MicroRNA‑18b acts as an oncogene in gastric cancer by directly targeting Kruppel‑like factor 6 Retraction in /10.3892/mmr.2022.12916

Luo,Dongming; Chen,Junqiang; Huang,Shifeng; Xu,Junyi; Song,Xuemin; Yu,Pengcheng

doi:10.3892/mmr.2019.9830

MicroRNA‑18b acts as an oncogene in gastric cancer by directly targeting Kruppel‑like factor 6

Retraction in: /10.3892/mmr.2022.12916

Authors:
- Dongming Luo
- Junqiang Chen
- Shifeng Huang
- Junyi Xu
- Xuemin Song
- Pengcheng Yu
View Affiliations

Affiliations: Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi 545005, P.R. China, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: January 8, 2019 https://doi.org/10.3892/mmr.2019.9830
Pages: 1926-1934

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gastric cancer (GC) is the fourth most frequently occurring cancer and the second most common cause of cancer‑associated mortality worldwide. An increasing number of studies have reported that microRNAs (miRNAs/miRs) contribute to the regulation of GC development and progression. Therefore, investigation of the miRNAs involved in the development of GC may result in identification of an effective therapeutic target for patients with this malignancy. miR‑18b has been reported to be aberrantly expressed in several types of human cancer. However, the expression pattern, biological role and specific functional mechanism of miR‑18b in GC remains to be elucidated. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis revealed that miR‑18b was significantly upregulated in GC tissues and cell lines compared with normal gastric tissues and the human gastric epithelial immortalized cell line GES‑1, respectively. High miR‑18b expression was significantly associated with lymph node metastasis, invasive depth and the Tumor Node Metastasis stage of patients with GC. Additionally, functional assays indicated that the inhibition of miR‑18b attenuated cell proliferation and invasion in GC. Furthermore, Kruppel‑like factor (KLF)‑6 was identified as a direct target gene of miR‑18b in GC, from the results of bioinformatics analysis, a luciferase reporter assay, RT‑qPCR and western blot analysis. An inverse association was observed between miR‑18b and KLF6 mRNA levels in GC tissues. KLF6 knockdown partially abrogated the effects of miR‑18b inhibition on GC cell proliferation and invasion. Therefore, miR‑18b/KLF6 targeted therapy may provide a promising treatment for patients with GC.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Cheng XJ, Lin JC and Tu SP: Etiology and prevention of gastric cancer. Gastrointest Tumors. 3:25–36. 2016. View Article : Google Scholar : PubMed/NCBI
3	Compare D, Rocco A and Nardone G: Risk factors in gastric cancer. Eur Rev Med Pharmacol Sci. 14:302–308. 2010.PubMed/NCBI
4	Newton AD, Datta J, Loaiza-Bonilla A, Karakousis GC and Roses RE: Neoadjuvant therapy for gastric cancer: Current evidence and future directions. J Gastrointest Oncol. 6:534–543. 2015.PubMed/NCBI
5	Otani K, Li X, Arakawa T, Chan FK and Yu J: Epigenetic-mediated tumor suppressor genes as diagnostic or prognostic biomarkers in gastric cancer. Expert Rev Mol Diagn. 13:445–455. 2013. View Article : Google Scholar : PubMed/NCBI
6	Monroig Pdel C, Chen L, Zhang S and Calin GA: Small molecule compounds targeting miRNAs for cancer therapy. Adv Drug Deliv Rev. 81:104–116. 2015. View Article : Google Scholar : PubMed/NCBI
7	Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS and Johnson JM: Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 433:769–773. 2005. View Article : Google Scholar : PubMed/NCBI
8	Krol J, Loedige I and Filipowicz W: The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610. 2010. View Article : Google Scholar : PubMed/NCBI
9	Ding X, Liu J, Liu T, Ma Z, Wen D and Zhu J: miR-148b inhibits glycolysis in gastric cancer through targeting SLC2A1. Cancer Med. 6:1301–1310. 2017. View Article : Google Scholar : PubMed/NCBI
10	Bai X, Meng L, Sun H, Li Z, Zhang X and Hua S: MicroRNA-196b inhibits cell growth and metastasis of lung cancer cells by targeting Runx2. Cell Physiol Biochem. 43:757–767. 2017. View Article : Google Scholar : PubMed/NCBI
11	Karatas OF, Wang J, Shao L, Ozen M, Zhang Y, Creighton CJ and Ittmann M: miR-33a is a tumor suppressor microRNA that is decreased in prostate cancer. Oncotarget. 8:60243–60256. 2017. View Article : Google Scholar : PubMed/NCBI
12	Pillai RS: MicroRNA function: Multiple mechanisms for a tiny RNA? RNA. 11:1753–1761. 2005. View Article : Google Scholar : PubMed/NCBI
13	Long MJ, Wu FX, Li P, Liu M, Li X and Tang H: MicroRNA-10a targets CHL1 and promotes cell growth, migration and invasion in human cervical cancer cells. Cancer Lett. 324:186–196. 2012. View Article : Google Scholar : PubMed/NCBI
14	Li Y, Zhang H, Dong Y, Fan Y, Li Y, Zhao C, Wang C, Liu J, Li X, Dong M, et al: MiR-146b-5p functions as a suppressor miRNA and prognosis predictor in non-small cell lung cancer. J Cancer. 8:1704–1716. 2017. View Article : Google Scholar : PubMed/NCBI
15	Chen Y, Zhang Z, Luo C, Chen Z and Zhou J: MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis. Oncol Rep. 36:471–479. 2016. View Article : Google Scholar : PubMed/NCBI
16	Li Y, Chen M, Liu J, Li L, Yang X, Zhao J, Wu M and Ye M: Upregulation of microRNA-18b contributes to the development of colorectal cancer through inhibiting CDKN2B. Mol Cell Biol. 37(pii): e00391–17. 2017.PubMed/NCBI
17	Murakami Y, Tamori A, Itami S, Tanahashi T, Toyoda H, Tanaka M, Wu W, Brojigin N, Kaneoka Y, Maeda A, et al: The expression level of miR-18b in hepatocellular carcinoma is associated with the grade of malignancy and prognosis. BMC Cancer. 13:992013. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Zhang Q, Tan XP, Yuan YS, Hu CM, He CH, Wang WZ, Li JC, Zhao Q and Liu NZ: Decreased expression of KLF6 and its significance in gastric carcinoma. Med Oncol. 27:1295–1302. 2010. View Article : Google Scholar : PubMed/NCBI
20	Sangodkar J, Shi J, DiFeo A, Schwartz R, Bromberg R, Choudhri A, McClinch K, Hatami R, Scheer E, Kremer-Tal S, et al: Functional role of the KLF6 tumour suppressor gene in gastric cancer. Eur J Cancer. 45:666–676. 2009. View Article : Google Scholar : PubMed/NCBI
21	Zhang X, Nie Y, Du Y, Cao J, Shen B and Li Y: MicroRNA-181a promotes gastric cancer by negatively regulating tumor suppressor KLF6. Tumour Biol. 33:1589–1597. 2012. View Article : Google Scholar : PubMed/NCBI
22	Shrestha S, Hsu SD, Huang WY, Huang HY, Chen W, Weng SL and Huang HD: A systematic review of microRNA expression profiling studies in human gastric cancer. Cancer Med. 3:878–888. 2014. View Article : Google Scholar : PubMed/NCBI
23	Zhu X, Lv M, Wang H and Guan W: Identification of circulating microRNAs as novel potential biomarkers for gastric cancer detection: A systematic review and meta-analysis. Dig Dis Sci. 59:911–919. 2014. View Article : Google Scholar : PubMed/NCBI
24	Rao M, Zhu Y, Zhou Y, Cong X and Feng L: MicroRNA-122 inhibits proliferation and invasion in gastric cancer by targeting CREB1. Am J Cancer Res. 7:323–333. 2017.PubMed/NCBI
25	Husby S, Ralfkiaer U, Garde C, Zandi R, Ek S, Kolstad A, Jerkeman M, Laurell A, Räty R, Pedersen LB, et al: miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood. 125:2669–2677. 2015. View Article : Google Scholar : PubMed/NCBI
26	Yu X, Zhen Y, Yang H, Wang H, Zhou Y, Wang E, Marincola FM, Mai C, Chen Y, Wei H, et al: Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma. Cell Death Dis. 4:e6342013. View Article : Google Scholar : PubMed/NCBI
27	Fonseca-Sanchéz MA, Pérez-Plasencia C, Fernandez-Retana J, Arechaga-Ocampo E, Marchat LA, Rodríguez-Cuevas S, Bautista-Piña V, Arellano-Anaya ZE, Flores-Pérez A, Diaz-Chávez J and López-Camarillo C: microRNA-18b is upregulated in breast cancer and modulates genes involved in cell migration. Oncol Rep. 30:2399–2410. 2013. View Article : Google Scholar : PubMed/NCBI
28	Dar AA, Majid S, Rittsteuer C, de Semir D, Bezrookove V, Tong S, Nosrati M, Sagebiel R, Miller JR III and Kashani-Sabet M: The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression. J Natl Cancer Inst. 105:433–442. 2013. View Article : Google Scholar : PubMed/NCBI
29	Ito G, Uchiyama M, Kondo M, Mori S, Usami N, Maeda O, Kawabe T, Hasegawa Y, Shimokata K and Sekido Y: Kruppel-like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells. Cancer Res. 64:3838–3843. 2004. View Article : Google Scholar : PubMed/NCBI
30	DiFeo A, Narla G and Martignetti JA: Emerging roles of Kruppel-like factor 6 and Kruppel-like factor 6 splice variant 1 in ovarian cancer progression and treatment. Mt Sinai J Med. 76:557–566. 2009. View Article : Google Scholar : PubMed/NCBI
31	Huang X, Li X and Guo B: KLF6 induces apoptosis in prostate cancer cells through up-regulation of ATF3. J Biol Chem. 283:29795–29801. 2008. View Article : Google Scholar : PubMed/NCBI
32	Kimmelman AC, Qiao RF, Narla G, Banno A, Lau N, Bos PD, Nuñez Rodriguez N, Liang BC, Guha A, Martignetti JA, et al: Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6. Oncogene. 23:5077–5083. 2004. View Article : Google Scholar : PubMed/NCBI
33	Cho YG, Choi BJ, Song JW, Kim SY, Nam SW, Lee SH, Yoo NJ, Lee JY and Park WS: Aberrant expression of krUppel-like factor 6 protein in colorectal cancers. World J Gastroenterol. 12:2250–2253. 2006. View Article : Google Scholar : PubMed/NCBI
34	Gao Y, Li H, Ma X, Fan Y, Ni D, Zhang Y, Huang Q, Liu K, Li X, Wang L, et al: KLF6 suppresses metastasis of clear cell renal cell carcinoma via transcriptional repression of E2F1. Cancer Res. 77:330–342. 2017. View Article : Google Scholar : PubMed/NCBI
35	Gehrau RC, D'Astolfo DS, Andreoli V, Bocco JL and Koritschoner NP: Differential expression of the klf6 tumor suppressor gene upon cell damaging treatments in cancer cells. Mutat Res. 707:15–23. 2011. View Article : Google Scholar : PubMed/NCBI