Tumor Biology

, Volume 36, Issue 4, pp 3035–3042 | Cite as

Serum miR-152, miR-148a, miR-148b, and miR-21 as novel biomarkers in non-small cell lung cancer screening

  • Jin-shan Yang
  • Bao-jian Li
  • Hua-wei Lu
  • Yu Chen
  • Chuan Lu
  • Rui-xia Zhu
  • Si-hai Liu
  • Qing-ting Yi
  • Jing Li
  • Chun-hui Song
Research Article

Abstract

Lung cancer, predominantly by non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths over the world. Late diagnosis is one of important reasons for high mortality rate in lung cancer. Current diagnostic approaches have disadvantages such as low accuracy, high cost, invasive procedure, etc. MicroRNAs were previously proposed as promising novel biomarkers in cancer screening. In this study, we evaluated the predictive power of four candidate miRNAs in NSCLC detection. Our study involved 152 NSCLC patients and 300 healthy controls. Blood samples were obtained from the total 452 subjects. After miRNA extraction from serum, the expression of miRNAs in cases and controls were quantified by qRT-PCR and normalized to the level of U6 small RNA. Statistical analyses were performed to compare miRNA levels between cases and controls. Stratified analyses were employed to compare miRNA levels in NSCLC patients with different clinical characteristics. Serum miR-148a, miR-148b, and miR-152 were significantly downregulated in NSCLC patients. However, overexpression of serum miR-21 was observed in NSCLC patients. The combination of four candidate miRNAs exhibited the highest predictive accuracy in NSCLC screening compared with individual miRNAs (AUC = 0.97). Low level of miRNA-148/152 members may associate with advanced stage, large tumor size, malignant cell differentiation, and metastasis. High expression of miR-21 was possibly correlated with large size tumor and advanced cancer stage. Our results showed the dysregulation of miR-148/152 family and miR-21 in NSCLC patients. Hence, the four candidate miRNAs have great potential to serve as promising novel biomarkers in NSCLC screening. Further large-scale studies are needed to validate our results.

Keywords

MicroRNAs miR-148a miR-148b miR-152 miR-21 Serum Non-small cell lung cancer Screening 

References

  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S. GLOBOCAN 2012 v1. 0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer. 2014.Google Scholar
  2. 2.
    Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA, editors. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clinic Proceedings: Elsevier; 2008.Google Scholar
  3. 3.
    Crino L, Weder W, Van Meerbeeck J, Felip E. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21:v103–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Swensen SJ, Jett JR, Sloan JA, Midthun DE, Hartman TE, Sykes A-M, et al. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med. 2002;165:508–13.CrossRefPubMedGoogle Scholar
  5. 5.
    Hwang H, Mendell J. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006;94:776–80.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yu L, Todd NW, Xing L, Xie Y, Zhang H, Liu Z, et al. Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer. 2010;127:2870–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Crawford M, Brawner E, Batte K, Yu L, Hunter M, Otterson G, et al. MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. Biochem Biophys Res Commun. 2008;373:607–12.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhu W, He J, Chen D, Zhang B, Xu L, Ma H, et al. Expression of miR-29c, miR-93, and miR-429 as potential biomarkers for detection of early stage non-small lung cancer. PLoS One. 2014;9:e87780.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci. 2007;104:15805–10.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Tang D, Shen Y, Wang M, Yang R, Wang Z, Sui A, et al. Identification of plasma microRNAs as novel noninvasive biomarkers for early detection of lung cancer. Eur J Cancer Prev. 2013;22:540–8. doi: 10.1097/CEJ.0b013e32835f3be9.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhong M, Ma X, Sun C, Chen L. MicroRNAs reduce tumor growth and contribute to enhance cytotoxicity induced by gefitinib in non-small cell lung cancer. Chem Biol Interact. 2010;184:431–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Nielsen LB, Wang C, Sørensen K, Bang-Berthelsen CH, Hansen L, Andersen M-LM, et al. Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. Experiment Diab Res. 2012;2012.Google Scholar
  13. 13.
    Bidzhekov K, Gan L, Denecke B, Rostalsky A, Hristov M, Koeppel TA, et al. microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans. Thromb Haemost. 2012;107:619.CrossRefPubMedGoogle Scholar
  14. 14.
    Serino G, Sallustio F, Cox SN, Pesce F, Schena FP. Abnormal miR-148b expression promotes aberrant glycosylation of IgA1 in IgA nephropathy. J Am Soc Nephrol. 2012;23:814–24.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhou X, Zhao F, Wang Z-N, Song Y-X, Chang H, Chiang Y, et al. Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation. Oncol Rep. 2012;27:447.PubMedGoogle Scholar
  16. 16.
    Li R, Qian N, Tao K, You N, Wang X, Dou K. MicroRNAs involved in neoplastic transformation of liver cancer stem cells. J Exp Clin Cancer Res. 2010;29:169.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Chen Y, Song Y, Wang Z, Yue Z, Xu H, Xing C, et al. Altered expression of MiR-148a and MiR-152 in gastrointestinal cancers and its clinical significance. J Gastrointest Surg. 2010;14:1170–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Song Y-X, Yue Z-Y, Wang Z-N, Xu Y-Y, Luo Y, Xu H-M, et al. MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation. Mol Cancer. 2011;10:1.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67:6130–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Iorio MV, Ferracin M, Liu C-G, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Motoyama K, Inoue H, Takatsuno Y, Tanaka F, Mimori K, Uetake H, et al. Over-and under-expressed microRNAs in human colorectal cancer. Int J Oncol. 2009;34:1069–75.PubMedGoogle Scholar
  22. 22.
    Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9:189–98.CrossRefPubMedGoogle Scholar
  23. 23.
    Katada T, Ishiguro H, Kuwabara Y, Kimura M, Mitui A, Mori Y, et al. microRNA expression profile in undifferentiated gastric cancer. Int J Oncol. 2009;34:537.PubMedGoogle Scholar
  24. 24.
    Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA, et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci. 2008;105:3903–8.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004;64:3753–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, et al. A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non–small cell lung cancer risk. Cancer Res. 2008;68:8535–40.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D, et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 2007;67:7713–22.CrossRefPubMedGoogle Scholar
  28. 28.
    Capodanno A, Boldrini L, Proietti A, Alì G, Pelliccioni S, Niccoli C, et al. Let-7g and miR-21 expression in non-small cell lung cancer: correlation with clinicopathological and molecular features. Int J Oncol. 2013;43:765–74.PubMedGoogle Scholar
  29. 29.
    Seike M, Goto A, Okano T, Bowman ED, Schetter AJ, Horikawa I, et al. MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci. 2009;106:12085–90.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhang J-g, Wang J-j, Zhao F, Liu Q, Jiang K, Yang G-h. MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta. 2010;411:846–52.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhao Y, Jia H, Zhou H, Dong Q, Fu L, Yan Z, et al. Identification of metastasis-related microRNAs of hepatocellular carcinoma in hepatocellular carcinoma cell lines by quantitative real time PCR. Zhonghua gan zang bing za zhi= Zhonghua ganzangbing zazhi= Chinese J Hepatol. 2009;17:526–530.Google Scholar
  32. 32.
    Huang J, Wang Y, Guo Y, Sun S. Down‐regulated microRNA‐152 induces aberrant DNA methylation in hepatitis B virus–related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology. 2010;52:60–70.CrossRefPubMedGoogle Scholar
  33. 33.
    Zhu A, Xia J, Zuo J, Jin S, Zhou H, Yao L, et al. MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer. Med Oncol. 2012;29:2701–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Lujambio A, Calin GA, Villanueva A, Ropero S, Sánchez-Céspedes M, Blanco D, et al. A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci. 2008;105:13556–61.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zheng B, Liang L, Wang C, Huang S, Cao X, Zha R, et al. MicroRNA-148a suppresses tumor cell invasion and metastasis by downregulating ROCK1 in gastric cancer. Clin Cancer Res. 2011;17:7574–83.CrossRefPubMedGoogle Scholar
  36. 36.
    Song Y, Xu Y, Wang Z, Chen Y, Yue Z, Gao P, et al. MicroRNA‐148b suppresses cell growth by targeting cholecystokinin‐2 receptor in colorectal cancer. Int J Cancer. 2012;131:1042–51.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Jin-shan Yang
    • 1
  • Bao-jian Li
    • 1
  • Hua-wei Lu
    • 3
  • Yu Chen
    • 2
  • Chuan Lu
    • 4
  • Rui-xia Zhu
    • 1
  • Si-hai Liu
    • 1
  • Qing-ting Yi
    • 1
  • Jing Li
    • 1
  • Chun-hui Song
    • 1
  1. 1.Department of OncologyCentral Hospital of Zaozhuang Mineral GroupZaozhuangChina
  2. 2.Department of Thoracic SurgeryCentral Hospital of Zaozhuang Mineral GroupZaozhuangChina
  3. 3.Department of OncologyPeople’s Hospital of XuechengZaozhuangChina
  4. 4.Taishan Medical UniversityTaianChina

Personalised recommendations