Young-Kook Kim1, Jieun Yu2, Tae Su Han2, Seong-Yeon Park1, Bumjin Namkoong1, Dong Hyuk Kim1, Keun Hur2, Moon-Won Yoo2,3, Hyuk-Joon Lee2,3, Han-Kwang Yang2,3,* and V. Narry Kim1,*
1Department of Biological Sciences, Seoul National University, 2Cancer Research Institute, Seoul National University College of Medicine and 3Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
*To whom correspondence should be addressed. Tel: +82 2 880 9120; Fax: +82 2 887 0244; Correspondence may also be addressed to Han-Kwang Yang. Tel: +82 2 2072 3797; Fax: +82 2 3672 0047
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.