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

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.

Overexpression of miR-370 and downregulation of its novel target TGFβ-RII contribute to the progression of gastric carcinoma

“…As the qPCR analysis gave quantification of the mature miRNAs rather than their precursors, our analysis should have identified functional miRNAs that are important to gastric tumorigenesis. The involvement of Let-7, miR-21 and miR-221, and miR-222 and miR-148 in gastric carcinogenesis has been identified previously (Volinia et al, 2006;Motoyama et al, 2008;Zhang et al, 2008;Katada et al, 2009;Kim et al, 2009). These miRNAs, because they were annotated in our analysis, substantiate the validity of our approach.…”

“…In previous studies, miR-21 and let-7 have been shown to be oncogenic and suppressive with respect to GC, respectively (Motoyama et al, 2008;Zhang et al, 2008). A recent study also found overexpression of the miR-221 and miR-222 clusters in GC tissues and that these miRNAs target the Cip/Kip cell cycle regulators in GC cells (Kim et al, 2009). Transforming growth factor-b (TGFb) has pluripotent roles in regulating biological and pathological processes (van den Brink and Offerhaus, 2007;Massague, 2008).…”

FoxM1 is Overexpressed in Helicobacter pylori–Induced Gastric Carcinogenesis and Is Negatively Regulated by miR-370

“…Numerous deregulated miRNAs are involved in gastric cancer and include miR-146a, miR-155, miR-21, miR-27a, miR-106-93-25, miR-221-222 clusters, and the miR-200 family (23)(24)(25)(43)(44)(45)(46). A growing number of studies also suggest the involvement of miRNAs in various steps of gastric carcinogenesis: from gastritis to metastatic disease (47).…”

5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro

“…miR-222 has been shown to be up-regulated in gastric cancer, thyroid tumors, pancreatic cancer, childhood B-cell precursor acute lymphoblastic leukemia and hepatic cell cancers (23,(31)(32)(33)(34). The overexpression of miR-222 is found to be correlated with the resistance to hormone treatment and aggressiveness in prostate carcinoma (35,36).…”

“…Furthermore, PLCD1 and RNF139, two predicted candidate target genes of miR-191, are tumor suppressors in esophageal squamous cell carcinoma and human hereditary kidney cancer, respectively (21,22). miR-93 is up-regulated in gastric cancer tissues compared to the corresponding normal tissues (23). It is also significantly overexpressed in the serum of ovarian cancer patients compared to controls (24).…”