Journal of Gastric Cancer

The Korean Gastric Cancer Association (대한위암학회)
권호 표지
DOI QR코드

DOI QR Code

LINC00703 Acts as a Tumor Suppressor via Regulating miR-181a/KLF6 Axis in Gastric Cancer

  • Yang, Haiyang (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences) ;
  • Peng, Minqi (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences) ;
  • Li, Yanjiao (Department of Pathophysiology, Shenzhen University) ;
  • Zhu, Renjie (East Hospital Affiliated to Tongji University) ;
  • Li, Xiang (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences) ;
  • Qian, Zhengjiang (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences)
  • Received : 2019.09.19
  • Accepted : 2019.11.25
  • Published : 2019.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: Long noncoding RNA 00703 (LINC00703) was found originating from a region downstream of Kruppel-like factor 6 (KLF6) gene, having 2 binding sites for miR-181a. Since KLF6 has been reported as a target of miR-181a in gastric cancer (GC), this study aims to investigate whether LINC00703 regulates the miR-181a/KLF6 axis and plays a functional role in GC pathogenesis. Materials and Methods: GC tissues, cell lines, and nude mice were included in this study. RNA binding protein immunoprecipitation (RIP) and pull-down assays were used to evaluate interaction between LINC00703 and miR-181a. Quantitative real-time polymerase chain reaction and western blot were applied for analysis of gene expression at the transcriptional and protein levels. A nude xenograft mouse model was used to determine LINC00703 function in vivo. Results: We revealed that LINC00703 competitively interacts with miR-181a to regulate KLF6. Overexpression of LINC00703 inhibited cell proliferation, migration/invasion, but promoted apoptosis in vitro, and arrested tumor growth in vivo. LINC00703 expression was found to be decreased in GC tissues, which was positively correlated with KLF6, but negatively with the miR-181a levels. Conclusions: LINC00703 may have an anti-cancer function via modulation of the miR-181a/KLF6 axis. This study also provides a new potential diagnostic marker and therapeutic target for GC treatment.

Keywords

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30. https://doi.org/10.3322/caac.21332
  2. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006;12:354-362. https://doi.org/10.3748/wjg.v12.i3.354
  3. Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet 2009;374:477-490. https://doi.org/10.1016/S0140-6736(09)60617-6
  4. Matsunaga N, Wakasaki T, Yasumatsu R, Kotake Y. Long noncoding RNA, ANRIL, regulates the proliferation of head and neck squamous cell carcinoma. Anticancer Res 2019;39:4073-4077. https://doi.org/10.21873/anticanres.13564
  5. Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell 2009;136:629-641. https://doi.org/10.1016/j.cell.2009.02.006
  6. Arita T, Ichikawa D, Konishi H, Komatsu S, Shiozaki A, Shoda K, et al. Circulating long non-coding RNAs in plasma of patients with gastric cancer. Anticancer Res 2013;33:3185-3193.
  7. Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 2009;23:1494-1504. https://doi.org/10.1101/gad.1800909
  8. Ergun S, Oztuzcu S. Oncocers: ceRNA-mediated cross-talk by sponging miRNAs in oncogenic pathways. Tumour Biol 2015;36:3129-3136. https://doi.org/10.1007/s13277-015-3346-x
  9. Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 2011;147:358-369. https://doi.org/10.1016/j.cell.2011.09.028
  10. Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer 2014;13:92. https://doi.org/10.1186/1476-4598-13-92
  11. Yan J, Dang Y, Liu S, Zhang Y, Zhang G. LncRNA HOTAIR promotes cisplatin resistance in gastric cancer by targeting miR-126 to activate the PI3K/AKT/MRP1 genes. Tumour Biol 2016;37:16345-16355. https://doi.org/10.1007/s13277-016-5448-5
  12. Song B, Guan Z, Liu F, Sun D, Wang K, Qu H. Long non-coding RNA HOTAIR promotes HLA-G expression via inhibiting miR-152 in gastric cancer cells. Biochem Biophys Res Commun 2015;464:807-813. https://doi.org/10.1016/j.bbrc.2015.07.040
  13. Peng W, Si S, Zhang Q, Li C, Zhao F, Wang F, et al. Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate gastric cancer progression. J Exp Clin Cancer Res 2015;34:79. https://doi.org/10.1186/s13046-015-0197-7
  14. McConnell BB, Yang VW. Mammalian Krüppel-like factors in health and diseases. Physiol Rev 2010;90:1337-1381. https://doi.org/10.1152/physrev.00058.2009
  15. Sangodkar J, Shi J, DiFeo A, Schwartz R, Bromberg R, Choudhri A, et al. Functional role of the KLF6 tumour suppressor gene in gastric cancer. Eur J Cancer 2009;45:666-676. https://doi.org/10.1016/j.ejca.2008.11.009
  16. Cho YG, Kim CJ, Park CH, Yang YM, Kim SY, Nam SW, et al. Genetic alterations of the KLF6 gene in gastric cancer. Oncogene 2005;24:4588-4590. https://doi.org/10.1038/sj.onc.1208670
  17. Bi J, Zeng X, Zhao L, Wei Q, Yu L, Wang X, et al. miR-181a induces macrophage polarized to M2 phenotype and promotes M2 macrophage-mediated tumor cell metastasis by targeting KLF6 and C/$EBP{\alpha}$. Mol Ther Nucleic Acids 2016;5:e368. https://doi.org/10.1038/mtna.2016.71
  18. Lei Z, Ma X, Li H, Zhang Y, Gao Y, Fan Y, et al. Up-regulation of miR-181a in clear cell renal cell carcinoma is associated with lower KLF6 expression, enhanced cell proliferation, accelerated cell cycle transition, and diminished apoptosis. Urol Oncol 2018;36:93.e23-93.e37. https://doi.org/10.1016/j.urolonc.2017.09.019
  19. Zhang X, Nie Y, Du Y, Cao J, Shen B, Li Y. MicroRNA-181a promotes gastric cancer by negatively regulating tumor suppressor KLF6. Tumour Biol 2012;33:1589-1597. https://doi.org/10.1007/s13277-012-0414-3
  20. Liu H, Li J, Koirala P, Ding X, Chen B, Wang Y, et al. Long non-coding RNAs as prognostic markers in human breast cancer. Oncotarget 2016;7:20584-20596. https://doi.org/10.18632/oncotarget.7828
  21. Qian Z, Li Y, Yang H, Chen J, Li X, Gou D. PDGFBB promotes proliferation and migration via regulating miR-1181/STAT3 axis in human pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2018;315:L965-L976. https://doi.org/10.1152/ajplung.00224.2018
  22. Li Y, Li L, Qian Z, Lin B, Chen J, Luo Y, et al. Phosphatidylinositol 3-kinase-DNA methyltransferase 1-miR-1281-histone deacetylase 4 regulatory axis mediates platelet-derived growth factor-induced proliferation and migration of pulmonary artery smooth muscle cells. J Am Heart Assoc 2018;7:e007572. https://doi.org/10.1161/JAHA.117.007572
  23. Qian Z, Li Y, Chen J, Li X, Gou D. miR-4632 mediates PDGF-BB-induced proliferation and antiapoptosis of human pulmonary artery smooth muscle cells via targeting cJUN. Am J Physiol Cell Physiol 2017;313:C380-C391. https://doi.org/10.1152/ajpcell.00061.2017
  24. Ma J, Yao Y, Wang P, Liu Y, Zhao L, Li Z, et al. MiR-181a regulates blood-tumor barrier permeability by targeting Kruppel-like factor 6. J Cereb Blood Flow Metab 2014;34:1826-1836. https://doi.org/10.1038/jcbfm.2014.152
  25. Zhao L, Han T, Li Y, Sun J, Zhang S, Liu Y, et al. The lncRNA SNHG5/miR-32 axis regulates gastric cancer cell proliferation and migration by targeting KLF4. FASEB J 2017;31:893-903. https://doi.org/10.1096/fj.201600994R
  26. Zhao H, Peng R, Liu Q, Liu D, Du P, Yuan J, et al. The lncRNA H19 interacts with miR-140 to modulate glioma growth by targeting iASPP. Arch Biochem Biophys 2016;610:1-7. https://doi.org/10.1016/j.abb.2016.09.014
  27. Wang SH, Wu XC, Zhang MD, Weng MZ, Zhou D, Quan ZW. Long noncoding RNA H19 contributes to gallbladder cancer cell proliferation by modulated miR-194-5p targeting AKT2. Tumour Biol 2016;37:9721-9730. https://doi.org/10.1007/s13277-016-4852-1
  28. Sun L, Sun P, Zhou QY, Gao X, Han Q. Long noncoding RNA MALAT1 promotes uveal melanoma cell growth and invasion by silencing of miR-140. Am J Transl Res 2016;8:3939-3946.
  29. Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 2011;472:120-124. https://doi.org/10.1038/nature09819
  30. Guil S, Esteller M. Cis-acting noncoding RNAs: friends and foes. Nat Struct Mol Biol 2012;19:1068-1075. https://doi.org/10.1038/nsmb.2428
  31. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell 2011;43:904-914. https://doi.org/10.1016/j.molcel.2011.08.018
  32. Wei Y, Sun Q, Zhao L, Wu J, Chen X, Wang Y, et al. LncRNA UCA1-miR-507-FOXM1 axis is involved in cell proliferation, invasion and G0/G1 cell cycle arrest in melanoma. Med Oncol 2016;33:88. https://doi.org/10.1007/s12032-016-0804-2

Cited by

  1. Long Noncoding RNA LINC00173 Promotes NUTF2 Expression Through Sponging miR-765 and Facilitates Tumorigenesis in Glioma vol.12, 2019, https://doi.org/10.2147/cmar.s262279
  2. mir‐22‐3p/KLF6/MMP14 axis in fibro‐adipogenic progenitors regulates fatty infiltration in muscle degeneration vol.34, pp.9, 2019, https://doi.org/10.1096/fj.202000506r