Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Silencing of long non-coding RNA LINC01270 inhibits esophageal cancer progression and enhances chemosensitivity to 5-fluorouracil by mediating GSTP1methylation

Cancer Gene Therapy volume 28, pages 471–485 (2021)Cite this article

Subjects

A Correction to this article was published on 11 March 2022

This article has been updated

Abstract

Esophageal cancer (EC) is a serious digestive malignancy which remains the sixth leading cause of cancer-related deaths worldwide. Emerging evidence suggests the involvement of long non-coding RNAs (lncRNAs) in the tumorigenesis of EC and thus, in this study we explored the potential effects of lncRNA LINC01270 on EC cell proliferation, migration, invasion and, drug resistance via regulation of glutathione S-transferase P1 (GSTP1) methylation. First, we screened out the EC-related differentially expressed lncRNAs, and the expression of our top candidate LINC01270 was quantified in EC tissues and cells. To define the role of LINC01270 in EC progression, we evaluated the proliferation, migration and invasion of EC cells when the LINC01270 was overexpressed or knocked down, in the presence of the GSTP1 methylation inhibitor SGI-1027 and 5-fluorouracil (5-FU). In addition, interaction between LINC01270 and methylation of the GSTP1 promoter was identified. Finally, we assessed transplantable tumor growth in nude mice. LINC01270 was up-regulated and GSTP1 was down-regulated in EC tissues and cells. Silencing of LINC01270 inhibited migration and invasion, and enhanced the sensitivity of 5-FU in EC cells. We found that LINC01270 recruited the DNA methyltransferases DNMT1, DNMT3A and DNMT3B initiating GSTP1 promoter methylation, thereby leading to the proliferation, migration, invasion and drug resistance of EC cells. Moreover, GSTP1 overexpression was observed to reverse the effects of LINC01270 overexpression on EC cells and their response to 5-FU. Taken together, this study shows that inhibition of LINC01270 can lead to suppression of EC progression via demethylation of GSTP1, highlighting this lncRNA as a potential target for EC treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Abundant LINC01270 expression and poor GSTP1 expression in EC tissues.
Fig. 2: Downregulation of LINC01270 restricts EC cell proliferation, migration, and invasion.
Fig. 3: LINC01270 enhances methylation of GSTP1 promoter by recruiting DNA methyltransferase proteins.
Fig. 4: LINC01270 downregulation suppresses EC cell proliferation, migration, and invasion via GSTP1 upregulation.
Fig. 5: LINC01270 silencing inhibits tumorigenesis and enhances the sensitivity of EC cells to 5-FU.
Fig. 6: A mechanistic model for the role of LINC01270 in EC.

Similar content being viewed by others

Change history

References

  1. Malhotra GK, Yanala U, Ravipati A, Follet M, Vijayakumar M, Are C. Global trends in esophageal cancer. J Surg Oncol. 2017;115:564–579.

    Article  PubMed  Google Scholar 

  2. Domper Arnal MJ, Ferrandez Arenas A, Lanas Arbeloa A. Esophageal cancer: Risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol. 2015;21:7933–7943.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kidane B, Coughlin S, Vogt K, Malthaner R. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev. 2015. https://doi.org/10.1002/14651858.CD001556.pub3CD001556.

  4. Song S, Honjo S, Jin J, Chang SS, Scott AW, Chen Q, et al. The hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in esophageal cancer. Clin Cancer Res. 2015;21:2580–2590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ajani JA, Wang X, Song S, Suzuki A, Taketa T, Sudo K, et al. ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients. Mol Oncol. 2014;8:142–149.

    Article  CAS  PubMed  Google Scholar 

  6. Shi X, Sun M, Liu H, Yao Y, Song Y. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett. 2013;339:159–166.

    Article  CAS  PubMed  Google Scholar 

  7. Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer 2011;10:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li JY, Ma X, Zhang CB. Overexpression of long non-coding RNA UCA1 predicts a poor prognosis in patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7:7938–7944.

    PubMed  PubMed Central  Google Scholar 

  9. Chen FJ, Sun M, Li SQ, Wu QQ, Ji L, Liu ZL, et al. Upregulation of the long non-coding RNA HOTAIR promotes esophageal squamous cell carcinoma metastasis and poor prognosis. Mol Carcinog. 2013;52:908–915.

    Article  CAS  PubMed  Google Scholar 

  10. Tong YS, Wang XW, Zhou XL, Liu ZH, Yang TX, Shi WH, Xie HW, Lv J, Wu QQ, Cao XF. Identification of the long non-coding RNA POU3F3 in plasma as a novel biomarker for diagnosis of esophageal squamous cell carcinoma. Mol Cancer 2015;14:3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Su M, Xiao Y, Ma J, Cao D, Zhou Y, Wang H, et al. Long non-coding RNAs in esophageal cancer: molecular mechanisms, functions, and potential applications. J Hematol Oncol. 2018;11:118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Wang YZ, An Y, Li BQ, Lu J, Guo JC. Research progress on circularRNAs in pancreatic cancer: emerging but promising. Cancer Biol Ther 2019;20:1163–1171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Uchida Y, Chiyomaru T, Enokida H, Kawakami K, Tatarano S, Kawahara K, Nishiyama K, Seki N, Nakagawa M. MiR-133a induces apoptosis through direct regulation of GSTP1 in bladder cancer cell lines. Urol Oncol. 2013;31:115–123.

    Article  CAS  PubMed  Google Scholar 

  14. Sergentanis TN, Economopoulos KP. GSTT1 and GSTP1 polymorphisms and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010;121:195–202.

    Article  CAS  PubMed  Google Scholar 

  15. Liu WZ, Sun Y, Feng X, Bi XH, Liu T, Zhou HF. An updated meta-analysis for association of glutathione S-transferase P1 gene polymorphism with the susceptibility of lung cancer. J Cancer Res Ther. 2018;14:S1084–S1090.

    Article  CAS  PubMed  Google Scholar 

  16. Li QF, Yao RY, Liu KW, Lv HY, Jiang T, Liang J. Genetic polymorphism of GSTP1: prediction of clinical outcome to oxaliplatin/5-FU-based chemotherapy in advanced gastric cancer. J Korean Med Sci. 2010;25:846–852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xu Z, Zhu H, Luk JM, Wu D, Gu D, Gong W, et al. Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer. Cancer 2012;118:5489–5496.

    Article  CAS  PubMed  Google Scholar 

  18. Bhat A, Masood A, Wani KA, Bhat YA, Nissar B, Khan NS, et al. Promoter methylation and gene polymorphism are two independent events in regulation of GSTP1 gene expression. Tumour Biol. 2017;39:1010428317697563.

    PubMed  Google Scholar 

  19. Li Y, Cai Y, Chen H, Mao L. Clinical significance and association of GSTP1 hypermethylation with hepatocellular carcinoma: a meta-analysis. J Cancer Res Ther. 2018;14:S486–S489.

    Article  CAS  PubMed  Google Scholar 

  20. Pandey M, Shukla S, Gupta S. Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells. Int J Cancer 2010;126:2520–2533.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Li D, Dandara C, Parker MI. The 341C/T polymorphism in the GSTP1 gene is associated with increased risk of oesophageal cancer. BMC Genet. 2010;11:47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Song Y, Du Y, Zhou Q, Ma J, Yu J, Tao X, et al. Association of GSTP1 Ile105Val polymorphism with risk of esophageal cancer: a meta-analysis of 21 case-control studies. Int J Clin Exp Med. 2014;7:3215–3224.

    PubMed  PubMed Central  Google Scholar 

  23. Emerson JJ, Li WH. The genetic basis of evolutionary change in gene expression levels. Philos Trans R Soc Lond B Biol Sci. 2010;365:2581–2590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010;26:139–140.

    Article  CAS  PubMed  Google Scholar 

  25. Luo HC, Lin GS, Cheng HH, Fu ZC. A preliminary study on the consistency between the non-surgical staging and the surgical-pathological staging in oesophageal carcinoma. Interact Cardiovasc Thorac Surg. 2012;15:344–347.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lin MF, Jungreis I, Kellis M. PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions. Bioinformatics. 2011;27:i275–i282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Merry CR, Forrest ME, Sabers JN, Beard L, Gao XH, Hatzoglou M, et al. DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer. Hum Mol Genet. 2015;24:6240–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. D’Journo XB, Thomas PA. Current management of esophageal cancer. J Thorac Dis. 2014;6:S253–S264.

    PubMed  PubMed Central  Google Scholar 

  29. Jiao C, Song Z, Chen J, Zhong J, Cai W, Tian S, Chen S, Yi Y, Xiao Y. lncRNA-UCA1 enhances cell proliferation through functioning as a ceRNA of Sox4 in esophageal cancer. Oncol Rep. 2016;36:2960–2966.

    Article  CAS  PubMed  Google Scholar 

  30. Chen MJ, Deng J, Chen C, Hu W, Yuan YC, Xia ZK. LncRNA H19 promotes epithelial mesenchymal transition and metastasis of esophageal cancer via STAT3/EZH2 axis. Int J Biochem Cell Biol. 2019;113:27–36.

    Article  CAS  PubMed  Google Scholar 

  31. Pan Z, Mao W, Bao Y, Zhang M, Su X, Xu X. The long noncoding RNA CASC9 regulates migration and invasion in esophageal cancer. Cancer Med. 2016;5:2442–2447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li S, Xu Y, Sun Z, Feng L, Shang D, Zhang C, et al. Identification of a lncRNA involved functional module for esophageal cancer subtypes. Mol Biosyst. 2016;12:3312–3323.

    Article  CAS  PubMed  Google Scholar 

  33. Abraham JM, Meltzer SJ. Long noncoding RNAs in the pathogenesis of Barrett’s esophagus and esophageal carcinoma. Gastroenterology 2017;153:27–34.

    Article  CAS  PubMed  Google Scholar 

  34. Monnier P, Martinet C, Pontis J, Stancheva I, Ait-Si-Ali S, Dandolo L. H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1. Proc Natl Acad Sci USA. 2013;110:20693–20698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Holoch D, Moazed D. RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet 2015;16:71–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhu L, Xu PC. Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem Biophys Res Commun. 2013;432:612–617.

    Article  CAS  PubMed  Google Scholar 

  37. Sun W, Yang Y, Xu C, Guo J. Regulatory mechanisms of long noncoding RNAs on gene expression in cancers. Cancer Genet. 2017;216-217:105–110.

    Article  CAS  PubMed  Google Scholar 

  38. Suzuki H, Maruyama R, Yamamoto E, Kai M. DNA methylation and microRNA dysregulation in cancer. Mol Oncol. 2012;6:567–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bell A, Bell D, Weber RS, El-Naggar AK. CpG island methylation profiling in human salivary gland adenoid cystic carcinoma. Cancer 2011;117:2898–2909.

    Article  CAS  PubMed  Google Scholar 

  40. Cui X, Zhao Z, Liu D, Guo T, Li S, Hu J, et al. Inactivation of miR-34a by aberrant CpG methylation in Kazakh patients with esophageal carcinoma. J Exp Clin Cancer Res. 2014;33:20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zovoilis A, Agbemenyah HY, Agis-Balboa RC, Stilling RM, Edbauer D, Rao P, et al. microRNA-34c is a novel target to treat dementias. EMBO J. 2011;30:4299–4308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kaz AM, Grady WM. Epigenetic biomarkers in esophageal cancer. Cancer Lett. 2014;342:193–199.

    Article  CAS  PubMed  Google Scholar 

  43. Mutallip M, Nohata N, Hanazawa T, Kikkawa N, Horiguchi S, Fujimura L, et al. Glutathione S-transferase P1 (GSTP1) suppresses cell apoptosis and its regulation by miR-133alpha in head and neck squamous cell carcinoma (HNSCC). Int J Mol Med. 2011;27:345–352.

    CAS  PubMed  Google Scholar 

  44. Louie SM, Grossman EA, Crawford LA, Ding L, Camarda R, Huffman TR, Miyamoto DK, Goga A, Weerapana E, Nomura DK. GSTP1 is a driver of triple-negative breast cancer cell metabolism and pathogenicity. Cell Chem Biol. 2016;23:567–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Miyake T, Nakayama T, Naoi Y, Yamamoto N, Otani Y, Kim SJ, et al. GSTP1 expression predicts poor pathological complete response to neoadjuvant chemotherapy in ER-negative breast cancer. Cancer Sci. 2012;103:913–920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhu ZQ, Zhu ZA, Cai HX. Continuous infusion of a large dose of CF (folinic acid) and 5-FU combined with CDDP in the treatment of advanced esophageal cancer. Int J Clin Pharm Ther. 2017;55:397–402.

    Article  CAS  Google Scholar 

  47. Bian Z, Jin L, Zhang J, Yin Y, Quan C, Hu Y, et al. LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p. Sci Rep. 2016;6:23892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chiam K, Centenera MM, Butler LM, Tilley WD, Bianco-Miotto T. GSTP1 DNA methylation and expression status is indicative of 5-aza-2′-deoxycytidine efficacy in human prostate cancer cells. PLoS ONE 2011;6:e25634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Singh S, Okamura T, Ali-Osman F. Serine phosphorylation of glutathione S-transferase P1 (GSTP1) by PKCalpha enhances GSTP1-dependent cisplatin metabolism and resistance in human glioma cells. Biochem Pharmacol. 2010;80:1343–1355.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang X, Zhu J, Xing R, Tie Y, Fu H, Zheng X, et al. miR-513a-3p sensitizes human lung adenocarcinoma cells to chemotherapy by targeting GSTP1. Lung Cancer 2012;77:488–494.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge our colleagues for their helpful comments on this paper.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, P.R. China

    Nuo Li, Zhifeng Zhao, Feng Miao, Shuang Cai, Pengliang Liu & Yang Yu

  2. Department of Intervention, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, P.R. China

    Baoming Wang

Authors
  1. Nuo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhifeng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuang Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pengliang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Baoming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design of research: N.L., Y.Y.; performed experiments: Z.F.Z., F.M., S.C.; analyzed data: Y.Y., B.M.W.; interpreted results of experiments: Z.F.Z., F.M.; prepared figures: N.L., P.L.L.; drafted paper: N.L., Y.Y., B.M.W.; Edited and revised paper: Z.F.Z., S.C., P.L.L.; approved final version of paper: N.L., Z.F.Z., F.M., S.C., P.L.L., Y.Y., B.M.W.

Corresponding author

Correspondence to Baoming Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

All patients have signed written informed consent prior to enrollment. The study was approved by the Ethics Committee of the Fourth Affiliated Hospital of China Medical University and carried out in accordance with the Declaration of Helsinki. Animal experiments were performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. The protocol was approved by the Institutional Animal Care and Use Committee of the Fourth Affiliated Hospital of China Medical University.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, N., Zhao, Z., Miao, F. et al. Silencing of long non-coding RNA LINC01270 inhibits esophageal cancer progression and enhances chemosensitivity to 5-fluorouracil by mediating GSTP1methylation. Cancer Gene Ther 28, 471–485 (2021). https://doi.org/10.1038/s41417-020-00232-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-020-00232-1

This article is cited by

Search

Advanced search

Quick links