Functional links between clustered microRNAs: Suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer

Young Kook Kim, Jieun Yu, Tae Su Han, Seong Yeon Park, Bumjin Namkoong, Dong Hyuk Kim, Keun Hur, Moon Won Yoo, Hyuk Joon Lee, Han Kwang Yang, V. Narry Kim

Research output: Contribution to journalArticle

362 Citations (Scopus)

Abstract

microRNAs (miRNAs) play integral roles in diverse processes including tumorigenesis. miRNA gene loci are often found in close conjunction, and such clustered miRNA genes are transcribed from a common promoter to generate polycistronic primary transcript. The primary transcript (pri-miRNA) is then processed by two RNase III proteins to release the mature miRNAs. Although it has been speculated that the miRNAs in the same cluster may play related biological functions, this has not been experimentally addressed. Here we report that the miRNAs in two clusters (miR-106b∼93 ∼ 25 and miR-222 ∼ 221) suppress the Cip/Kip family members of Cdk inhibitors (p57Kip2, p21Cip1 and p27Kip1). We show that miR-25 targets p57 through the 3′-UTR. Furthermore, miR-106b and miR-93 control p21 while miR-222 and miR-221 regulate both p27 and p57. Ectopic expression of these miRNAs results in activation of Cdk2 and facilitation of G1/S phase transition. Consistent with these results, both clusters are abnormally upregulated in gastric cancer tissues compared to the corresponding normal tissues. Ectopic expression of miR-222 cluster enhanced tumor growth in the mouse xenograft model. Our study demonstrates the functional associations between clustered miRNAs and further implicates that effective cancer treatment may require a combinatorial approach to target multiple oncogenic miRNA clusters.

Original languageEnglish
Pages (from-to)1672-1681
Number of pages10
JournalNucleic Acids Research
Volume37
Issue number5
DOIs
StatePublished - 2 Apr 2009

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MicroRNAs
Stomach Neoplasms
Cell Cycle
Ribonuclease III
Phase Transition
G1 Phase
3' Untranslated Regions
S Phase
Heterografts
Genes
Neoplasms
Carcinogenesis
Growth

Cite this

Kim, Young Kook ; Yu, Jieun ; Han, Tae Su ; Park, Seong Yeon ; Namkoong, Bumjin ; Kim, Dong Hyuk ; Hur, Keun ; Yoo, Moon Won ; Lee, Hyuk Joon ; Yang, Han Kwang ; Kim, V. Narry. / Functional links between clustered microRNAs : Suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. In: Nucleic Acids Research. 2009 ; Vol. 37, No. 5. pp. 1672-1681.
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Functional links between clustered microRNAs : Suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. / Kim, Young Kook; Yu, Jieun; Han, Tae Su; Park, Seong Yeon; Namkoong, Bumjin; Kim, Dong Hyuk; Hur, Keun; Yoo, Moon Won; Lee, Hyuk Joon; Yang, Han Kwang; Kim, V. Narry.

In: Nucleic Acids Research, Vol. 37, No. 5, 02.04.2009, p. 1672-1681.

Research output: Contribution to journalArticle

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T2 - Suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer

AU - Kim, Young Kook

AU - Yu, Jieun

AU - Han, Tae Su

AU - Park, Seong Yeon

AU - Namkoong, Bumjin

AU - Kim, Dong Hyuk

AU - Hur, Keun

AU - Yoo, Moon Won

AU - Lee, Hyuk Joon

AU - Yang, Han Kwang

AU - Kim, V. Narry

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N2 - microRNAs (miRNAs) play integral roles in diverse processes including tumorigenesis. miRNA gene loci are often found in close conjunction, and such clustered miRNA genes are transcribed from a common promoter to generate polycistronic primary transcript. The primary transcript (pri-miRNA) is then processed by two RNase III proteins to release the mature miRNAs. Although it has been speculated that the miRNAs in the same cluster may play related biological functions, this has not been experimentally addressed. Here we report that the miRNAs in two clusters (miR-106b∼93 ∼ 25 and miR-222 ∼ 221) suppress the Cip/Kip family members of Cdk inhibitors (p57Kip2, p21Cip1 and p27Kip1). We show that miR-25 targets p57 through the 3′-UTR. Furthermore, miR-106b and miR-93 control p21 while miR-222 and miR-221 regulate both p27 and p57. Ectopic expression of these miRNAs results in activation of Cdk2 and facilitation of G1/S phase transition. Consistent with these results, both clusters are abnormally upregulated in gastric cancer tissues compared to the corresponding normal tissues. Ectopic expression of miR-222 cluster enhanced tumor growth in the mouse xenograft model. Our study demonstrates the functional associations between clustered miRNAs and further implicates that effective cancer treatment may require a combinatorial approach to target multiple oncogenic miRNA clusters.

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