Oncogenic microRNA‐27a is a target for anticancer agent methyl 2‐cyano‐3,11‐dioxo‐18β‐olean‐1,12‐dien‐30‐oate in colon cancer cells

Abstract

Methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate (CDODAMe) is a synthetic derivative of glycyrrhetinic acid, a triterpenoid phytochemical found in licorice extracts. CDODA-Me inhibited growth of RKO and SW480 colon cancer cells and this was accompanied by decreased expression of Sp1, Sp3 and Sp4 protein and mRNA and several Sp-dependent genes including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1 or Flt-1). CDODA-Me also induced apoptosis, arrested RKO and SW480 cells at G 2 /M, and inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. CDODA-Me decreased expression of microRNA-27a (miR-27a), and this was accompanied by increased expression of 2 miR-27a-regulated mRNAs, namely ZBTB10 (an Sp repressor) and Myt-1 which catalyzes phosphorylation of cdc2 to inhibit progression of cells through G 2 /M. Both CDODA-Me and antisense miR-27a induced comparable responses in RKO and SW480 cells, suggesting that the potent anticarcinogenic activity of CDODA-Me is due to repression of oncogenic miR-27a. ' UICCKey words: CDODA-Me; anticarcinogenicity; miR-27a; colon cancer; cell cycle MicroRNAs (miRNAs) are 20-25 bp oligonucleotides that interact with complementary binding sites in 3 0 -untranslated regions of target mRNAs to inhibit their expression by blocking translation or by decreasing mRNA stability.1,2 miRNA interactions with mRNA requires the overlap of 6-8 base pairs and, due to this relatively low stringency, computational studies show that miRNAs can potentially interact with several hundred mRNAs.Despite this lack of specificity, miRNAs have a profound effect on gene expression and cellular homeostasis and, in cancer cells, expression of several critical oncogenes and tumor suppressor genes are regulated by miRNA expression.3-6 miR-221 and miR-222 target the cyclin-dependent kinase inhibitor p27 6 and miR-21 decreases expression of several mRNAs including the tumor suppressor gene tropomyosin 1. 3 Recent studies in this laboratory showed that miR-27a targets ZBTB10 mRNA, a putative zinc finger protein that suppresses specificity protein (Sp) transcription factors and Sp-dependent gene expression. 7 The Sp transcription factors Sp1, Sp3 and Sp4 are highly expressed in cancer cell lines, and results of RNA interference studies show that Sp proteins regulate expression of angiogenic genes such as vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR1, Flt-1), VEGFR2 (KDR) and the antiapoptotic gene survivin. 8-14Betulinic acid and the nonsteroidal anti-inflammatory drug tolfenamic acid inhibit prostate and pancreatic cell and tumor growth through activation of proteasome-dependent degradation of Sp1, Sp3 and Sp4 proteins. 13,14 In our study, we show that methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate (CDODA-Me) is highly cytotoxic to colon cancer cells and also decreases Sp and Sp-dependent genes and proteins. However, these effects are proteasome-independent. We now show for the first time that CDODA-Me acts through downregulation of...

The microRNA-27a: ZBTB10-specificity protein pathway is involved in follicle stimulating hormone-induced VEGF, Cox2 and survivin expression in ovarian epithelial cancer cells

“…This putative zinc finger protein suppresses specificity protein (Sp) transcription factors and Sp-dependent gene expression (7,25). It was reported that microRNA-27a targets ZBTB10 gene in breast cancer and regulates cell proliferation (7).…”

MicroRNAs as Regulators of Signal Transduction in Urological Tumors

“…For both compounds, inhibition of tumor growth was successfully shown. Methyl 2-cyano-3,11-dioxy-18beta-olean-1,12-dien-30-oate inhibits the oncogenic function of miR-27a in colon cancer (73 ), and retinoic acid receptor antagonists have been shown to block the function of miR-10a in pancreatic cancer (74 ).…”

miR-27a as an Oncogenic microRNA of Hepatitis B Virus-related Hepatocellular Carcinoma

“…However, we found that miR-27a was significantly up-regulated in HCC samples. miR-27a has been found to be an oncogene, which is abnormally upregulated in several types of cancers, including gastric cancer (Liu et al, 2009), colon cancer (Chintharlapalli et al, 2009), pancreatic cancer (Szafranska et al, 2007;Ma et al, 2010), breast cancer (Guttilla et al, 2009), ovarian cancer , and kidney cancer (Gottardo et al, 2007), pediatric acute lymphoblastic leukemia (ALL) (Lerner et al, 2011). It has been demonstrated that miR-27a play important roles in mediating cancer cell proliferation, cell cycle, apoptosis, migration and drug resistance (Mertens-Talcott et al, 2007;Liu et al, 2009;Ma et al, 2010;Lerner et al, 2011).…”

“…Low expression level of miR-27a in plasma was observed in patients with HCC compared with control groups of healthy, chronic hepatitis B, liver cirrhosis (Zhou et al, 2011). However, miR-27a has been found to be an oncogene, which is abnormally up-regulated in several types of cancers (Mertens-Talcott et al, 2007;Chintharlapalli et al, 2009;Guttilla et al, 2009;Liu et al, 2009). Thus, it remains to be determined whether miR-27a is altered in HCC and adjacent nontumor tissues.…”