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Serum exosomal miR-301a as a potential diagnostic and prognostic biomarker for human glioma

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Abstract

Purpose

Exosomal miRNAs that play an important role in cell-cell communication have attracted major attention as potential diagnostic and prognostic biomarkers for various cancers. The aim of this study was to determine the diagnostic/prognostic significance of serum exosomal miR-301a in glioma patients.

Methods

Quantitative real-time PCR was used to determine the serum exosomal expression levels of miR-301a. Kaplan-Meier survival analyses, Cox regression analyses and ROC working curve analyses were applied to assess the diagnostic and prognostic values of miR-301a in glioma patients. Also, several in vitro assays were used, including proliferation, invasion and cell signaling assays.

Results

First, we established that serum exosomal miR-301a extracted from grade IV glioblastoma (GBM) patients was biologically active, i.e., promoted the proliferation and invasion of glioma-derived H4 cells. Subsequently, we found that serum exosomal miR-301a levels were significantly up-regulated in glioma patients compared to healthy controls. Additionally, we found that increased serum exosomal miR-301a levels were correlated with ascending pathological grades and lower Karnofsky performance status (KPS) scores. Importantly, we also found that the serum exosomal miR-301a levels were significantly reduced after surgical resection of primary tumors and increased again during GBM recurrence. Kaplan-Meier analysis of patients with an advanced pathological grade (III or IV) and an increased serum exosomal miR-301a level revealed a longer overall survival (OS) compared to those with a lower level (p < 0.01). Both univariate and multivariate Cox regression analyses confirmed that serum exosomal miR-301a levels are independently associated with OS. Finally, we found that miR-301a may activate the AKT and FAK signaling pathways by down regulating PTEN.

Conclusions

Our data indicate that serum exosomal miR-301a levels may reflect the cancer-bearing status and pathological changes in glioma patients. Serum exosomal miR-301a expression may serve as a novel biomarker for glioma diagnosis and as a prognostic factor for advanced grade disease.

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References

  1. M. Osswald, G. Solecki, W. Wick, F. Winkler, A malignant cellular network in gliomas: potential clinical implications. Neuro-Oncology 18, 479–485 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  2. M. Weller, S.M. Pfister, W. Wick, M.E. Hegi, G. Reifenberger, R. Stupp, Molecular neuro-oncology in clinical practice: a new horizon. Lancet Oncol 14, e370–e379 (2013)

    Article  CAS  PubMed  Google Scholar 

  3. X. Yue, F. Lan, M. Hu, Q. Pan, Q. Wang, J. Wang, Downregulation of serum microRNA-205 as a potential diagnostic and prognostic biomarker for human glioma. J Neurosurg 124, 122–128 (2016)

    Article  PubMed  Google Scholar 

  4. S.L. Ameres, P.D. Zamore, Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol 14, 475–488 (2013)

    Article  CAS  PubMed  Google Scholar 

  5. L. Li, C. Li, S. Wang, Z. Wang, J. Jiang, W. Wang, X. Li, J. Chen, K. Liu, C. Li, G. Zhu, Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype. Cancer Res 76, 1770–1780 (2016)

    Article  CAS  PubMed  Google Scholar 

  6. G.S. Markopoulos, E. Roupakia, M. Tokamani, E. Chavdoula, M. Hatziapostolou, C. Polytarchou, K.B. Marcu, A.G. Papavassiliou, R. Sandaltzopoulos, E. Kolettas, A step-by-step microRNA guide to cancer development and metastasis. Cell Oncol 40, 303–339 (2017)

    Article  CAS  Google Scholar 

  7. V. Taucher, H. Mangge, J. Haybaeck, R.N.A. Non-coding, in pancreatic cancer: challenges and opportunities for clinical application. Cell Oncol 39, 295–318 (2016)

    Article  CAS  Google Scholar 

  8. A. Ferraro, Altered primary chromatin structures and their implications in cancer development. Cell Oncol 39, 195–210 (2016)

    Article  Google Scholar 

  9. G.Y. Xiao, C.C. Cheng, Y.S. Chiang, W.T. Cheng, I.H. Liu, S.C. Wu, Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy. Sci Rep 6, 23120 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. X. Meng, V. Muller, K. Milde-Langosch, F. Trillsch, K. Pantel, H. Schwarzenbach, Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Oncotarget 7, 16923–16935 (2016)

    PubMed  PubMed Central  Google Scholar 

  11. S. Taverna, M. Giallombardo, I. Gil-Bazo, A.P. Carreca, M. Castiglia, J. Chacartegui, A. Araujo, R. Alessandro, P. Pauwels, M. Peeters, C. Rolfo, Exosomes isolation and characterization in serum is feasible in non-small cell lung cancer patients: critical analysis of evidence and potential role in clinical practice. Oncotarget 7, 28748–28760 (2016)

    PubMed  PubMed Central  Google Scholar 

  12. N. Nouraee, S. Khazaei, M. Vasei, S.F. Razavipour, M. Sadeghizadeh, S.J. Mowla, MicroRNAs contribution in tumor microenvironment of esophageal cancer. Cancer Biomark 16, 367–376 (2016)

    Article  CAS  PubMed  Google Scholar 

  13. R. Munagala, F. Aqil, R.C. Gupta, Exosomal miRNAs as biomarkers of recurrent lung cancer. Tumour Biol 37, 10703–10714 (2016)

    Article  CAS  PubMed  Google Scholar 

  14. X. Yue, D. Cao, F. Lan, Q. Pan, T. Xia, H. Yu, MiR-301a is activated by the Wnt/beta-catenin pathway and promotes glioma cell invasion by suppressing SEPT7. Neuro-Oncology 18, 1288–1296 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  15. Y. Tanaka, H. Kamohara, K. Kinoshita, J. Kurashige, T. Ishimoto, M. Iwatsuki, M. Watanabe, H. Baba, Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer 119, 1159–1167 (2013)

    Article  CAS  PubMed  Google Scholar 

  16. F. Ma, J. Zhang, L. Zhong, L. Wang, Y. Liu, Y. Wang, L. Peng, B. Guo, Upregulated microRNA-301a in breast cancer promotes tumor metastasis by targeting PTEN and activating Wnt/beta-catenin signaling. Gene 535, 191–197 (2014)

    Article  CAS  PubMed  Google Scholar 

  17. L. Dou, S. Wang, X. Sui, X. Meng, T. Shen, X. Huang, J. Guo, W. Fang, Y. Man, J. Xi, J. Li, MiR-301a mediates the effect of IL-6 on the AKT/GSK pathway and hepatic glycogenesis by regulating PTEN expression. Cell Physiol Biochem 35, 1413–1424 (2015)

    Article  CAS  PubMed  Google Scholar 

  18. F. Lan, H. Yu, M. Hu, T. Xia, X. Yue, miR-144-3p exerts anti-tumor effects in glioblastoma by targeting c-Met. J Neurochem 135, 274–286 (2015)

    Article  CAS  PubMed  Google Scholar 

  19. P. Parajuli, R. Anand, C. Mandalaparty, R. Suryadevara, P.U. Sriranga, S.K. Michelhaugh, S. Cazacu, S. Finniss, A. Thakur, L.G. Lum, D. Schalk, C. Brodie, S. Mittal, Preferential expression of functional IL-17R in glioma stem cells: potential role in self-renewal. Oncotarget 7, 6121–6135 (2016)

    PubMed  PubMed Central  Google Scholar 

  20. H. Tang, Q. Liu, X. Liu, F. Ye, X. Xie, X. Xie, M. Wu, Plasma miR-185 as a predictive biomarker for prognosis of malignant glioma. J Cancer Res Ther 11, 630–634 (2015)

    Article  CAS  PubMed  Google Scholar 

  21. G. Bertoli, C. Cava, I. Castiglioni, MicroRNAs as Biomarkers for Diagnosis, Prognosis and Theranostics in Prostate Cancer. Int J Mol Sci 17, 421 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  22. X. Qiu, J. Zhang, W. Shi, S. Liu, M. Kang, H. Chu, D. Wu, N. Tong, W. Gong, G. Tao, Q. Zhao, F. Qiang, H. Zhu, Q. Wu, M. Wang, Z. Zhang, Circulating MicroRNA-26a in Plasma and Its Potential Diagnostic Value in Gastric Cancer. PLoS One 11, e0151345 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  23. C.H. Lawrie, S. Gal, H.M. Dunlop, B. Pushkaran, A.P. Liggins, K. Pulford, A.H. Banham, F. Pezzella, J. Boultwood, J.S. Wainscoat, C.S. Hatton, A.L. Harris, Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol 141, 672–675 (2008)

    Article  PubMed  Google Scholar 

  24. M. Miyamae, S. Komatsu, D. Ichikawa, T. Kawaguchi, S. Hirajima, W. Okajima, T. Ohashi, T. Imamura, H. Konishi, A. Shiozaki, R. Morimura, H. Ikoma, T. Ochiai, K. Okamoto, H. Taniguchi, E. Otsuji, Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer. Br J Cancer 113, 1467–1476 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. L. Zhang, Y. Xu, X. Jin, Z. Wang, Y. Wu, D. Zhao, G. Chen, D. Li, X. Wang, H. Cao, Y. Xie, Z. Liang, A circulating miRNA signature as a diagnostic biomarker for non-invasive early detection of breast cancer. Breast Cancer Res Treat 154, 423–434 (2015)

    Article  CAS  PubMed  Google Scholar 

  26. J. Skog, T. Wurdinger, S. van Rijn, D.H. Meijer, L. Gainche, M. Sena-Esteves, W.T. Curry, Jr., B.S. Carter, A.M. Krichevsky and X.O. Breakefield, Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10, 1470–1476 (2008)

  27. L. Zhang, S. Zhang, J. Yao, F.J. Lowery, Q. Zhang, W.C. Huang, P. Li, M. Li, X. Wang, C. Zhang, H. Wang, K. Ellis, M. Cheerathodi, J.H. McCarty, D. Palmieri, J. Saunus, S. Lakhani, S. Huang, A.A. Sahin, K.D. Aldape, P.S. Steeg, D. Yu, P.T.E.N. Microenvironment-induced, loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. G. Lou, X. Song, F. Yang, S. Wu, J. Wang, Z. Chen, Y. Liu, Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol 8, 122 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  29. K. O'Brien, M.C. Lowry, C. Corcoran, V.G. Martinez, M. Daly, S. Rani, W.M. Gallagher, M.W. Radomski, R.A. MacLeod, L. O'Driscoll, miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity. Oncotarget 6, 32774–32789 (2015)

    PubMed  PubMed Central  Google Scholar 

  30. T. Matsumura, K. Sugimachi, H. Iinuma, Y. Takahashi, J. Kurashige, G. Sawada, M. Ueda, R. Uchi, H. Ueo, Y. Takano, Y. Shinden, H. Eguchi, H. Yamamoto, Y. Doki, M. Mori, T. Ochiya, K. Mimori, Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer 113, 275–281 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. R. Shi, P.Y. Wang, X.Y. Li, J.X. Chen, Y. Li, X.Z. Zhang, C.G. Zhang, T. Jiang, W.B. Li, W. Ding, S.J. Cheng, Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients. Oncotarget 6, 26971–26981 (2015)

    PubMed  PubMed Central  Google Scholar 

  32. X. Huang, T. Yuan, M. Liang, M. Du, S. Xia, R. Dittmar, D. Wang, W. See, B.A. Costello, F. Quevedo, W. Tan, D. Nandy, G.H. Bevan, S. Longenbach, Z. Sun, Y. Lu, T. Wang, S.N. Thibodeau, L. Boardman, M. Kohli, L. Wang, Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. Eur Urol 67, 33–41 (2015)

    Article  CAS  PubMed  Google Scholar 

  33. Y. Zhang, G. Duan, S. Feng, MicroRNA-301a modulates doxorubicin resistance in osteosarcoma cells by targeting AMP-activated protein kinase alpha 1. Biochem Biophys Res Commun 459, 367–373 (2015)

    Article  CAS  PubMed  Google Scholar 

  34. X. Xia, K. Zhang, G. Cen, T. Jiang, J. Cao, K. Huang, C. Huang, Q. Zhao, Z. Qiu, MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4. Oncotarget 6, 21046–21063 (2015)

    PubMed  PubMed Central  Google Scholar 

  35. H. Xie, L. Li, G. Zhu, Q. Dang, Z. Ma, D. He, L. Chang, W. Song, H.C. Chang, J.J. Krolewski, K.L. Nastiuk, S. Yeh, C. Chang, Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-beta1/Smad/MMP9 signals. Oncotarget 6, 12326–12339 (2015)

    PubMed  PubMed Central  Google Scholar 

  36. H. Yu, H. Li, H. Qian, X. Jiao, X. Zhu, X. Jiang, G. Dai, J. Huang, Upregulation of miR-301a correlates with poor prognosis in triple-negative breast cancer. Med Oncol 31, 283 (2014)

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the China National Natural Scientific Fund (No. 81772690, 81502654, 81472814, 81672969, 81573904), the Natural Scientific Fund of Shan Dong province (ZR2014HM011) and the College Foundation of the Laiwu Hospital Affilliated to Taishan Medical College (No. YYLX2014011).

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Authors and Affiliations

  1. Department of Radiation Oncology, Tianjin Hospital, 406 Jiefangnan Road, Tianjin, 300211, People’s Republic of China

    Fengming Lan

  2. Department of Radiation Oncology, PLA Airforce General Hospital of Anhui Medical University, Beijing, 100142, People’s Republic of China

    Qin Qing

  3. Department of Neurosurgery, Laiwu City People’s Hospital, Laiwu, Shandong Province, 271100, People’s Republic of China

    Qiang Pan

  4. Departments of Radiation Oncology and Shandong Province Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong, 250117, People’s Republic of China

    Man Hu

  5. Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of radiotherapy, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijin, 100142, People’s Republic of China

    Huiming Yu

  6. Tianjin Huanhu Hospital, Tianjin Neurosurgery Institute, 6 Jizhao Road, Tianjin, 300350, People’s Republic of China

    Xiao Yue

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  1. Fengming Lan
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Correspondence to Huiming Yu or Xiao Yue.

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Lan, F., Qing, Q., Pan, Q. et al. Serum exosomal miR-301a as a potential diagnostic and prognostic biomarker for human glioma. Cell Oncol. 41, 25–33 (2018). https://doi.org/10.1007/s13402-017-0355-3

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