. 5, pp. 1595-1601. https://doi.org/10.1002/hep.22838
Selaru, Florin M. ; Olaru, Alexandru V. ; Kan, Takatsugu ; David, Stefan ; Cheng, Yulan ; Mori, Yuriko ; Yang, Jian ; Paun, Bogdan ; Jin, Zhe ; Agarwal, Rachana ; Hamilton, James P. ; Abraham, John ; Georgiades, Christos ; Alvarez, Hector ; Vivekanandan, Perumal ; Yu, Wayne ; Maitra, Anirban ; Torbenson, Michael ; Thuluvath, Paul J. ; Gores, Gregory James ; La Russo, Nicholas F ; Hruban, Ralph ; Meltzer, Stephen J. / MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3. In: Hepatology. 2009 ; Vol. 49, No. 5. pp. 1595-1601.
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title = "MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3",
abstract = "Cholangiocarcinomas (CCAs) are aggressive cancers, with high mortality and poor survival rates. Only radical surgery offers patients some hope of cure; however, most patients are not surgical candidates because of late diagnosis secondary to relatively poor accuracy of diagnostic means. MicroRNAs (miRs) are involved in every cancer examined, but they have not been evaluated in primary CCA. In this study, miR arrays were performed on five primary CCAs and five normal bile duct specimens (NBDs). Several miRs were dysregulated and miR-21 was overexpressed in CCAs. miR-21 differential expression in these 10 specimens was verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). To validate these findings, qRT-PCR for miR-21 was then performed on 18 additional primary CCAs and 12 normal liver specimens. MiR-21 was 95{\%} sensitive and 100{\%} specific in distinguishing between CCA and normal tissues, with an area under the receiver operating characteristic curve of 0.995. Inhibitors of miR-21 increased protein levels of programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinases 3 (TIMP3). Notably, messenger RNA levels of TIMP3 were significantly lower in CCAs than in normals. Conclusions: MiR-21 is overexpressed in human CCAs. Furthermore, miR-21 may be oncogenic, at least in part, by inhibiting PDCD4 and TIMP3. Finally, these data suggest that TIMP3 is a candidate tumor suppressor gene in the biliary tree.",
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T1 - MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3

AU - Selaru, Florin M.

AU - Olaru, Alexandru V.

AU - Kan, Takatsugu

AU - David, Stefan

AU - Cheng, Yulan

AU - Mori, Yuriko

AU - Yang, Jian

AU - Paun, Bogdan

AU - Jin, Zhe

AU - Agarwal, Rachana

AU - Hamilton, James P.

AU - Abraham, John

AU - Georgiades, Christos

AU - Alvarez, Hector

AU - Vivekanandan, Perumal

AU - Yu, Wayne

AU - Maitra, Anirban

AU - Torbenson, Michael

AU - Thuluvath, Paul J.

AU - Gores, Gregory James

AU - La Russo, Nicholas F

AU - Hruban, Ralph

AU - Meltzer, Stephen J.

PY - 2009/5

Y1 - 2009/5

N2 - Cholangiocarcinomas (CCAs) are aggressive cancers, with high mortality and poor survival rates. Only radical surgery offers patients some hope of cure; however, most patients are not surgical candidates because of late diagnosis secondary to relatively poor accuracy of diagnostic means. MicroRNAs (miRs) are involved in every cancer examined, but they have not been evaluated in primary CCA. In this study, miR arrays were performed on five primary CCAs and five normal bile duct specimens (NBDs). Several miRs were dysregulated and miR-21 was overexpressed in CCAs. miR-21 differential expression in these 10 specimens was verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). To validate these findings, qRT-PCR for miR-21 was then performed on 18 additional primary CCAs and 12 normal liver specimens. MiR-21 was 95% sensitive and 100% specific in distinguishing between CCA and normal tissues, with an area under the receiver operating characteristic curve of 0.995. Inhibitors of miR-21 increased protein levels of programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinases 3 (TIMP3). Notably, messenger RNA levels of TIMP3 were significantly lower in CCAs than in normals. Conclusions: MiR-21 is overexpressed in human CCAs. Furthermore, miR-21 may be oncogenic, at least in part, by inhibiting PDCD4 and TIMP3. Finally, these data suggest that TIMP3 is a candidate tumor suppressor gene in the biliary tree.

AB - Cholangiocarcinomas (CCAs) are aggressive cancers, with high mortality and poor survival rates. Only radical surgery offers patients some hope of cure; however, most patients are not surgical candidates because of late diagnosis secondary to relatively poor accuracy of diagnostic means. MicroRNAs (miRs) are involved in every cancer examined, but they have not been evaluated in primary CCA. In this study, miR arrays were performed on five primary CCAs and five normal bile duct specimens (NBDs). Several miRs were dysregulated and miR-21 was overexpressed in CCAs. miR-21 differential expression in these 10 specimens was verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). To validate these findings, qRT-PCR for miR-21 was then performed on 18 additional primary CCAs and 12 normal liver specimens. MiR-21 was 95% sensitive and 100% specific in distinguishing between CCA and normal tissues, with an area under the receiver operating characteristic curve of 0.995. Inhibitors of miR-21 increased protein levels of programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinases 3 (TIMP3). Notably, messenger RNA levels of TIMP3 were significantly lower in CCAs than in normals. Conclusions: MiR-21 is overexpressed in human CCAs. Furthermore, miR-21 may be oncogenic, at least in part, by inhibiting PDCD4 and TIMP3. Finally, these data suggest that TIMP3 is a candidate tumor suppressor gene in the biliary tree.

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U2 - 10.1002/hep.22838

DO - 10.1002/hep.22838

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