MicroRNA-375 targets the 3-phosphoinositide-dependent protein kinase‑1 gene in pancreatic carcinoma

Song,Shi-Duo; Zhou,Jian; Zhou,Jin; Zhao,Hua; Cen,Jian-Nong; Li,De-Chun

doi:10.3892/ol.2013.1510

MicroRNA-375 targets the 3-phosphoinositide-dependent protein kinase‑1 gene in pancreatic carcinoma

Authors:
- Shi-Duo Song
- Jian Zhou
- Jin Zhou
- Hua Zhao
- Jian-Nong Cen
- De-Chun Li
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Affiliations: Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China , Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215006, P.R. China
Published online on: August 2, 2013 https://doi.org/10.3892/ol.2013.1510
Pages: 953-959

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Abstract

Pancreatic carcinoma (PC) is an aggressive malignancy with one of the poorest mortality rates. It is the sixth leading cause of mortality from malignant disease in China and the fourth leading cause of cancer‑related mortality in the United States. The poor outcome reﬂects the requirement for an improved understanding of the transcriptional control of oncogenic signaling pathways. 3‑phosphoinositide‑dependent protein kinase‑1 (PDK1) is a potent oncogenic driver of PC. The present study aimed to elucidate the transcriptional regulation of microRNA (miR)‑375-targeted PDK1. miR‑375 is a putative target and, in the present study, was observed to be significantly downregulated in the tumor compared with non‑tumor tissues from patients with PC (n=44). As determined by a luciferase reporter assay, the ectopic expression of miR‑375 was identified to diminish the transcriptional activity of PDK1. Furthermore, immunoblotting revealed that miR‑375 suppressed endogenous PDK1 protein levels. Functional assays showed that miR‑375 was able to inhibit proliferation and promote apoptosis of the PC cells. miR‑375 is a significant regulator of the PDK1 oncogene, suggesting that it may have a potential therapeutic role in the treatment of PC.

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1	Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar
2	Guo X and Cui Z: Current diagnosis and treatment of pancreatic cancer in China. Pancreas. 31:13–22. 2005. View Article : Google Scholar : PubMed/NCBI
3	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
4	Hingorani SR, Wang L, Multani AS, et al: Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 7:469–483. 2005. View Article : Google Scholar : PubMed/NCBI
5	Bardeesy N, Aguirre AJ, Chu GC, et al: Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci USA. 103:5947–5952. 2006. View Article : Google Scholar : PubMed/NCBI
6	Feldmann G, Beaty R, Hruban RH and Maitra A: Molecular genetics of pancreatic intraepithelial neoplasia. J Hepatobiliary Pancreat Surg. 14:224–232. 2007. View Article : Google Scholar : PubMed/NCBI
7	Westmoreland JJ, Wang Q, Bouzaffour M, et al: Pdk1 activity controls proliferation, survival, and growth of developing pancreatic cells. Dev Biol. 334:285–298. 2009. View Article : Google Scholar : PubMed/NCBI
8	Bushati N and Cohen SM: microRNA functions. Annu Rev Cell Dev Biol. 23:175–205. 2007. View Article : Google Scholar
9	Carthew RW and Sontheimer EJ: Origins and mechanisms of miRNAs and siRNAs. Cell. 136:642–655. 2009. View Article : Google Scholar : PubMed/NCBI
10	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
11	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
12	He L and Hannon GJ: MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
13	Zaman MS, Chen Y, Deng G, et al: The functional significance of microRNA-145 in prostate cancer. Br J Cancer. 103:256–264. 2010. View Article : Google Scholar : PubMed/NCBI
14	Yu S, Lu Z, Liu C, et al: miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res. 70:6015–6025. 2010. View Article : Google Scholar : PubMed/NCBI
15	Schickel R, Park SM, Murmann AE and Peter ME: miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell. 38:908–915. 2010. View Article : Google Scholar : PubMed/NCBI
16	Szafranska AE, Davison TS, John J, et al: MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 26:4442–4452. 2007. View Article : Google Scholar : PubMed/NCBI
17	Avissar M, Christensen BC, Kelsey KT and Marsit CJ: MicroRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin Cancer Res. 15:2850–2855. 2009. View Article : Google Scholar : PubMed/NCBI
18	Ladeiro Y, Couchy G, Balabaud C, et al: MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 47:1955–1963. 2008. View Article : Google Scholar : PubMed/NCBI
19	Zhou J, Song S, Cen J, Zhu D, Li D and Zhang Z: MicroRNA-375 is downregulated in pancreatic cancer and inhibits cell proliferation in vitro. Oncol Res. 20:197–203. 2012. View Article : Google Scholar : PubMed/NCBI
20	Hamilton SR and Aaltonen LA: Pathology and genetics of tumours of the digestive system. World Health Organization Classification of Tumours. IARC Press; Lyon: 2000
21	Wang XQ, Luk JM, Leung PP, et al: Alternative mRNA splicing of liver intestine-cadherin in hepatocellular carcinoma. Clin Cancer Res. 11:483–489. 2005.PubMed/NCBI
22	Wong KF, Luk JM, Cheng RH, et al: Characterization of two novel LPS-binding sites in leukocyte integrin betaA domain. FASEB J. 21:3231–3239. 2007. View Article : Google Scholar : PubMed/NCBI
23	Liu LX, Lee NP, Chan VW, et al: Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology. 50:1453–1463. 2009. View Article : Google Scholar : PubMed/NCBI
24	Kozma SC and Thomas G: Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioessays. 24:65–71. 2002. View Article : Google Scholar : PubMed/NCBI
25	Mora A, Komander D, van Aalten DM and Alessi DR: PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 15:161–170. 2004. View Article : Google Scholar : PubMed/NCBI
26	Storz P and Toker A: 3′-phosphoinositide-dependent kinase-1 (PDK-1) in PI 3-kinase signaling. Front Biosci. 7:d886–d902. 2002.
27	El Ouaamari A, Baroukh N, Martens GA, et al: miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic beta-cells. Diabetes. 57:2708–2717. 2008.
28	Bloomston M, Frankel WL, Petrocca F, et al: MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 297:1901–1908. 2007. View Article : Google Scholar : PubMed/NCBI
29	Hou Z, Xie L, Yu L, Qian X and Liu B: MicroRNA-146a is down-regulated in gastric cancer and regulates cell proliferation and apoptosis. Med Oncol. 29:886–892. 2012. View Article : Google Scholar : PubMed/NCBI
30	Lee EJ, Gusev Y, Jiang J, et al: Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer. 120:1046–1054. 2007. View Article : Google Scholar : PubMed/NCBI
31	Poy MN, Eliasson L, Krutzfeldt J, et al: A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 432:226–230. 2004. View Article : Google Scholar : PubMed/NCBI
32	Liu AM, Poon RT and Luk JM: MicroRNA-375 targets Hippo-signaling effector YAP in liver cancer and inhibits tumor properties. Biochem Biophys Res Commun. 394:623–627. 2010. View Article : Google Scholar : PubMed/NCBI
33	Ding L, Xu Y, Zhang W, et al: MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2. Cell Res. 20:784–793. 2010. View Article : Google Scholar : PubMed/NCBI
34	Li X, Lin R and Li J: Epigenetic silencing of microRNA-375 regulates PDK1 expression in esophageal cancer. Dig Dis Sci. 56:2849–2856. 2011. View Article : Google Scholar : PubMed/NCBI
35	Tsukamoto Y, Nakada C, Noguchi T, et al: MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 70:2339–2349. 2010. View Article : Google Scholar : PubMed/NCBI