Skip to main content

Advertisement

SpringerLink
Log in

Exosomal long non-coding RNA SOX2 overlapping transcript enhances the resistance to EGFR-TKIs in non-small cell lung cancer cell line H1975

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Crosstalk between cancer cells and macrophages plays a crucial role in the development of cancer. In this study, our data showed that M1 macrophages attenuate, while M2 macrophages and tumor-associated macrophages enhance the EGFR-TKIs resistance in non-small cell lung cancer (NSCLC) cell line H1975. Next, long non-coding RNA SOX2 overlapping transcript (SOX2-OT) is highly expressed in NSCLC cells-derived exosomes. NSCLC cells-derived exosomes promote macrophages M2 polarization and inhibit M1 polarization through transferring SOX2-OT to macrophages. Subsequently, our results indicated that NSCLC cells-induced M2-polarized macrophages enhance the EGFR-TKIs resistance in H1975 cells. Furthermore, our data revealed that NSCLC cells-derived exosomes inhibit the expression of miR-627-3p, while promote Smads expression in THP-1 cells. SOX2-OT acts as miR-627-3p sponge to facilitate Smad2, Smad3 and Smad4 expression. Finally, our results indicated that NSCLC cells promote macrophages M2 polarization and suppress M1 polarization through targeting miR-627-3p/Smads signaling pathway by transferring exosomes to THP-1 cells. In conclusion, our data revealed that NSCLC cells promote macrophages M2 polarization through transferring exosomal SOX2-OT, thus to enhance its own EGFR-TKIs resistance. Mechanismly, NSCLC cells-derived exosomal SOX2-OT promotes macrophages M2 polarization via promoting Smads by sponging miR-627-3p. Our data provide a novel therapeutic target for EGFR-TKIs resistance in NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Goebel C, Louden CL, McKenna R Jr, Onugha O, Wachtel A, Long T. Diagnosis of non-small cell lung cancer for early stage asymptomatic patients. Cancer Genomics Proteomics. 2019;16(4):229–44. https://doi.org/10.21873/cgp.20128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Saito S, Espinoza-Mercado F, Liu H, Sata N, Cui X, Soukiasian HJ. Current status of research and treatment for non-small cell lung cancer in never-smoking females. Cancer Biol Ther. 2017;18(6):359–68. https://doi.org/10.1080/15384047.2017.1323580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Remark R, Becker C, Gomez JE, Damotte D, Dieu-Nosjean MC, Sautès-Fridman C, Fridman WH, Powell CA, Altorki NK, Merad M, Gnjatic S. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med. 2015;191(4):377–90. https://doi.org/10.1164/rccm.201409-1671PP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jonna S, Subramaniam DS. Molecular diagnostics and targeted therapies in non-small cell lung cancer (NSCLC): an update. Discov Med. 2019;27(148):167–70.

    PubMed  Google Scholar 

  5. Leighl NB, Karaseva N, Nakagawa K, Cho BC, Gray JE, Hovey T, Walding A, Rydén A, Novello S. Patient-reported outcomes from FLAURA: Osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small-cell lung cancer. Eur J Cancer (Oxford, England: 1990). 2020;125:49–57. https://doi.org/10.1016/j.ejca.2019.11.006.

    Article  CAS  Google Scholar 

  6. Isidro RA, Appleyard CB. Colonic macrophage polarization in homeostasis, inflammation, and cancer. Am J Physiol Gastrointest Liver Physiol. 2016;311(1):G59-73. https://doi.org/10.1152/ajpgi.00123.2016.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Genin M, Clement F, Fattaccioli A, Raes M, Michiels C. M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer. 2015;15:577. https://doi.org/10.1186/s12885-015-1546-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27(4):462–72. https://doi.org/10.1016/j.ccell.2015.02.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li H, Huang N, Zhu W, Wu J, Yang X, Teng W, Tian J, Fang Z, Luo Y, Chen M, Li Y. Modulation the crosstalk between tumor-associated macrophages and non-small cell lung cancer to inhibit tumor migration and invasion by ginsenoside Rh2. BMC Cancer. 2018;18(1):579. https://doi.org/10.1186/s12885-018-4299-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li Y, Cao F, Li M, Li P, Yu Y, Xiang L, Xu T, Lei J, Tai YY, Zhu J, Yang B, Jiang Y, Zhang X, Duo L, Chen P, Yu X. Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages. J Exp Clin Cancer Res. 2018;37(1):259. https://doi.org/10.1186/s13046-018-0938-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zheng H, Zhan Y, Liu S, Lu J, Luo J, Feng J, Fan S. The roles of tumor-derived exosomes in non-small cell lung cancer and their clinical implications. J Exp Clin Cancer Res. 2018;37(1):226. https://doi.org/10.1186/s13046-018-0901-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pang X, Wang SS, Zhang M, Jiang J, Fan HY, Wu JS, Wang HF, Liang XH. OSCC cell-secreted exosomal CMTM6 induced M2-like macrophages polarization via ERK1/2 signaling pathway. Cancer Immunol Immunother. 2020. https://doi.org/10.1007/s00262-020-02741-2.

    Article  PubMed  Google Scholar 

  13. Teng Y, Kang H, Chu Y. Identification of an exosomal long noncoding RNA SOX2-OT in plasma as a promising biomarker for lung squamous cell carcinoma. Genet Test Mol Biomarkers. 2019;23(4):235–40. https://doi.org/10.1089/gtmb.2018.0103.

    Article  CAS  PubMed  Google Scholar 

  14. Yang N, Wang Y, Hui L, Li X, Jiang X. Silencing SOX2 expression by RNA interference inhibits proliferation, invasion and metastasis, and induces apoptosis through MAP4K4/JNK signaling pathway in human laryngeal cancer TU212 cells. J Histochem Cytochem. 2015;63(9):721–33. https://doi.org/10.1369/0022155415590829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zeng Z, Li Y, Pan Y, Lan X, Song F, Sun J, Zhou K, Liu X, Ren X, Wang F, Hu J, Zhu X, Yang W, Liao W, Li G, Ding Y, Liang L. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018;9(1):5395. https://doi.org/10.1038/s41467-018-07810-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zeng M, Zhu L, Li L, Kang C. miR-378 suppresses the proliferation, migration and invasion of colon cancer cells by inhibiting SDAD1. Cell Mol Biol Lett. 2017;22:12. https://doi.org/10.1186/s11658-017-0041-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Poulet C, Njock MS. Exosomal long non-coding RNAs in lung diseases. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21103580.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25. https://doi.org/10.1056/NEJMoa1713137.

    Article  CAS  PubMed  Google Scholar 

  19. Loong HH, Kwan SS, Mok TS, Lau YM. Therapeutic strategies in EGFR mutant non-small cell lung cancer. Curr Treat Options Oncol. 2018;19(11):58. https://doi.org/10.1007/s11864-018-0570-9.

    Article  PubMed  Google Scholar 

  20. Xu F, Cui WQ, Wei Y, Cui J, Qiu J, Hu LL, Gong WY, Dong JC. Astragaloside IV inhibits lung cancer progression and metastasis by modulating macrophage polarization through AMPK signaling. J Exp Clin Cancer Res. 2018;37(1):207. https://doi.org/10.1186/s13046-018-0878-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang X, Zeng Y, Qu Q, Zhu J, Liu Z, Ning W, Zeng H, Zhang N, Du W, Chen C, Huang JA. PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol. 2017;22(6):1026–33. https://doi.org/10.1007/s10147-017-1161-7.

    Article  CAS  PubMed  Google Scholar 

  22. Xiao F, Liu N, Ma X, Qin J, Liu Y, Wang X. M2 macrophages reduce the effect of gefitinib by activating AKT/mTOR in gefitinib-resistant cell lines HCC827/GR. Thoracic Cancer. 2020. https://doi.org/10.1111/1759-7714.13670.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer. 2019;18(1):75. https://doi.org/10.1186/s12943-019-0991-5.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Whiteside TL. Tumor-derived exosomes and their role in cancer progression. Adv Clin Chem. 2016;74:103–41. https://doi.org/10.1016/bs.acc.2015.12.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li X, Lei Y, Wu M, Li N. Regulation of macrophage activation and polarization by HCC-derived exosomal lncRNA TUC339. Int J Mol Sci. 2018. https://doi.org/10.3390/ijms19102958.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: a new paradigm. Can Res. 2017;77(15):3965–81. https://doi.org/10.1158/0008-5472.can-16-2634.

    Article  CAS  Google Scholar 

  27. Lei Y, Guo W, Chen B, Chen L, Gong J, Li W. Tumor-released lncRNA H19 promotes gefitinib resistance via packaging into exosomes in non-small cell lung cancer. Oncol Rep. 2018;40(6):3438–46. https://doi.org/10.3892/or.2018.6762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang Z, Tan M, Chen G, Li Z, Lu X. LncRNA SOX2-OT is a novel prognostic biomarker for osteosarcoma patients and regulates osteosarcoma cells proliferation and motility through modulating SOX2. IUBMB Life. 2017;69(11):867–76. https://doi.org/10.1002/iub.1681.

    Article  CAS  PubMed  Google Scholar 

  29. Herrera-Solorio AM, Peralta-Arrieta I. LncRNA SOX2-OT regulates AKT/ERK and SOX2/GLI-1 expression, hinders therapy, and worsens clinical prognosis in malignant lung diseases. Mol Onocol. 2021;15(4):1110–29. https://doi.org/10.1002/1878-0261.12875.

    Article  Google Scholar 

  30. Yin X, Han S, Song C, Zou H, Wei Z, Xu W, Ran J, Tang C, Wang Y, Cai Y, Hu Q, Han W. Metformin enhances gefitinib efficacy by interfering with interactions between tumor-associated macrophages and head and neck squamous cell carcinoma cells. Cell Oncol (Dordr). 2019;42(4):459–75. https://doi.org/10.1007/s13402-019-00446-y.

    Article  CAS  Google Scholar 

  31. Wei C, Yang C, Wang S, Shi D, Zhang C, Lin X, Liu Q, Dou R, Xiong B. Crosstalk between cancer cells and tumor-associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer. 2019;18(1):64. https://doi.org/10.1186/s12943-019-0976-4.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Piao YJ, Kim HS, Hwang EH, Woo J, Zhang M, Moon WK. Breast cancer cell-derived exosomes and macrophage polarization are associated with lymph node metastasis. Oncotarget. 2018;9(7):7398–410. https://doi.org/10.18632/oncotarget.23238.

    Article  PubMed  Google Scholar 

  33. Huang Y. The novel regulatory role of lncRNA-miRNA-mRNA axis in cardiovascular diseases. J Cell Mol Med. 2018;22(12):5768–75. https://doi.org/10.1111/jcmm.13866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by Changsha Natural Science Foundation (No. kq2014273); National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Building Project for Major Diseases (Lung Cancer).

Author information

Authors and Affiliations

  1. Department of Geriatric, Respiratory Medicine, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, 410008, China

    Dongbo Zhou, Zhi Xia, Mingxuan Xie, Ying Gao, Qiao Yu & Baimei He

  2. Clinical Research Center for Geriatric Disorders National, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Kaifu District, Changsha, 410008, China

    Dongbo Zhou, Zhi Xia, Mingxuan Xie, Ying Gao, Qiao Yu & Baimei He

  3. Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China

    Dongbo Zhou & Baimei He

Authors
  1. Dongbo Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingxuan Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Baimei He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baimei He.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

13577_2021_572_MOESM1_ESM.tif

Supplementary figure 1. Detection of the expression of SOX2-OT. (A) The expression of SOX2-OT in BEAS-2B- and NSCLC cells-derived exosomes was detected using qRT-PCR assay. β-actin served as an internal reference. **P < 0.01 compared with ExoBEAS-2B group. (B) The expression of SOX2-OT in H1975 cells was determined using qRT-PCR to detect the interference efficiency of SOX2-OT shRNA. β-actin served as internal reference. ##P < 0.01 compared with shCtrl group. (C) qRT-PCR assay was performed to determine the expression of SOX2-OT in LPS-stimulated THP-1 cells after exosomes incubation. β-actin served as internal reference. $$P < 0.01 compared with LPS + ExoBEAS-2B group, and &&P < 0.01 contrasted with LPS + ExoH1975 group. The number of repetitions was 3 (TIF 797 KB)

Supplementary figure 2. Detection of the combination of miR-623-3p and SOX2-OT, Smad2, Smad3 as well as Smad4

. (A) RNA pull down was performed to detect the combination of SOX2-OT and miR-627-3p. (B-D) The combination of miR-627-3p and Smad2, Smad3 as well as Smad4 was determined using RNA binding protein immunoprecipitation assay. The number of repetitions was 3 (TIF 864 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, D., Xia, Z., Xie, M. et al. Exosomal long non-coding RNA SOX2 overlapping transcript enhances the resistance to EGFR-TKIs in non-small cell lung cancer cell line H1975. Human Cell 34, 1478–1489 (2021). https://doi.org/10.1007/s13577-021-00572-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-021-00572-6

Keywords

Search

Navigation