Upregulated miRNA-622 inhibited cell proliferation, motility, and invasion via repressing Kirsten rat sarcoma in glioblastoma
- 222 Downloads
Glioblastoma has been reported as one of the leading causes of cancer-related death, and some factors including oncogenic genes and environments are involved in tumorigenesis. MicroRNAs (miRNAs) act as a kind of small and noncoding RNA, which can target the downstream molecules. Emerging reports demonstrate that microRNAs regulate the initiation and progression of different cancers. In the present study, we conducted in vitro experiment as well as clinical studies in a cohort of 20 glioblastoma samples. We demonstrated that miR-622 expression was lower in tumor tissues and cells, when compared to normal brain tissues and normal human astrocyte (NHA) cells, while K-Ras messenger RNA (mRNA) and protein showed the opposite expression profile. Overexpression of miR-622 suppressed tumor cell proliferation, migration, and invasion of A172, U87, and U251 cells. Accordingly, the proliferating cell nuclear antigen (PCNA), matrix metallopeptidase 2 (MMP2), and MMP9 expressions were also decreased due to miR-622 overexpression. Importantly, we discovered that wild Kirsten rat sarcoma (K-Ras) was a direct target of miR-622, which decreased the expression of K-Ras protein in A172, U87, and U251 cells. In conclusion, upregulated miRNA-622 inhibited cell proliferation, migration, and invasion via repressing K-Ras in the progression of glioblastoma, and miR-622-K-Ras pathway can be recommended as a potential target for treatment of glioblastoma.
KeywordsmiR-622 K-Ras Glioblastoma Biology
Xinzhi Wang and Zhenxue Xin conceived and designed the experiments. Zhenxue Xin and Yinfu Xu, performed the experiments. Yinfu Xu and Jinbang Ma analyzed the data. Jinbang Ma contributed reagents/materials/analysis tools and wrote the paper.
Compliance with ethical standards
Conflicts of interest
- 2.Yao C, Lv S, Han M, Zhang J, Zhang Y, Zhang L, et al. The association of Crk-like adapter protein with poor prognosis in glioma patients. Tumour Biol. 2014;35(6):5695–700.Google Scholar
- 3.Liao A, Shi R, Jiang Y, Tian S, Li P, Song F, et al. SDF-1/CXCR4 axis regulates cell cycle progression and epithelial-mesenchymal transition via up-regulation of survivin in glioblastoma. Mol Neurobiol. 2014. doi: 10.1007/s12035-014-9006-0.
- 4.Lv B, Yang X, Lv S, Wang L, Fan K, Shi R, et al. CXCR4 signaling induced epithelial-mesenchymal transition by PI3K/AKT and ERK pathways in glioblastoma. Mol Neurobiol. 2015;52(3):1263–8.Google Scholar
- 5.Altieri R, Fontanella M, Agnoletti A, Panciani PP, Spena G, Crobeddu E, et al. Role of nitric oxide in glioblastoma therapy: another step to resolve the terrible puzzle? Transl Med UniSa. 2014;12:54–9.Google Scholar
- 6.De Paepe A, Vandeneede N, Strens D, Specenier P. The economics of the treatment and follow-up of patients with glioblastoma. Value Health. 2015;18(7):A448.Google Scholar
- 9.Luna-Aguirre CM, de la Luz Martinez-Fierro M, Mar-Aguilar F, Garza-Veloz I, Treviño-Alvarado V, Rojas-Martinez A, et al. Circulating microRNA expression profile in B-cell acute lymphoblastic leukemia. Cancer Biomark. 2015;15(3):299–310.Google Scholar
- 10.Sampson VB, Yoo S, Kumar A, Vetter NS, Kolb EA. MicroRNAs and potential targets in osteosarcoma: review. Front Pediatr. 2015;3:69.Google Scholar
- 12.Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433(7027):769–73.Google Scholar
- 13.Han Z, Yang Q, Liu B, Wu J, Li Y, Yang C, et al. MicroRNA-622 functions as a tumor suppressor by targeting K-Ras and enhancing the anticarcinogenic effect of resveratrol. Carcinogenesis. 2012;33:131–9.Google Scholar
- 14.Guo XB, Jing CQ, Li LP, Zhang L, Shi YL, Wang JS, et al. Down-regulation of miR-622 in gastric cancer promotes cellular invasion and tumor metastasis by targeting ING1 gene. World J Gastroenterol. 2011;17:1895–902.Google Scholar
- 17.Schramm K, Krause K, Bittroff-Leben A, Goldin-Lang P, Thiel E, Kreuser ED, et al. Activated K-ras is involved in regulation of integrin expression in human colon carcinoma cells. Int J Cancer. 2000;87(2):155–64.Google Scholar
- 18.Schultz NA, Werner J, Willenbrock H, Roslind A, Giese N, Horn T, et al. MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma. Mod Pathol. 2012;25(12):1609–22.Google Scholar
- 19.Celis JE, Madsen P, Nielsen S, Celis A, Nuclear patterns of cyclin (PCNA) antigen distribution subdivide S-phase in cultured cells-some applications of PCNA antibodies. Leuk Res. 1986;10:237–349.Google Scholar
- 20.Li J, Li H, Liu J, Feng B, Feng M, Lv B, et al. The clinical implications of human telomerase reverse transcriptase expression in grade and prognosis of gliomas: a systematic review and meta-analysis. Mol Neurobiol. 2015. doi: 10.1007/s12035-015-9170-x.
- 21.Yang X, Lv S, Liu Y, Li D, Shi R, Tang Z, et al. The clinical utility of matrix metalloproteinase 9 in evaluating pathological grade and prognosis of glioma patients: a meta-analysis. Mol Neurobiol. 2015;52(1):38–44.Google Scholar
- 22.Kumar B, Koul S, Petersen J, Khandrika L, Hwa JS, Meacham RB, et al. p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res. 2010;70(2):832–41.Google Scholar
- 23.Chen W, Zhong X, Wei Y, Liu Y, Yi Q, Zhang G, et al. TGF-β regulates survivin to affect cell cycle and the expression of EGFR and MMP9 in glioblastoma. Mol Neurobiol. 2015. doi: 10.1007/s12035-015-9121-6.
- 24.Choe G, Park JK, Jouben-Steele L, Kremen TJ, Liau LM, Vinters HV, et al. Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype. Clin Cancer Res. 2002;8(9):2894–901.Google Scholar
- 25.Yao C, Li P, Song H, Song F, Qu Y, Ma X, et al. CXCL12/CXCR4 axis upregulates twist to induce EMT in human glioblastoma. Mol Neurobiol. 2015. doi: 10.1007/s12035-015-9340-x.