MicroRNA-508-5p suppresses metastasis in human gastric cancer by targeting S-phase kinase‑associated protein 2

Duan,Xiangguo; Bai,Jing; Wei,Jun; Li,Zhenhao; Liu,Xinlan; Xu,Guangxian

doi:10.3892/mmr.2017.6793

MicroRNA-508-5p suppresses metastasis in human gastric cancer by targeting S-phase kinase‑associated protein 2

Authors:
- Xiangguo Duan
- Jing Bai
- Jun Wei
- Zhenhao Li
- Xinlan Liu
- Guangxian Xu
View Affiliations

Affiliations: Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China, Department of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China, Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
Published online on: June 15, 2017 https://doi.org/10.3892/mmr.2017.6793
Pages: 2163-2171

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

S-phase kinase-associated protein 2 (SKP2), a potent oncogene was revealed to be upregulated in gastric cancer (GC) tissue samples, in which SKP2 was inversely correlated with microRNA (miR)‑508‑5p transcripts. In present study, the functional effect of miR‑508‑5p on SKP2 and its metastatic potential were investigated in SGC‑7901 GC cells. Significant downregulation of the miR‑508‑5p transcript was associated with the progression of GC. Furthermore, the overexpression of miR‑508‑5p was demonstrated to inhibit the proliferation, migration and invasion of SGC‑7901 cells, as well as induced cell apoptosis and cell cycle arrest at the G0/G1 phase in vitro. The overexpression of miR‑508‑5p was able to downregulate the expression of the SKP2 oncogene, through a mechanism by which miR‑508‑5p directly targeted the SKP2 gene. Thus, regulating transcriptional and post‑transcriptional SKP2 expression, as demonstrated using luciferase reporter assays, reverse transcription‑quantitative polymerase chain reaction analysis and immunoblotting assays. The results of the present study identified that miR‑508‑5p functionally affects the SKP2 gene and reduces metastatic potential in GC, suggesting a novel role of miR‑508‑5p in the regulation of SKP2 and cell cycle.

View Figures

View References

1	Yang L: Incidence and mortality of gastric cancer in China. World J Gastroenterol. 12:17–20. 2006. View Article : Google Scholar : PubMed/NCBI
2	Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, Huang HY, Tsai KK, Flores LG, Shao Y, et al: The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell. 149:1098–1111. 2012. View Article : Google Scholar : PubMed/NCBI
3	Pascal LE and Wang Z: Virtual drug design: Skp1-Skp2 inhibition targets cancer stem cells. Asian J Androl. 15:717–718. 2013. View Article : Google Scholar : PubMed/NCBI
4	Wang Z, Gao D, Fukushima H, Inuzuka H, Liu P, Wan L, Sarkar FH and Wei W: Skp2: A novel potential therapeutic target for prostate cancer. Biochim Biophys Acta. 1825:11–17. 2012.PubMed/NCBI
5	Sonoda H, Inoue H, Ogawa K, Utsunomiya T, Masuda TA and Mori M: Significance of skp2 expression in primary breast cancer. Clin Cancer Res. 12:1215–1220. 2006. View Article : Google Scholar : PubMed/NCBI
6	Ma XM, Liu Y, Guo JW, Liu JH and Zuo LF: Relation of overexpression of S phase kinase-associated protein 2 with reduced expression of p27 and PTEN in human gastric carcinoma. World J Gastroenterol. 11:6716–6721. 2005. View Article : Google Scholar : PubMed/NCBI
7	Zhang B, Ji LH, Liu W, Zhao G and Wu ZY: Skp2-RNAi suppresses proliferation and migration of gallbladder carcinoma cells by enhancing p27 expression. World J Gastroenterol. 19:4917–4924. 2013. View Article : Google Scholar : PubMed/NCBI
8	Wei Z, Jiang X, Liu F, Qiao H, Zhou B, Zhai B, Zhang L, Zhang X, Han L, Jiang H, et al: Downregulation of Skp2 inhibits the growth and metastasis of gastric cancer cells in vitro and in vivo. Tumor Biol. 34:181–192. 2013. View Article : Google Scholar
9	Tian YF, Chen TJ, Lin CY, Chen LT, Lin LC, Hsing CH, Lee SW, Sheu MJ, Lee HH, Shiue YL, et al: SKP2 overexpression is associated with a poor prognosis of rectal cancer treated with chemoradiotherapy and represents a therapeutic target with high potential. Tumour Biol. 34:1107–1117. 2013. View Article : Google Scholar : PubMed/NCBI
10	Lv A, Li Z, Tian X, Guan X, Zhao M, Dong B and Hao C: SKP2 high expression, KIT exon 11 deletions, and gastrointestinal bleeding as predictors of poor prognosis in primary gastrointestinal stromal tumors. PLoS One. 8:e62912013. View Article : Google Scholar
11	Manikandan J, Aarthi JJ, Kumar SD and Pushparaj PN: Oncomirs: The potential role of non-coding microRNAs in understanding cancer. Bioinformation. 2:330–334. 2008. View Article : Google Scholar : PubMed/NCBI
12	Gao M, Yin H and Fei ZW: Clinical application of microRNA in gastric cancer in Eastern Asian area. World J Gastroenterol. 19:2019–2027. 2013. View Article : Google Scholar : PubMed/NCBI
13	Zhao X, Li X and Yuan H: microRNAs in gastric cancer invasion and metastasis. Front Biosci (Landmark Ed). 18:803–810. 2013. View Article : Google Scholar : PubMed/NCBI
14	Li X, Zhang Y, Zhang H, Liu X, Gong T, Li M, Sun L, Ji G, Shi Y, Han Z, et al: miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3. Mol Cancer Res. 9:824–833. 2011. View Article : Google Scholar : PubMed/NCBI
15	Chen W, Tang Z, Sun Y, Zhang Y, Wang X, Shen Z, Liu F and Qin X: miRNA expression profile in primary gastric cancers and paired lymph node metastases indicates that miR-10a plays a role in metastasis from primary gastric cancer to lymph nodes. Exp Ther Med. 3:351–356. 2012.PubMed/NCBI
16	Zhao Y, Huang J, Zhang L, Qu Y, Li J, Yu B, Yan M, Yu Y, Liu B and Zhu Z: MiR-133b is frequently decreased in gastric cancer and its overexpression reduces the metastatic potential of gastric cancer cells. BMC Cancer. 14:342014. View Article : Google Scholar : PubMed/NCBI
17	Wei Z, Jiang X, Qiao H, Zhai B, Zhang L, Zhang Q, Wu Y, Jiang H and Sun X: STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cell Signal. 25:931–938. 2013. View Article : Google Scholar : PubMed/NCBI
18	Hung WC, Tseng WL, Shiea J and Chang HC: Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett. 288:156–161. 2010. View Article : Google Scholar : PubMed/NCBI
19	Tong F, Cao P, Yin Y, Xia S, Lai R and Liu S: MicroRNAs in gastric cancer: From benchtop to bedside. Dig Dis Sci. 59:24–30. 2014. View Article : Google Scholar : PubMed/NCBI
20	Tapias A, Ciudad CJ, Roninson IB and Noe V: Regulation of Sp1 by cell cycle related proteins. Cell Cycle. 7:2856–2867. 2008. View Article : Google Scholar : PubMed/NCBI
21	Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29:e452001. View Article : Google Scholar : PubMed/NCBI
22	Shang Y, Zhang Z, Liu Z, Feng B, Ren G, Li K, Zhou L, Sun Y, Li M, Zhou J, et al: miR-508-5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1. Oncogene. 33:3267–3276. 2014. View Article : Google Scholar : PubMed/NCBI
23	Wang Z, Wang J, Yang Y, Hao B, Wang R, Li Y and Wu Q: Loss of has-miR-337-3p expression is associated with lymph node metastasis of human gastric cancer. J Exp Clin Cancer Res. 32:762013. View Article : Google Scholar : PubMed/NCBI
24	Yan H, Wang S, Yu H, Zhu J and Chen C: Molecular pathways and functional analysis of miRNA expression associated with paclitaxel-induced apoptosis in hepatocellular carcinoma cells. Pharmacology. 92:167–174. 2013. View Article : Google Scholar : PubMed/NCBI
25	Lonjedo M, Poch E, Mocholí E, Hernández-Sánchez M, Ivorra C, Franke TF, Guasch RM and Pérez-Roger I: The Rho family member RhoE interacts with Skp2 and is degraded at the proteasome during cell cycle progression. J Biol Chem. 288:30872–30882. 2013. View Article : Google Scholar : PubMed/NCBI
26	Fukuchi M, Masuda N, Nakajima M, Fukai Y, Miyazaki T, Kato H and Kuwano H: Inverse correlation between expression levels of p27 and the ubiquitin ligase subunit Skp2 in early esophageal squamous cell carcinoma. Anticancer Res. 24:777–783. 2004.PubMed/NCBI
27	Harada K, Kawaguchi S Supriatno, Kawashima Y, Itashiki Y, Yoshida H and Sato M: High expression of S-phase kinase-associated protein 2 (Skp2) is a strong prognostic marker in oral squamous cell carcinoma patients treated by UFT in combination with radiation. Anticancer Res. 25:2471–2475. 2005.PubMed/NCBI
28	Wei S, Chu PC, Chuang HC, Hung WC, Kulp SK and Chen CS: Targeting the oncogenic E3 ligase Skp2 in prostate and breast cancer cells with a novel energy restriction-mimetic agent. PLoS One. 7:e472982012. View Article : Google Scholar : PubMed/NCBI
29	He W, Li Y, Chen X, Lu L, Tang B, Wang Z, Pan Y, Cai S, He Y and Ke Z: miR-494 acts as an anti-oncogene in gastric carcinoma by targeting c-myc. J Gastroenterol Hepatol. 29:1427–1434. 2014. View Article : Google Scholar : PubMed/NCBI
30	Liu T, Tang H, Lang Y, Liu M and Li X: MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. Cancer Lett. 273:233–242. 2009. View Article : Google Scholar : PubMed/NCBI
31	Takagi T, Iio A, Nakagawa Y, Naoe T, Tanigawa N and Akao Y: Decreased expression of microRNA-143 and −145 in human gastric cancers. Oncology. 77:12–21. 2009. View Article : Google Scholar : PubMed/NCBI
32	Yao Q, Cao Z, Tu C, Zhao Y, Liu H and Zhang S: MicroRNA-146a acts as a metastasis suppressor in gastric cancer by targeting WASF2. Cancer Lett. 335:219–224. 2013. View Article : Google Scholar : PubMed/NCBI
33	Sanchez N, Gallagher M, Lao N, Gallagher C, Clarke C, Doolan P, Aherne S, Blanco A, Meleady P, Clynes M and Barron N: MiR-7 triggers cell cycle arrest at the G1/S transition by targeting multiple genes including Skp2 and Psme3. PLoS One. 8:e656712013. View Article : Google Scholar : PubMed/NCBI
34	Qiang L, Hong L, Ningfu W, Huaihong C and Jing W: Expression of miR-126 and miR-508-5p in endothelial progenitor cells is associated with the prognosis of chronic heart failure patients. Int J Cardiol. 168:2082–2088. 2013. View Article : Google Scholar : PubMed/NCBI