MicroRNA-29a inhibits cell migration and invasion via targeting Roundabout homolog 1 in gastric cancer cells

Liu,Xueting; Cai,Jun; Sun,Yanjun; Gong,Renhua; Sun,Dengqun; Zhong,Xingguo; Jiang,Shitao; He,Xinmiao; Bao,Enwu; Yang,Liusheng; Li,Yongxiang

doi:10.3892/mmr.2015.3817

MicroRNA-29a inhibits cell migration and invasion via targeting Roundabout homolog 1 in gastric cancer cells

Authors:
- Xueting Liu
- Jun Cai
- Yanjun Sun
- Renhua Gong
- Dengqun Sun
- Xingguo Zhong
- Shitao Jiang
- Xinmiao He
- Enwu Bao
- Liusheng Yang
- Yongxiang Li
View Affiliations

Affiliations: Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, Department of General Surgery, Armed Police Corps Hospital of Anhui, Hefei, Anhui 230041, P.R. China
Published online on: May 22, 2015 https://doi.org/10.3892/mmr.2015.3817
Pages: 3944-3950

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

Deregulation of Roundabout homolog 1 (Robo1) has been demonstrated to be associated with several types of human cancer, including gastric cancer. However, the detailed role of Robo1 and its regulatory mechanism in gastric cancer remain largely unclear. In the current study, it was demonstrated that the expression of microRNA (miR)‑29a was frequently reduced in gastric cancer tissues, compared with their matched normal adjacent tissues. Similar results were additionally observed in AGS and SGC‑7901 human gastric cancer cells. Overexpression of miR‑29a led to reduced migration and invasion of AGS cells. To explore the targets of miR‑29a in gastric cancer, bioinformatics analysis was conducted and Robo1 was identified as a putative target of miR‑29a. Further western blotting and luciferase activity assay data confirmed that miR‑29a was able to negatively regulate the protein expression of Robo1, through directly binding to the 3'‑untranslated region of Robo1 mRNA in gastric cancer cells. In addition, it was demonstrated that Robo1 was frequently upregulated in gastric cancer tissues compared with their matched adjacent normal tissues, and a significant inverse correlation was identified between miR‑29a and Robo1 expression. In addition, knockdown of Robo1 by small interfering RNA markedly inhibited the migratory and invasive capabilities of AGS cells, which the results obtained with overexpression of miR‑29a. In conclusion, to the best of our knowledge the current study suggested for the first time, that miR‑29a inhibits migration and invasion in part via direct inhibition of Robo1 in gastric cancer cells. Therefore, Robo1 and miR‑29a may serve as diagnostic or therapeutic targets for gastric cancer.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Ishiguro H, Kimura M and Takeyama H: Role of microRNAs in gastric cancer. World J Gastroenterol. 20:5694–5699. 2014. View Article : Google Scholar : PubMed/NCBI
3	Piazuelo MB and Correa P: Gastric cancer: Overview. Colomb Med (Cali). 44:192–201. 2013.
4	Cornide-Petronio ME and Barreiro-Iglesias A: Role of Slit and Robo proteins in the development of dopaminergic neurons. Dev Neurosci. 35:285–292. 2013. View Article : Google Scholar : PubMed/NCBI
5	Dickinson RE and Duncan WC: The SLIT-ROBO pathway: A regulator of cell function with implications for the reproductive system. Reproduction. 139:697–704. 2010. View Article : Google Scholar : PubMed/NCBI
6	Je EM, Gwak M, Oh H, et al: Frameshift mutations of axon guidance genes ROBO1 and ROBO2 in gastric and colorectal cancers with microsatellite instability. Pathology. 45:645–650. 2013. View Article : Google Scholar : PubMed/NCBI
7	Tie J, Pan Y, Zhao L, et al: MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 6:e10008792010. View Article : Google Scholar : PubMed/NCBI
8	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
9	Cheung IY, Farazi TA, Ostrovnaya I, et al: Deep microRNA sequencing reveals downregulation of miR-29a in neuro-blastoma central nervous system metastasis. Genes Chromosomes Cancer. 53:803–814. 2014. View Article : Google Scholar : PubMed/NCBI
10	Zhao D, Jiang X, Yao C, et al: Heat shock protein 47 regulated by miR-29a to enhance glioma tumor growth and invasion. J Neurooncol. 118:39–47. 2014. View Article : Google Scholar : PubMed/NCBI
11	Chen L, Xiao H, Wang ZH, et al: miR-29a suppresses growth and invasion of gastric cancer cells in vitro by targeting VEGF-A. BMB Rep. 47:39–44. 2014. View Article : Google Scholar :
12	Zhong S, Li W, Chen Z, Xu J and Zhao J: MiR-222 and miR-29a contribute to the drug-resistance of breast cancer cells. Gene. 531:8–14. 2013. View Article : Google Scholar : PubMed/NCBI
13	Dontula R, Dinasarapu A, Chetty C, et al: MicroRNA 203 modulates glioma cell migration via Robo1/ERK/MMP-9 Signaling. Genes Cancer. 4:285–296. 2013. View Article : Google Scholar : PubMed/NCBI
14	Fabbri M, Calore F, Paone A, Galli R and Calin GA: Epigenetic regulation of miRNAs in cancer. Adv Exp Med Biol. 754:137–148. 2013. View Article : Google Scholar
15	Kapinas K, Kessler CB and Delany AM: miR-29 suppression of osteonectin in osteoblasts: Regulation during differentiation and by canonical Wnt signaling. J Cell Biochem. 108:216–224. 2009. View Article : Google Scholar : PubMed/NCBI
16	Wang XH, Hu Z, Klein JD, Zhang L, Fang F and Mitch WE: Decreased miR-29 suppresses myogenesis in CKD. J Am Soc Nephrol. 22:2068–2076. 2011. View Article : Google Scholar : PubMed/NCBI
17	Maurer B, Stanczyk J, Jüngel A, et al: MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 62:1733–1743. 2010. View Article : Google Scholar : PubMed/NCBI
18	Roncarati R, Viviani Anselmi C, Losi MA, et al: Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 63:920–927. 2014. View Article : Google Scholar
19	Ahluwalia JK, Khan SZ, Soni K, et al: Human cellular microRNA hsa-miR-29a interferes with viral nef protein expression and HIV-1 replication. Retrovirology. 5:1172008. View Article : Google Scholar : PubMed/NCBI
20	Peng H, Zhong M, Zhao W, et al: Urinary miR-29 correlates with albuminuria and carotid intima-media thickness in type 2 diabetes patients. PLoS One. 8:e826072013. View Article : Google Scholar : PubMed/NCBI
21	Shioya M, Obayashi S, Tabunoki H, et al: Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3. Neuropathol Appl Neurobiol. 36:320–330. 2010. View Article : Google Scholar : PubMed/NCBI
22	Cui Y, Su WY, Xing J, et al: MiR-29a inhibits cell proliferation and induces cell cycle arrest through the downregulation of p42.3 in human gastric cancer. PLoS One. 6:e258722011. View Article : Google Scholar : PubMed/NCBI
23	Fukui H, Zhang X, Sun C, et al: IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling. Br J Cancer. 111:763–771. 2014. View Article : Google Scholar : PubMed/NCBI
24	Do MT, Na M, Kim HG, et al: Ilimaquinone induces death receptor expression and sensitizes human colon cancer cells to TRAIL-induced apoptosis through activation of ROS-ERK/p38 MAPK-CHOP signaling pathways. Food Chem Toxicol. 71:51–59. 2014. View Article : Google Scholar : PubMed/NCBI
25	Yang Y, Zhao W, Xu QW, Wang XS, Zhang Y and Zhang J: IQGAP3 promotes EGFR-ERK signaling and the growth and metastasis of lung cancer cells. PLoS One. 9:e975782014. View Article : Google Scholar : PubMed/NCBI
26	Wu G, Qin XQ, Guo JJ, Li TY and Chen JH: AKT/ERK activation is associated with gastric cancer cell resistance to paclitaxel. Int J Clin Exp Pathol. 7:1449–1458. 2014.PubMed/NCBI
27	Guo N, Liu F, Yang L, Huang J, Ding X and Sun C: Chemokine receptor 7 enhances cell chemotaxis and migration of metastatic squamous cell carcinoma of head and neck through activation of matrix metalloproteinase-9. Oncol Rep. 32:794–800. 2014.PubMed/NCBI
28	Pal S, Moulik S, Dutta A and Chatterjee A: Extracellular matrix protein laminin induces matrix metalloproteinase-9 in human breast cancer cell line mcf-7. Cancer Microenviron. 7:71–78. 2014. View Article : Google Scholar : PubMed/NCBI
29	Chen J, Chen LJ, Zhou HC, et al: Prognostic value of matrix metalloproteinase-9 in gastric cancer: a meta-analysis. Hepatogastroenterology. 61:518–524. 2014.PubMed/NCBI