Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

LINC01232 Promotes Gastric Cancer Proliferation through Interacting with EZH2 to Inhibit the Transcription of KLF2

  • Liu, Jing (Department of Pathology, Yantai Yuhuangding Hospital) ;
  • Li, Zhen (Department of General and Pediatric Surgery, Yantai Yuhuangding Hospital) ;
  • Yu, Guohua (Department of Pathology, Yantai Yuhuangding Hospital) ;
  • Wang, Ting (Department of Pathology, Yantai Yuhuangding Hospital) ;
  • Qu, Guimei (Department of Pathology, Yantai Yuhuangding Hospital) ;
  • Wang, Yunhui (Department of General and Pediatric Surgery, Yantai Yuhuangding Hospital)
  • Received : 2021.06.15
  • Accepted : 2021.08.17
  • Published : 2021.10.28
Download PDF
⟨ Previous Next ⟩

Abstract

To clarify the role of long intergenic nonprotein-coding RNA 1232 (LINC01232) in the progression of gastric cancer and the potential mechanism, we analyzed the expression of LINC01232 in TCGA database using the GEPIA online tool, and the LINC01232 level in gastric cancer cell lines was detected by quantitative real time-polymerase chain reaction (qRT-PCR) as well. Cell proliferation assay, colony formation assay, transwell assay and tumor formation experiment in nude mice were conducted to observe the biological behavior changes of gastric cancer cells through the influence of LINC01232 knockdown. LncATLAS database and subcellular isolation assay were used for subcellular distribution of LINC01232 in gastric cancer cells. The interaction among LINC01232, zeste homolog 2 (EZH2) and kruppel-like factor 2 (KLF2) was clarified by RNA-protein interaction prediction (RPISeq), RNA immunoprecipitation (RIP), qRT-PCR and chromatin immunoprecipitation (ChIP) assay. Rescue experiments were further conducted to elucidate the biological function of LINC01232/KLF2 axis in the progression of gastric cancer. LINC01232 was upregulated in stomach adenocarcinoma (STAD) tissues and gastric cancer lines. LINC01232 knockdown inhibited the proliferative capacities of gastric cancer cells in vitro, and impaired in vivo tumorigenicity. LINC01232 was mainly distributed in the cell nucleus where it epigenetically repressed KLF2 expression via binding to the enhancer of EZH2, which was capable of binding to promoter regions of KLF2 to induce histone H3 lysine 27 trimethylation (H3K27me3). LINC01232 exerts oncogenic activities in gastric cancer via inhibition of KLF2, and therefore, the knockdown of KLF2 could reverse the regulatory effect of LINC01232 in the proliferative ability of gastric cancer cells.

Keywords

References

  1. Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. 2020. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int. J. Mol. Sci. 21: 4012. https://doi.org/10.3390/ijms21114012
  2. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. 2014. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer. Epidemiol. Biomarkers Prev. 23: 700-713. https://doi.org/10.1158/1055-9965.EPI-13-1057
  3. Johnston FM, Beckman M.2019. Updates on management of gastric cancer. Curr. Oncol. Rep. 21: 67. https://doi.org/10.1007/s11912-019-0820-4
  4. Ransohoff JD, Wei Y, Khavari PA. 2018. The functions and unique features of long intergenic non-coding RNA. Nat. Rev. Mol. Cell Biol. 19: 143-157. https://doi.org/10.1038/nrm.2017.104
  5. Sun Y, Ma L. 2019. New insights into long non-coding RNA MALAT1 in cancer and metastasis. Cancers (Basel) 11: 216. https://doi.org/10.3390/cancers11020216
  6. Sarfi M, Abbastabar M, Khalili E. 2019. Long noncoding RNAs biomarker-based cancer assessment. J. Cell. Physiol. 234: 16971-16986. https://doi.org/10.1002/jcp.28417
  7. Meng Q, Li Z, Pan J, Sun X. 2020. Long noncoding RNA DUXAP8 regulates proliferation and apoptosis of ovarian cancer cells via targeting miR-590-5p. Hum. Cell 33: 1240-1251.
  8. Zhao M, Cui H, Zhao B, Li M, Man H. 2020. Long intergenic non-coding RNA LINC01232 contributes to esophageal squamous cell carcinoma progression by sequestering microRNA-654-3p and consequently promoting hepatoma-derived growth factor expression. Int. J. Mol. Med. 46: 2007-2018. https://doi.org/10.3892/ijmm.2020.4750
  9. Du W, Lei C, Wang Y, Ding Y, Tian P. 2021. LINC01232 Sponges multiple miRNAs and its clinical significance in pancreatic adenocarcinoma diagnosis and prognosis. Technol. Cancer Res. Treat. 20: 1533033820988525.
  10. Laha D, Deb M, Das H. 2019. KLF2 (kruppel-like factor 2 [lung]) regulates osteoclastogenesis by modulating autophagy. Autophagy 15: 2063-2075. https://doi.org/10.1080/15548627.2019.1596491
  11. Sindi HA, Russomanno G, Satta S, Abdul-Salam VB, Jo KB, Qazi-Chaudhry B, et al. 2020. Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension. Nat. Commun. 11: 1185. https://doi.org/10.1038/s41467-020-14966-x
  12. Li Q, Lei C, Lu C, Wang J, Gao M, Gao W. 2019. LINC01232 exerts oncogenic activities in pancreatic adenocarcinoma via regulation of TM9SF2. Cell Death Dis. 10: 698. https://doi.org/10.1038/s41419-019-1896-3
  13. Li Z, Guo X, Wu S. 2020. Epigenetic silencing of KLF2 by long non-coding RNA SNHG1 inhibits periodontal ligament stem cell osteogenesis differentiation. Stem. Cell Res. Ther. 11: 435. https://doi.org/10.1186/s13287-020-01953-8
  14. Lian W, Jiang X, Li L, Wang Q, Hong C, Yang P, Chen D. 2020. Upregulated long non-coding RNA LL22NC03-N64E9.1 promotes the proliferation and migration of human breast cancer cells by silencing Kruppel-like factor 2 expression. Cancer Manag. Res. 12: 10763-10770. https://doi.org/10.2147/CMAR.S268725
  15. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. 2020. Gastric cancer. Lancet 396: 635-648. https://doi.org/10.1016/s0140-6736(20)31288-5
  16. Correa P. 2013. Gastric cancer: overview. Gastroenterol. Clin. North Am. 42: 211-217. https://doi.org/10.1016/j.gtc.2013.01.002
  17. Rui X, Xu Y, Huang Y, Ji L, Jiang X. 2018. lncRNA DLG1-AS1 promotes cell proliferation by competitively binding with miR-107 and up-regulating ZHX1 expression in cervical cancer. Cell. Physiol. Biochem. 49: 1792-1803. https://doi.org/10.1159/000493625
  18. Dong J, Wang Q, Li L, Xiao-Jin Z. 2018. Upregulation of long non-coding RNA small nucleolar RNA host gene 12 contributes to cell growth and invasion in cervical cancer by acting as a sponge for MiR-424-5p. Cell. Physiol. Biochem. 45: 2086-2094 https://doi.org/10.1159/000488045
  19. Bhan A, Soleimani M, Mandal SS. 2017. Long noncoding RNA and cancer: A new paradigm. Cancer Res. 77: 3965-3981. https://doi.org/10.1158/0008-5472.CAN-16-2634
  20. Lim LJ, Wong SYS, Huang F, Lim S, Chong SS, Ooi LL, et al. 2019. Roles and regulation of long noncoding RNAs in hepatocellular carcinoma. Cancer Res. 79: 5131-5139. https://doi.org/10.1158/0008-5472.can-19-0255
  21. Ou M, Li X, Zhao S, Cui S, Tu J. 2020. Long non-coding RNA CDKN2B-AS1 contributes to atherosclerotic plaque formation by forming RNA-DNA triplex in the CDKN2B promoter. EBioMedicine 55: 102694. https://doi.org/10.1016/j.ebiom.2020.102694
  22. Lv L, He L, Chen S, Yu Y, Che G, Tao X, et al. 2019. Long non-coding RNA LINC00114 facilitates colorectal cancer development through EZH2/DNMT1-induced miR-133b suppression. Front. Oncol. 9: 1383. https://doi.org/10.3389/fonc.2019.01383
  23. Li Z, Guo X, Wu S. 2020. Epigenetic silencing of KLF2 by long non-coding RNA SNHG1 inhibits periodontal ligament stem cell osteogenesis differentiation. Stem. Cell Res. Ther. 11: 435. https://doi.org/10.1186/s13287-020-01953-8
  24. Novodvorsky P, Chico TJ. 2014. The role of the transcription factor KLF2 in vascular development and disease. Prog. Mol. Biol. Transl. Sci. 124: 155-188. https://doi.org/10.1016/B978-0-12-386930-2.00007-0