Extracellular vesicle‑delivered miR‑505‑5p, as a diagnostic biomarker of early lung adenocarcinoma, inhibits cell apoptosis by targeting TP53AIP1

  • Authors:
    • Hua Fang
    • Yutao Liu
    • Yaohong He
    • Yang Jiang
    • Yaping Wei
    • Han Liu
    • Yueqing Gong
    • Guangyu An
  • View Affiliations

  • Published online on: March 1, 2019     https://doi.org/10.3892/ijo.2019.4738
  • Pages: 1821-1832
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Lung adenocarcinoma (LA) is the most commonly occurring histological type of non‑small cell lung cancer. Diagnosis and treatment of LA remain a major clinical challenge. In the present study, to identify early LA biomarkers, extracellular vesicles (EVs) were separated from the plasma samples from 153 patients with LA and 75 healthy controls. microRNA (miRNA) expression profiling was performed at the screening stage (5 patients with LA vs. 5 controls), followed by verification at the validation stage (40 patients with LA vs. 20 controls) using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The four disordered miRNAs (miR‑505‑5p, miR‑486‑3p, miR‑486‑3p and miR‑382‑3p) identified in the plasma EVs were further evaluated at the testing stage (108 patients with LA vs. 50 controls) by RT‑qPCR. It was revealed that miR‑505‑5p was upregulated, whereas miR‑382‑3p was downregulated, in the EVs from patients with LA. Furthermore, miR‑505‑5p was also upregulated in tumor tissues, compared with adjacent non‑tumor control tissues. Subsequently, the direct targets of miR‑505‑5p were predicted using bioinformatics analyses, and verified by luciferase assay and immunoblotting. The present study determined that miR‑505‑5p functions as an oncogene, promoting lung cancer cell proliferation and inhibiting cancer cell apoptosis via the targeting of tumor protein P53‑regulated apoptosis‑inducing protein 1 (TP53AIP1). Finally, it was confirmed that miR‑505‑5p in plasma EVs could be delivered to lung cancer cells, inhibiting cell apoptosis and promoting cell proliferation by targeting TP53AIP1. In conclusion, the present study indicated that miRNA‑505‑5p functions as an oncogene that may be used as a novel biomarker for the diagnosis and treatment of LA.

References

1 

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018.

2 

Zhou C: Lung cancer molecular epidemiology in China: Recent trends. Transl Lung Cancer Res. 3:270–279. 2014.

3 

Chen Z, Fillmore CM, Hammerman PS, Kim CF and Wong KK: Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 14:535–546. 2014.

4 

Li Q, Liu M, Ma F, Luo Y, Cai R, Wang L, Xu N and Xu B: Circulating miR-19a and miR-205 in serum may predict the sensitivity of luminal A subtype of breast cancer patients to neoadjuvant chemotherapy with epirubicin plus paclitaxel. PLoS One. 9:e1048702014.

5 

Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, Byers T, Colditz GA, Gould MK, Jett JR, et al: Benefits and harms of CT screening for lung cancer: a systematic review. JAMA. 307:2418–2429. 2012.

6 

Saghir Z, Dirksen A, Ashraf H, Bach KS, Brodersen J, Clementsen PF, Døssing M, Hansen H, Kofoed KF, Larsen KR, et al: Lung cancer screening with low dose CT requires careful consideration. Ugeskr Laeger. 176:pii: V061403412014.In Danish.

7 

Holdenrieder S, Wehnl B, Hettwer K, Simon K, Uhlig S and Dayyani F: Carcinoembryonic antigen and cytokeratin-19 fragments for assessment of therapy response in non-small cell lung cancer: A systematic review and meta-analysis. Br J Cancer. 116:1037–1045. 2017.

8 

Okamura K, Takayama K, Izumi M, Harada T, Furuyama K and Nakanishi Y: Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. Lung cancer. 80:45–49. 2013.

9 

Chen F, Wang XY, Han XH, Wang H and Qi J: Diagnostic value of Cyfra21-1, SCC and CEA for differentiation of early-stage NSCLC from benign lung disease. Int J Clin Exp Med. 8:11295–11300. 2015.

10 

Reck M and Rabe KF: Precision Diagnosis and Treatment for Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 377:849–861. 2017.

11 

Zaborowski MP, Balaj L, Breakefield XO and Lai CP: Extracellular Vesicles: Composition, Biological Relevance, and Methods of Study. Bioscience. 65:783–797. 2015.

12 

Vlassov AV, Magdaleno S, Setterquist R and Conrad R: Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta. 1820:940–948. 2012.

13 

Trinchieri G: Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol. 30:677–706. 2012.

14 

Pereira ER, Jones D, Jung K and Padera TP: The lymph node microenvironment and its role in the progression of metastatic cancer. Semin Cell Dev Biol. 38:98–105. 2015.

15 

O’Loghlen A: Role for extracellular vesicles in the tumour micro-environment. Philos Trans R Soc Lond B Biol Sci. 373:3732018.

16 

Wang Y, Yi J, Chen X, Zhang Y, Xu M and Yang Z: The regulation of cancer cell migration by lung cancer cell-derived exosomes through TGF-β and IL-10. Oncol Lett. 11:1527–1530. 2016.

17 

Tang Y, Cui Y, Li Z, Jiao Z, Zhang Y, He Y, Chen G, Zhou Q, Wang W, Zhou X, et al: Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells. J Exp Clin Cancer Res. 35:72016.

18 

Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005.

19 

Ma J and Li X: MicroRNAs are involved in the toxicity of microcystins. Toxin Rev. 36:112017.

20 

Ma J, Li Y, Yao L and Li X: Analysis of MicroRNA Expression Profiling Involved in MC-LR-Induced Cytotoxicity by High-Throughput Sequencing. Toxins (Basel). 9:92017.

21 

Zhao Y, Xie P and Fan H: Genomic profiling of microRNAs and proteomics reveals an early molecular alteration associated with tumorigenesis induced by MC-LR in mice. Environ Sci Technol. 46:34–41. 2012.

22 

Maes OC, Chertkow HM, Wang E and Schipper HM: MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders. Curr Genomics. 10:154–168. 2009.

23 

Xu J, Li Y, Wang F, Wang X, Cheng B, Ye F, Xie X, Zhou C and Lu W: Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer. Oncogene. 32:976–987. 2013.

24 

Farazi TA, Hoell JI, Morozov P and Tuschl T: MicroRNAs in human cancer. Adv Exp Med Biol. 774:1–20. 2013.

25 

Detterbeck FC, Boffa DJ, Kim AW and Tanoue LT: The Eighth Edition Lung Cancer Stage Classification. Chest. 151:193–203. 2017.

26 

Coglitore D, Edwardson SP, Macko P, Patterson EA and Whelan M: Transition from fractional to classical Stokes-Einstein behaviour in simple fluids. R Soc Open Sci. 4:1705072017.

27 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 25:402–408. 2001.

28 

Raposo G and Stoorvogel W: Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol. 200:373–383. 2013.

29 

Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M and Nakamura Y: p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis. Mol Cell. 8:85–94. 2001.

30 

Yamashita S, Chujo M, Miyawaki M, Tokuishi K, Anami K, Yamamoto S and Kawahara K: Combination of p53AIP1 and survivin expression is a powerful prognostic marker in non-small cell lung cancer. J Exp Clin Cancer Res. 28:222009.

31 

Yamashita SI, Masuda Y, Yoshida N, Matsuzaki H, Kurizaki T, Haga Y, Ikei S, Miyawaki M, Kawano Y, Chujyo M and Kawahara K: p53AIP1 expression can be a prognostic marker in non-small cell lung cancer. Clin Oncol (R Coll Radiol). 20:148–151. 2008.

32 

Verma M, Lam TK, Hebert E and Divi RL: Extracellular vesicles: Potential applications in cancer diagnosis, prognosis, and epidemiology. BMC Clin Pathol. 15:62015.

33 

Liu S, Zhan Y, Luo J, Feng J, Lu J, Zheng H, Wen Q and Fan S: Roles of exosomes in the carcinogenesis and clinical therapy of non-small cell lung cancer. Biomed Pharmacother. 111:338–346. 2018.

34 

Bonjoch L, Gironella M, Iovanna JL and Closa D: REG3β modifies cell tumor function by impairing extracellular vesicle uptake. Sci Rep. 7:31432017.

35 

Mrowczynski OD, Madhankumar AB, Slagle Webb B, Lee SY, Zacharia BE and Connor JR: HFE genotype affects exosome phenotype in cancer. Biochim Biophys Acta Gen Subj. 1861:1921–1928. 2017.

36 

Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, et al: Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 18:997–1006. 2008.

37 

Lin Q, Mao W, Shu Y, Lin F, Liu S, Shen H, Gao W, Li S and Shen D: A cluster of specified microRNAs in peripheral blood as biomarkers for metastatic non-small-cell lung cancer by stem-loop RT-PCR. J Cancer Res Clin Oncol. 138:85–93. 2012.

38 

Wang ZX, Bian HB, Wang JR, Cheng ZX, Wang KM and De W: Prognostic significance of serum miRNA-21 expression in human non-small cell lung cancer. J Surg Oncol. 104:847–851. 2011.

39 

Silva J, Garcia V, Zaballos A, Provencio M, Lombardía L, Almonacid L, García JM, Domínguez G, Peña C, Diaz R, et al: Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J. 37:617–623. 2011.

40 

Kozomara A and Griffiths-Jones S: miRBase: Annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42(D1): D68–D73. 2014.

41 

Chen S, Sun KX, Liu BL, Zong ZH and Zhao Y: MicroRNA-505 functions as a tumor suppressor in endometrial cancer by targeting TGF-α. Mol Cancer. 15:112016.

42 

Liu YJ, Li W, Chang F, Liu JN, Lin JX and Chen DX: MicroRNA-505 is downregulated in human osteosarcoma and regulates cell proliferation, migration and invasion. Oncol Rep. 39:491–500. 2018.

43 

Lu L, Qiu C, Li D, Bai G, Liang J and Yang Q: MicroRNA-505 suppresses proliferation and invasion in hepatoma cells by directly targeting high-mobility group box 1. Life Sci. 157:12–18. 2016.

44 

Chen T, Ren H, Thakur A, Yang T, Li Y, Zhang S, Wang T and Chen M: miR-382 inhibits tumor progression by targeting SETD8 in non-small cell lung cancer. Biomed Pharmacother. 86:248–253. 2017.

45 

Zhou X, Wen W, Shan X, Zhu W, Xu J, Guo R, Cheng W, Wang F, Qi LW, Chen Y, et al: A six-microRNA panel in plasma was identified as a potential biomarker for lung adenocarcinoma diagnosis. Oncotarget. 8:6513–6525. 2017.

46 

Feng M, Zhao J, Wang L and Liu J: Upregulated Expression of Serum Exosomal microRNAs as Diagnostic Biomarkers of Lung Adenocarcinoma. Ann Clin Lab Sci. 48:712–718. 2018.

47 

Maemura K, Watanabe K, Ando T, Hiyama N, Sakatani T, Amano Y, Kage H, Nakajima J, Yatomi Y, Nagase T, et al: Altered editing level of microRNAs is a potential biomarker in lung adenocarcinoma. Cancer Sci. 109:3326–3335. 2018.

Related Articles

Journal Cover

May 2019
Volume 54 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Fang, H., Liu, Y., He, Y., Jiang, Y., Wei, Y., Liu, H. ... An, G. (2019). Extracellular vesicle‑delivered miR‑505‑5p, as a diagnostic biomarker of early lung adenocarcinoma, inhibits cell apoptosis by targeting TP53AIP1. International Journal of Oncology, 54, 1821-1832. https://doi.org/10.3892/ijo.2019.4738
MLA
Fang, H., Liu, Y., He, Y., Jiang, Y., Wei, Y., Liu, H., Gong, Y., An, G."Extracellular vesicle‑delivered miR‑505‑5p, as a diagnostic biomarker of early lung adenocarcinoma, inhibits cell apoptosis by targeting TP53AIP1". International Journal of Oncology 54.5 (2019): 1821-1832.
Chicago
Fang, H., Liu, Y., He, Y., Jiang, Y., Wei, Y., Liu, H., Gong, Y., An, G."Extracellular vesicle‑delivered miR‑505‑5p, as a diagnostic biomarker of early lung adenocarcinoma, inhibits cell apoptosis by targeting TP53AIP1". International Journal of Oncology 54, no. 5 (2019): 1821-1832. https://doi.org/10.3892/ijo.2019.4738