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

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Tumor Biology

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.

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References

  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.

  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.

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  5. Hwang H, Mendell J. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006;94:776–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Jin-shan Yang.

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Jin-shan Yang and Bao-jian Li contribute equally to this work.

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Yang, Js., Li, Bj., Lu, Hw. et al. Serum miR-152, miR-148a, miR-148b, and miR-21 as novel biomarkers in non-small cell lung cancer screening. Tumor Biol. 36, 3035–3042 (2015). https://doi.org/10.1007/s13277-014-2938-1

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  • DOI: https://doi.org/10.1007/s13277-014-2938-1

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