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:

Long noncoding RNA LINC00173 induces radioresistance in nasopharyngeal carcinoma via inhibiting CHK2/P53 pathway

Cancer Gene Therapy volume 30, pages 1249–1259 (2023)Cite this article

Subjects

Abstract

Radiotherapy is the backbone of nasopharyngeal carcinoma (NPC), nearly 11–17% NPC patients suffered local relapse and 18–37% suffered distant metastasis mainly due to radioresistance. Therefore, the key of improving patients’ survivals is to investigate the mechanism of radioresistance. In this study, we revealed that the expression level of long intergenic nonprotein coding RNA 173 (LINC00173) was significantly increased in the radioresistant NPC patients’ tumour tissues compared with the radiosensitive patients by RNA-sequencing, which also predict poor prognosis in NPC. Overexpression of LINC00173 induced radioresistance of NPC cells in vitro and in vivo. Mechanistically, LINC00173 bound with checkpoint kinase 2 (CHK2) in nucleus, and impaired the irradiation-induced CHK2 phosphorylation, then suppressed the activation of P53 signalling pathway, which eventually inhibiting apoptosis and leading to radioresistance in NPC cells. In summary, LINC00173 decreases the occurrence of apoptosis through inhibiting the CHK2/P53 pathway, leads to NPC radioresistance and could be considered as a novel predictor and therapeutic target in NPC.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: LINC00173 was upregulated in radioresistant NPC tissues and cell lines.
Fig. 2: LINC00173 induced radioresistance of NPC in vitro.
Fig. 3: LINC00173 induced radioresistance of NPC in vivo.
Fig. 4: LINC00173 interacted directly with CHK2.
Fig. 5: LINC00173 inhibited apoptosis via ATM/CHK2/P53 signalling pathway in NPC.
Fig. 6: Model of LINC00173 inducing radioresistance via inhibiting CHK2/P53 signalling pathway in NPC.

Similar content being viewed by others

Data availability

The RNA-seq data will be deposited in the National Centre for Biotechnology Information Sequence Read Archive database. Data described in the manuscript, code book, and analytic code will be made available upon request pending application and approval.

References

  1. Wei KR, Zheng RS, Zhang SW, Liang ZH, Li ZM, Chen WQ. Nasopharyngeal carcinoma incidence and mortality in China, 2013. Chin J Cancer. 2017;36:90.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  3. Su SF, Han F, Zhao C, Huang Y, Chen CY, Xiao WW, et al. Treatment outcomes for different subgroups of nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy. Chin J Cancer. 2011;30:565–73.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wu F, Wang RS, Lu HM, Wei B, Feng GS, Li GS, et al. Concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma treatment outcomes of a prospective, multicentric clinical study. Radiother Oncol. 2014;112:106–11.

    Article  PubMed  Google Scholar 

  5. Ou XM, Zhou X, Shi Q, Xing X, Yang YQ, Xu TT, et al. Treatment outcomes and late toxicities of 869 patients with nasopharyngeal carcinoma treated with definitive intensity modulated radiation therapy: new insight into the value of total dose of cisplatin and radiation boost. Oncotarget. 2015;6:38381–97.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lee AW, Ng WT, Chan LL, Hung WM, Chan CC, Sze HC, et al. Evolution of treatment for nasopharyngeal cancer–success and setback in the intensity-modulated radiotherapy era. Radiother Oncol. 2014;110:377–84.

    Article  PubMed  Google Scholar 

  7. Miao JJ, Di MP, Chen BY, Wang L, Cao YQ, Xiao WW, et al. A prospective 10-year observational study of reduction of radiotherapy clinical target volume and dose in early-stage nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2020;107:672–82.

    Article  PubMed  Google Scholar 

  8. Wang L, Miao JJ, Huang HG, Chen BY, Xiao X, Zhu MY, et al. Long-term survivals, toxicities and the role of chemotherapy in early-stage nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy: a retrospective study with 15-year follow-up. Cancer Res Treat. 2022;54:118–29.

    Article  CAS  PubMed  Google Scholar 

  9. Zhan Y, Fan S. Multiple mechanisms involving in radioresistance of nasopharyngeal carcinoma. J Cancer. 2020;11:4193–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ward JF. DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol. 1988;35:95–125.

    Article  CAS  PubMed  Google Scholar 

  11. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Squatrito M, Brennan CW, Helmy K, Huse JT, Petrini JH, Holland EC. Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas. Cancer Cell. 2010;18:619–629.

    Article  CAS  PubMed  Google Scholar 

  13. Shi Y, Felley-Bosco E, Marti TM, Orlowski K, Pruschy M, Stahel RA. Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin. BMC Cancer. 2012;12:571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Benada J, Macurek L. Targeting the checkpoint to kill cancer cells. Biomolecules. 2015;5:1912–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nie X, Guo EG, Wu C, Liu DB, Sun W, Zhang LL, et al. SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway. Cancer Med. 2019;8:1779–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou XH, Zheng JL, Tang Y, Lin YL, Wang LZ, Li Y, et al. EBV encoded miRNA BART8-3p promotes radioresistance in nasopharyngeal carcinoma by regulating ATM/ATR signaling pathway. Biosci Rep. 2019;39:BSR20190415.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yang CF, Peng LX, Huang TJ, Yang GD, Chu QQ, Liang YY, et al. Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway. Cancer Lett. 2014;344:260–71.

    Article  CAS  PubMed  Google Scholar 

  18. Wu ZQ, Qiu MH, Guo Y, Zhao JL, Liu Z, Wang H, et al. OTU deubiquitinase 4 is silenced and radiosensitizes non-small cell lung cancer cells via inhibiting DNA repair. Cancer Cell Int. 2019;19:99.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kawasaki Y, Komiya M, Matsumura K, Negishi L, Suda S, Okuno M, et al. MYU, a Target lncRNA for Wnt/c-Myc Signaling, Mediates Induction of CDK6 to Promote Cell Cycle Progression. Cell Rep. 2016;16:2554–64. Sep 6

    Article  CAS  PubMed  Google Scholar 

  20. Wang K, Long B, Zhou LY, Liu F, Zhou QY, Liu CY, et al. CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. Nat Commun. 2014;5:3596.

    Article  PubMed  Google Scholar 

  21. Grote P, Wittler L, Hendrix D, Koch F, Währisch S, Beisaw A, et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell. 2013;24:206–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Savić N, Bär D, Leone S, Frommel SC, Weber FA, Vollenweider E, et al. lncRNA maturation to initiate heterochromatin formation in the nucleolus is required for exit from pluripotency in ESCs. Cell Stem Cell. 2014;15:720–34.

    Article  PubMed  Google Scholar 

  23. 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;147:358–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sun TT, He J, Liang Q, Ren LL, Yan TT, Yu TC, et al. LncRNA GClnc1 promotes gastric carcinogenesis and may act as a modular scaffold of WDR5 and KAT2A complexes to specify the histone modification pattern. Cancer Discov. 2016;6:784–801.

    Article  CAS  PubMed  Google Scholar 

  25. Chen CH, Luo YM, He W, Zhao Y, Kong Y, Liu HW, et al. Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer. J Clin Invest. 2020;130:404–21.

    Article  CAS  PubMed  Google Scholar 

  26. Li R, Chen SW, Zhan JD, Li XH, Liu WL, Sheng XL, et al. Long noncoding RNA FOXD2-AS1 enhances chemotherapeutic resistance of laryngeal squamous cell carcinoma via STAT3 activation. Cell Death Dis. 2020;11:41.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zeng FR, Wang QY, Wang SY, Liang SM, Huang WM, et al. Linc00173 promotes chemoresistance and progression of small cell lung cancer by sponging miR-218 to regulate Etk expression. Oncogene. 2020;39:293–307.

    Article  CAS  PubMed  Google Scholar 

  28. Chen JR, Liu AB, Wang ZH, Wang B, Chai XX, Lu WJ, et al. LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression. Mol Cancer. 2020;19:98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schwarzer A, Emmrich S, Schmidt F, Beck D, Ng M, Reimer C, et al. The non-coding RNA landscape of human hematopoiesis and leukemia. Nat Commun. 2017;8:218.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yang Q, Kong S, Zheng M, Hong YL, Sun J, Ming XT, et al. Long intergenic noncoding RNA LINC00173 as a potential serum biomarker for diagnosis of non-small-cell lung cancer. Cancer Biomark. 2020;29:441–51.

    Article  CAS  PubMed  Google Scholar 

  31. Fan HJ, Yuan J, Li XY, Ma YH, Wang XF, Xu BL, et al. LncRNA LINC00173 enhances triple-negative breast cancer progression by suppressing miR-490-3p expression. Biomed Pharmacother. 2020;125:109987.

    Article  CAS  PubMed  Google Scholar 

  32. Kung JT, Colognori D, Lee JT. Long noncoding RNAs: past, present, and future. Genetics. 2013;193:651–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mattick JS, Rinn JL. Discovery and annotation of long noncoding RNAs. Nat Struct Mol Biol. 2015;22:5–7.

    Article  CAS  PubMed  Google Scholar 

  34. Fang Y, Fullwood MJ. Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer. Genomics Proteomics Bioinformatics. 2016;14:42–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xue X, Yang YA, Zhang A, Fong KW, Kim J, Song B, et al. LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene. 2016;35:2746–55.

    Article  CAS  PubMed  Google Scholar 

  36. Lin K, Jiang H, Zhuang SS, Qin YS, Qiu GD, She YQ, et al. Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer. FASEB J. 2019;33:1972–88.

    Article  CAS  PubMed  Google Scholar 

  37. Wang Y, Chen WY, Lian JY, Zhang HB, Yu B, Zhang MJ, et al. The lncRNA PVT1 regulates nasopharyngeal carcinoma cell proliferation via activating the KAT2A acetyltransferase and stabilizing HIF-1α. Cell Death Differ. 2020;27:695–710.

    Article  CAS  PubMed  Google Scholar 

  38. Guo Z, Wang YH, Xu H, Yuan CS, Zhou HH, Huang WH, et al. LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma. Cell Death Dis. 2021;12:69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yi L, Ouyang L, Wang S, Li SS, Yang XM. Long noncoding RNA PTPRG-AS1 acts as a microRNA-194-3p sponge to regulate radiosensitivity and metastasis of nasopharyngeal carcinoma cells via PRC1. J Cell Physiol. 2019;234:19088–102.

    Article  CAS  PubMed  Google Scholar 

  40. Maréchal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013;5:a012716.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kozlov SV, Graham ME, Jakob B, Tobias F, Kijas AW, Tanuji M, et al. Autophosphorylation and ATM activation: additional sites add to the complexity. J Biol Chem. 2011;286:9107–19.

    Article  CAS  PubMed  Google Scholar 

  42. Zannini L, Delia D, Buscemi G. CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol. 2014;6:442–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14:197–210.

    Article  CAS  PubMed  Google Scholar 

  44. Fischer M. Census and evaluation of p53 target genes. Oncogene. 2017;36:3943–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roos WP, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332:237–48.

    Article  CAS  PubMed  Google Scholar 

  46. Chen C, Shimizu S, Tsujimoto Y, Motoyama N. Chk2 regulates transcription-independent p53-mediated apoptosis in response to DNA damage. Biochem Biophys Res Commun. 2005;333:427–31.

    Article  CAS  PubMed  Google Scholar 

  47. Hein AL, Ouellette MM, Yan Y. Radiation-induced signaling pathways that promote cancer cell survival (review). Int J Oncol. 2014;45:1813–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li TY, Kon N, Jiang L, Tan MJ, Ludwig T, Zhao YM, et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell. 2012;149:1269–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yuan ZY, Ma JC, Meng X, Chen N, Shen M. Chk2 deficiency alleviates irradiation-induced taste dysfunction by inhibiting p53-dependent apoptosis. Oral Dis. 2018;24:856–63.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by National Natural Science Foundation of China for Young Scholars [No. 82202946 and No. 82003081] and National Natural Science Foundation of China [No. 82073330]; Guangdong Basic and Applied Basic Research Foundation [No. 2021A1515111112]; China Postdoctoral Science Foundation [No. 2021M703726]; Science and Technology Planning Project of Guangzhou City [No. 202102020106].

Author information

Author notes

  1. These authors contributed equally: Jingjing Miao, Boyu Chen, Yunyun Xiao.

  2. These authors jointly supervised this work: Lin Wang, Haiqiang Mai, Chong Zhao.

Authors and Affiliations

  1. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China

    Jingjing Miao, Xiao Xiao, Shunzhen Lu, Xuguang Wang, Qiuyan Chen, Yanqun Xiang, Xiang Guo, Lin Wang, Haiqiang Mai & Chong Zhao

  2. Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China

    Boyu Chen, Yunyun Xiao, Ying Ouyang & Xiangfu Chen

  3. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China

    Runda Huang, Lu Zhang & Xiaowu Deng

Authors
  1. Jingjing Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Boyu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yunyun Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Runda Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shunzhen Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xuguang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ying Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiangfu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qiuyan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yanqun Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiaowu Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Haiqiang Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Chong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JM, BC, YX, LW, HM, and CZ conceived, designed, and directed the study. JM, BC, and YX performed the in vitro and in vivo experiments and data analyses. RH, XX, SL, LZ, and XW performed the clinical data analyses. YO performed the ISH and TENEL experiments. XC performed part of the WB experiments. JM, BC, YX, LW, HM, and CZ wrote and critically reviewed the manuscript. All authors read and approved the final manuscript. The order of the co–first authors was assigned based on the relative contributions of these individuals.

Corresponding authors

Correspondence to Lin Wang, Haiqiang Mai or Chong Zhao.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miao, J., Chen, B., Xiao, Y. et al. Long noncoding RNA LINC00173 induces radioresistance in nasopharyngeal carcinoma via inhibiting CHK2/P53 pathway. Cancer Gene Ther 30, 1249–1259 (2023). https://doi.org/10.1038/s41417-023-00634-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-023-00634-x

Search

Advanced search

Quick links