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Critical role of miR-155/FoxO1/ROS axis in the regulation of non-small cell lung carcinomas

  • Original Article
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Tumor Biology

Abstract

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung carcinomas (NSCLC) account for 85 % of lung cancer cases. Despite enormous achievement in the treatment of NSCLC, the molecular mechanisms underlying the pathogenesis are largely unknown. The current study was designed to evaluate the role of miR-155 in NSCLC cell proliferation and to explore the possible molecular mechanisms. We found that miR-155 expression was increased in NSCLC tissues and cell lines. The increase of miR-155 significantly increased A549 cell proliferation, decreased S phase cell population and increased G2/M phase cell population. Decrease of miR-155 expression markedly inhibited cell proliferation, increased S phase cell population, and decreased G2/M phase cell population. Increase of miR-155 significantly decreased forkhead box protein O1 (FoxO1) 3’UTR luciferase activity and expression and decrease of miR-155 notably increased FoxO1 expression. Overexpression of FoxO1 significantly inhibited miR-155-exerted increase of cell proliferation and G2/M cell population. Downregulation of FoxO1 by siRNAs significantly promoted cell proliferation, decreased S phase cell numbers, and increased G2/M cell population. Downregulation of FoxO1 markedly increased ROS level, as reflected by increased DHE staining. Moreover, when N-acetylcysteine was present, increase of cell proliferation induced by downregulation of FoxO1, and upregulation of miR-155 was significantly inhibited. In conclusion, we found that miR-155 promoted NSCLC cell proliferation through inhibition of FoxO1 and the subsequent increase of ROS generation. Our findings highlight miR-155/FoxO1/ROS axis as a novel therapeutic target for the inhibition of NSCLC growth.

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Abbreviations

FoxO1:

forkhead box protein O1

NAC:

N-acetylcysteine

NSCLC:

non-small cell lung carcinomas

ROS:

reactive oxygen species

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  2. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367–80.

    Article  CAS  PubMed  Google Scholar 

  3. Shtivelman E, Hensing T, Simon GR, Dennis PA, Otterson GA, Bueno R, et al. Molecular pathways and therapeutic targets in lung cancer. Oncotarget. 2014;5:1392–433.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Stinchcombe TE, Fried D, Morris DE, Socinski MA. Combined modality therapy for stage III non-small cell lung cancer. Oncologist. 2006;11:809–23.

    Article  CAS  PubMed  Google Scholar 

  5. Scagliotti GV, Novello S. Adjuvant therapy in completely resected non-small-cell lung cancer. Curr Oncol Rep. 2003;5:318–25.

    Article  PubMed  Google Scholar 

  6. Wagner KW, Alam H, Dhar SS, Giri U, Li N, Wei Y, et al. KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J Clin Invest. 2013;123:5231–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Socinski MA. Seeking new options for the treatment of small-cell lung cancer. Lung Cancer. 2005;50 Suppl 1:S25–6.

    Article  PubMed  Google Scholar 

  8. Wen D, Danquah M, Chaudhary AK, Mahato RI. Small molecules targeting microRNA for cancer therapy: Promises and obstacles. J Control Release.2015.

  9. Ohtsuka M, Ling H, Doki Y, Mori M, Calin GA. MicroRNA processing and human cancer. J Clin Med. 2015;4:1651–67.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Li MH, Fu SB, Xiao HS. Genome-wide analysis of microRNA and mRNA expression signatures in cancer. ACTA Pharmacol SIN. 2015

  11. Orellana EA, Kasinski AL. MicroRNAs in cancer: a historical perspective on the path from discovery to therapy. Cancer Basel. 2015;7:1388–405.

    Article  Google Scholar 

  12. Kishikawa T, Otsuka M, Ohno M, Yoshikawa T, Takata A, Koike K. Circulating RNAs as new biomarkers for detecting pancreatic cancer. World J Gastroenterol. 2015;21:8527–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hollis M, Nair K, Vyas A, Chaturvedi LS, Gambhir S, Vyas D. MicroRNAs potential utility in colon cancer: early detection, prognosis, and chemosensitivity. World J Gastroenterol. 2015;21:8284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bertoli G, Cava C, Castiglioni I. MicroRNAs: New biomarkers for diagnosis, prognosis, therapy prediction and therapeutic tools for breast cancer. Theranostics. 2015;5:1122–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Puissegur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K, et al. MiR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 2011;18:465–78.

    Article  CAS  PubMed  Google Scholar 

  16. Kim JO, Gazala S, Razzak R, Guo L, Ghosh S, Roa WH, et al. Non-small cell lung cancer detection using microRNA expression profiling of bronchoalveolar lavage fluid and sputum. Anticancer Res. 2015;35:1873–80.

    CAS  PubMed  Google Scholar 

  17. Wang Y, Li J, Tong L, Zhang J, Zhai A, Xu K, et al. The prognostic value of miR-21 and miR-155 in non-small-cell lung cancer: a meta-analysis. JPN J Clin Oncol. 2013;43:813–20.

    Article  PubMed  Google Scholar 

  18. Yang M, Shen H, Qiu C, Ni Y, Wang L, Dong W, et al. High expression of miR-21 and miR-155 predicts recurrence and unfavourable survival in non-small cell lung cancer. Eur J Cancer. 2013;49:604–15.

    Article  CAS  PubMed  Google Scholar 

  19. Xu TP, Zhu CH, Zhang J, Xia R, Wu FL, Han L, et al. MicroRNA-155 expression has prognostic value in patients with non-small cell lung cancer and digestive system carcinomas. Asian Pac J Cancer Prev. 2013;14:7085–90.

    Article  PubMed  Google Scholar 

  20. Maekawa T, Maniwa Y, Doi T, Nishio W, Yoshimura M, Ohbayashi C, et al. Expression and localization of FOXO1 in non-small cell lung cancer. Oncol Rep. 2009;22:57–64.

    CAS  PubMed  Google Scholar 

  21. Ma J, Wang N, Zhang Y, Wang C, Ge T, Jin H, et al. KDM6B elicits cell apoptosis by promoting nuclear translocation of FOXO1 in non-small cell lung cancer. Cell Physiol Biochem. 2015;37:201–13.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang L, Quan H, Wang S, Li X, Che X. MiR-183 promotes growth of non-small cell lung cancer cells through FoxO1 inhibition. Tumour Biol. 2015;36:8121–6.

    Article  CAS  PubMed  Google Scholar 

  23. Zhao JG, Ren KM, Tang J. Zinc finger protein ZBTB20 promotes cell proliferation in non-small cell lung cancer through repression of FoxO1. FEBS Lett. 2014;588:4536–42.

    Article  CAS  PubMed  Google Scholar 

  24. Arruda LC, Lorenzi JC, Sousa AP, Zanette DL, Palma PV, Panepucci RA, et al. Autologous hematopoietic SCT normalizes miR-16, −155 and −142-3p expression in multiple sclerosis patients. Bone Marrow Transplant. 2015;50:380–9.

    Article  CAS  PubMed  Google Scholar 

  25. Lawrie CH. MicroRNAs and lymphomagenesis: a functional review. Br J Haematol. 2013;160:571–81.

    Article  CAS  PubMed  Google Scholar 

  26. Yu DD, Lv MM, Chen WX, Zhong SL, Zhang XH, Chen L, et al. Role of miR-155 in drug resistance of breast cancer. Tumour Biol. 2015;36:1395–401.

    Article  CAS  PubMed  Google Scholar 

  27. Mattiske S, Suetani RJ, Neilsen PM, Callen DF. The oncogenic role of miR-155 in breast cancer. Cancer Epidemiol Biomarkers Prev. 2012;21:1236–43.

    Article  CAS  PubMed  Google Scholar 

  28. Jurkovicova D, Magyerkova M, Kulcsar L, Krivjanska M, Krivjansky V, Gibadulinova A, et al. MiR-155 as a diagnostic and prognostic marker in hematological and solid malignancies. Neoplasma. 2014;61:241–51.

    Article  CAS  PubMed  Google Scholar 

  29. Xu ZH, Shun WW, Hang JB, Gao BL, Hu JA. Posttranslational modifications of FOXO1 regulate epidermal growth factor receptor tyrosine kinase inhibitor resistance for non-small cell lung cancer cells. Tumour Biol. 2015;36:5485–95.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang L, Quan H, Wang S, Li X, Che X. MiR-183 promotes growth of non-small cell lung cancer cells through FoxO1 inhibition. Tumour Biol. 2015

  31. Wang K, Zhang T, Dong Q, Nice EC, Huang C, Wei Y. Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death Dis. 2013;4:e537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bartell SM, Kim HN, Ambrogini E, Han L, Iyer S, Serra US, et al. FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nat Commun. 2014;5:3773.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhang S, Zhao Y, Xu M, Yu L, Zhao Y, Chen J, et al. FoxO3a modulates hypoxia stress induced oxidative stress and apoptosis in cardiac microvascular endothelial cells. PLoS ONE. 2013;8:e80342.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kim DH, Kim JM, Lee EK, Choi YJ, Kim CH, Choi JS, et al. Modulation of FoxO1 phosphorylation/acetylation by baicalin during aging. J Nutr Biochem. 2012;23:1277–84.

    Article  CAS  PubMed  Google Scholar 

  35. Kim W, Youn H, Kang C, Youn B. Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells. Apoptosis. 2015;20:1242–52.

    Article  CAS  PubMed  Google Scholar 

  36. Gu Q, He Y, Ji J, Yao Y, Shen W, Luo J, et al. Hypoxia-inducible factor 1alpha (HIF-1alpha) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1alpha/CXCR4 pathway in non-small cell lung carcinoma cells. Oncotarget. 2015;6:10893–907.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai, 200433, China

    Likun Hou & Chunyan Wu

  2. Department of Radiology, Shanghai Construction Group Hospital, Shanghai, 200083, China

    Jian Chen

  3. Department of Pathology, Fujian Medical University Hospital, Fuzhou, 350001, China

    Yuhui Zheng

Authors
  1. Likun Hou
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  2. Jian Chen
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  3. Yuhui Zheng
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  4. Chunyan Wu
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Correspondence to Chunyan Wu.

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The authors declare that they have no competing interests.

Additional information

Likun Hou, Jian Chen and Yuhui Zheng contributed equally to this work.

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Hou, L., Chen, J., Zheng, Y. et al. Critical role of miR-155/FoxO1/ROS axis in the regulation of non-small cell lung carcinomas. Tumor Biol. 37, 5185–5192 (2016). https://doi.org/10.1007/s13277-015-4335-9

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  • DOI: https://doi.org/10.1007/s13277-015-4335-9

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