miR-224-5p-enriched exosomes promote tumorigenesis by directly targeting androgen receptor in non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) is the most common form of cancer, resulting in cancer-related deaths worldwide. Exosomes, a subclass of extracellular vesicles, are produced and secreted from various types of cells, including cancer cells. Cancer-derived exosomes can deliver nucleic acids, proteins, and lipids to provide a favorable microenvironment that supports tumor growth through enhancing cell proliferation and metastasis. Our results showed that miR-224-5p was upregulated in NSCLC patient tissues and cell lines, with a tumor-promoting phenotype. Meanwhile, exosome-derived miR-224-5p induced cell proliferation and metastasis in NSCLC and human lung cells. Moreover, we characterized the androgen receptor (AR) as a direct target of miR-224-5p. Tumor xenograft assay experiments revealed that overexpression of miR-224-5p drove NSCLC tumor growth via the suppression of AR and the mediation of epithelial-mesenchymal transition (EMT). Collectively, our results suggest that miR-224-5p-enriched exosomes promote tumorigenesis by directly targeting AR in NSCLC, which may provide novel potential therapeutic and preventive targets for NSCLC. Non-small cell lung cancer (NSCLC) is the most common form of cancer, resulting in cancer-related deaths worldwide. Exosomes, a subclass of extracellular vesicles, are produced and secreted from various types of cells, including cancer cells. Cancer-derived exosomes can deliver nucleic acids, proteins, and lipids to provide a favorable microenvironment that supports tumor growth through enhancing cell proliferation and metastasis. Our results showed that miR-224-5p was upregulated in NSCLC patient tissues and cell lines, with a tumor-promoting phenotype. Meanwhile, exosome-derived miR-224-5p induced cell proliferation and metastasis in NSCLC and human lung cells. Moreover, we characterized the androgen receptor (AR) as a direct target of miR-224-5p. Tumor xenograft assay experiments revealed that overexpression of miR-224-5p drove NSCLC tumor growth via the suppression of AR and the mediation of epithelial-mesenchymal transition (EMT). Collectively, our results suggest that miR-224-5p-enriched exosomes promote tumorigenesis by directly targeting AR in NSCLC, which may provide novel potential therapeutic and preventive targets for NSCLC. IntroductionLung cancer is the most common malignant cancer and the leading cause of cancer-related deaths worldwide.1Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 2018; 68: 394-424Crossref PubMed Scopus (47594) Google Scholar,2Chen Z. Fillmore C.M. Hammerman P.S. Kim C.F. Wong K.K. Non-small-cell lung cancers: a heterogeneous set of diseases.Nat. Rev. Cancer. 2014; 14: 535-546Crossref PubMed Scopus (1025) Google Scholar More than 85% of lung cancer cases are classified as non-small cell lung cancer (NSCLC), with the predicted 5-year survival rate remaining below 15%.2Chen Z. Fillmore C.M. Hammerman P.S. Kim C.F. Wong K.K. Non-small-cell lung cancers: a heterogeneous set of diseases.Nat. Rev. Cancer. 2014; 14: 535-546Crossref PubMed Scopus (1025) Google Scholar,3Herbst R.S. Morgensztern D. Boshoff C. The biology and management of non-small cell lung cancer.Nature. 2018; 553: 446-454Crossref PubMed Scopus (1747) Google Scholar There are many factors associated with the high incidence and mortality of NSCLC, such as late diagnosis, smoking history,4Reck M. Blais N. Juhasz E. Gorbunova V. Jones C.M. Urban L. Orlov S. Barlesi F. Kio E. Keilholz U. et al.Smoking history predicts sensitivity to PARP inhibitor veliparib in patients with advanced non-small cell lung cancer.J. Thorac. Oncol. 2017; 12: 1098-1108Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar age differences,5Hansen O. Schytte T. Nielsen M. Brink C. Age dependent prognosis in concurrent chemo-radiation of locally advanced NSCLC.Acta Oncol. 2015; 54: 333-339Crossref PubMed Scopus (11) Google Scholar and sex.6Harichand-Herdt S. Ramalingam S.S. Gender-associated differences in lung cancer: clinical characteristics and treatment outcomes in women.Semin. Oncol. 2009; 36: 572-580Crossref PubMed Scopus (39) Google ScholarExosomes are extracellular vesicles with a size range of 30–150 nm in diameter that are secreted from almost all types of cells, including cancer cells.7Ruivo C.F. Adem B. Silva M. Melo S.A. The biology of cancer exosomes: insights and new perspectives.Cancer Res. 2017; 77: 6480-6488Crossref PubMed Scopus (322) Google Scholar Cancer-derived exosomes can deliver nucleic acids,8Fang T. Lv H. Lv G. Li T. Wang C. Han Q. Yu L. Su B. Guo L. Huang S. et al.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.Nat. Commun. 2018; 9: 191Crossref PubMed Scopus (456) Google Scholar proteins,9Zhang H. Deng T. Liu R. Bai M. Zhou L. Wang X. Li S. Wang X. Yang H. Li J. et al.Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis.Nat. Commun. 2017; 8: 15016Crossref PubMed Scopus (320) Google Scholar and lipids10Skotland T. Sandvig K. Llorente A. Lipids in exosomes: current knowledge and the way forward.Prog. Lipid Res. 2017; 66: 30-41Crossref PubMed Scopus (532) Google Scholar to neighboring or distant cells and subsequently modulate recipient cells. Recently, high levels of microRNAs (miRNAs) have been identified in cancer-derived exosomes, which provide a favorable microenvironment that contribute to tumorigenesis,11Melo S.A. Sugimoto H. O’Connell J.T. Kato N. Villanueva A. Vidal A. Qiu L. Vitkin E. Perelman L.T. Melo C.A. et al.Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis.Cancer Cell. 2014; 26: 707-721Abstract Full Text Full Text PDF PubMed Scopus (1069) Google Scholar tumor metastasis,8Fang T. Lv H. Lv G. Li T. Wang C. Han Q. Yu L. Su B. Guo L. Huang S. et al.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.Nat. Commun. 2018; 9: 191Crossref PubMed Scopus (456) Google Scholar,9Zhang H. Deng T. Liu R. Bai M. Zhou L. Wang X. Li S. Wang X. Yang H. Li J. et al.Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis.Nat. Commun. 2017; 8: 15016Crossref PubMed Scopus (320) Google Scholar angiogenesis,12Zeng Z. Li Y. Pan Y. Lan X. Song F. Sun J. Zhou K. Liu X. Ren X. Wang F. et al.Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by and Commun. 2018; 9: PubMed Scopus Google Scholar Z. Y. Y. X. A. J. L. J. D. from induced by treatment promotes lung 2017; 36: PubMed Scopus Google Scholar and Y. H. Li X. X. Li Y. Liu D. J. Liu F. L. Y. Y. to the therapeutic of cells 2017; PubMed Scopus Google Scholar miR-224-5p been to in NSCLC and tumor and R. Sun Kim T. Z. M. Li B. C. Y. et promotes tumor in cell lung 2015; PubMed Scopus Google S. J. Y. Wang F. Y. X. and metastasis by targeting in non-small cell lung cancer 2018; Google Scholar Meanwhile, the high of exosomal miR-224-5p can promote the proliferation and of liver cancer cells, which may as a and of Y. Liu Zhou Y. of exosomal in of and and J. PubMed Scopus Google Scholar cancer-derived exosomal miR-224-5p is in NSCLC tumorigenesis been and are to the survival rate of lung cancer R. R. et and non-small cell lung cancer: in tumor Cancer 2018; PubMed Scopus Google K. T. E. T. T. S. L.T. S. of receptor and in non-small cell lung PubMed Scopus Google D. C. O. F. The of tumor cell of and androgen receptor in patients for cell lung PubMed Scopus Google Scholar The androgen receptor (AR) to the receptor as a the of androgen AR to the or of C. H. N. in 2017; PubMed Scopus Google M. T. B. D. receptor and androgen in cancer: a Oncol. 2017; PubMed Scopus Google Scholar the of AR for is as a and potential therapeutic target in E. S. A. A. J. et microRNAs provide and therapeutic targets in advanced PubMed Scopus Google Scholar J. H. receptor in 2017; 9: Scopus Google Scholar and M. T. B. D. receptor and androgen in cancer: a Oncol. 2017; PubMed Scopus Google B. A. et receptor and cancer results from the Cancer PubMed Scopus Google Scholar the of AR in the of cancers a and NSCLC patients to androgen associated with a survival C. G. R. and survival in patients with lung Cancer. 2015; PubMed Scopus Google Scholar the survival rate of NSCLC patients with levels of AR was than that in NSCLC patients with AR R. F. A. A. T. A. M. A. M. Z. et in lung and in by PubMed Scopus Google Scholar AR in the outcomes and of NSCLC to our results showed that miR-224-5p-enriched exosomes can to and cells, human lung cells or NSCLC cell proliferation and by targeting is upregulated in to miR-224-5p a in the of NSCLC, of NSCLC patient tissues for the of miR-224-5p. with the results that miR-224-5p was upregulated in NSCLC tissues the levels of miR-224-5p to tumor and in patient tissues Meanwhile, miR-224-5p was in and cells, and is in and cells, with cells as a Collectively, results that miR-224-5p to the of promotes cell proliferation and of overexpression of miR-224-5p by with or in and cells. by miR-224-5p in cell Meanwhile, inhibitor was and cells to the of and the results that of the miR-224-5p inhibitor with a inhibitor promotes cell proliferation and of and of miR-224-5p in and cells, with by or with was as and proliferation of and cells with and with inhibitor as by a and and of formation in and cells with and with inhibitor and of cell in and cells with and with inhibitor as by the the of miR-224-5p NSCLC cell and formation of miR-224-5p a of cell proliferation and The was in cells with of miR-224-5p of miR-224-5p cell in and cells and we the of miR-224-5p NSCLC by a miR-224-5p overexpression to and miR-224-5p to a in the rate of NSCLC cells that from the in the to the in and by a assay and results that miR-224-5p to NSCLC cell proliferation and in and the of miR-224-5p and we miR-224-5p overexpression or in NSCLC cells. to miR-224-5p overexpression or miR-224-5p in NSCLC cells or the from the to the we to the rate in NSCLC cells. The results showed that of miR-224-5p NSCLC cell and and Meanwhile, rate was in the with miR-224-5p inhibitor as with inhibitor and our results that miR-224-5p and of NSCLC and results and of the in and cells with and and with inhibitor and and the of cells in the and results and and of the rate of in and cells, with and with inhibitor and rate of by the exosomes tumorigenesis of NSCLC cells in have that can exosomes and to neighboring or cells, which modulate the of target to target cell T. Lv H. Lv G. Li T. Wang C. Han Q. Yu L. Su B. Guo L. Huang S. et al.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.Nat. Commun. 2018; 9: 191Crossref PubMed Scopus (456) Google T. X. L. Wang Y. Liu X. H. Wang L. Li Y. et of Cancer. PubMed Scopus Google X. Guo H. Wang X. X. M. Wang X. Q. J. E. J. from cancer-associated in and cancer through targeting and PubMed Scopus Google Scholar we and extracellular exosomes from the of and cells with or we a of the exosomes by the and size of the exosomes The exosomal and identified in the exosomes by assay with cell exosomes tumorigenesis of NSCLC cells in and and identified the size and of exosomes from cell of exosomal in or cell was for as of miR-224-5p in or from and cells. and of miR-224-5p and cell proliferation in and cells with or was as and and of cell in and cells with or as by the miR-224-5p NSCLC cell growth and we miR-224-5p contribute to through we that miR-224-5p was in from and cells, to that and cells miR-224-5p levels with that miR-224-5p-enriched exosomes the of miR-224-5p in cells. the proliferation and of and cells to with suggest that miR-224-5p can in exosomes and to neighboring cells, recipient cell proliferation and in is a direct target of the of to the tumorigenesis of NSCLC, we identified AR as a potential target for miR-224-5p with by and The and of miR-224-5p with the AR are in a assay was to AR is a direct target of miR-224-5p. or with and miR-224-5p or cells. The results showed that to with the was by in the cells with that the of AR are by miR-224-5p and and of AR that the of AR and was in cells and in cells Moreover, with the of AR in and cells the in the of AR results that AR is a direct target of and miR-224-5p can directly target AR exosomes by is a direct target of The predicted and of the AR with miR-224-5p. The the miR-224-5p and the AR and of the AR and in cells with or including and was for as and of AR or in and cells with or with of AR in and cells with or of AR and with tumor and in of NSCLC patient tumor and of AR in human lung cell and in NSCLC cell and and as for and of survival of lung cancer patients from a The miR-224-5p and to the the the of AR in NSCLC we the of AR in the of NSCLC and which to that of miR-224-5p The of AR was in tumor was the of AR and tumor or in patient tissues with cells, the levels of AR in and cells The of AR was in cells, which was to the of miR-224-5p the we a survival of NSCLC revealed that AR overexpression was with survival in NSCLC cases the a AR and miR-224-5p in of NSCLC patient Collectively, results suggest that AR is in NSCLC tissues and cell lines, and a novel potential for to the of AR in NSCLC cells, AR was by with AR The levels of AR and subsequently in and cells, of AR and and that and cell and to we the of and The results of showed that the of cell from the to the and the rate of in and cells and that AR a as miR-224-5p overexpression in NSCLC cells. showed that miR-224-5p promotes tumorigenesis of NSCLC by directly to and and of AR and in and cells with or and as for and and of cell proliferation formation and of and cells with and results and of the and rate of in and cells with or and the of cells in the and and rate of by the tumor growth and in the of miR-224-5p NSCLC tumor growth and in we a xenograft and and with or cells, in the and subsequently and The xenograft in the tumor growth and of and size with the of miR-224-5p and of AR levels in xenograft from the with and tumor growth in and and of xenograft from with or cells. Tumor growth with and of miR-224-5p and AR in xenograft of in the of of with and of tumor tissues with and and of for and AR in tumor tissues the the and xenograft of to and in the of the showed and or with which that miR-224-5p the lung of cells Moreover, in xenograft of the showed levels of the cell proliferation and epithelial-mesenchymal transition with levels of and with the results that miR-224-5p can tumor growth and lung in via the suppression of AR and the mediation of results that miR-224-5p was upregulated in NSCLC patient tissues and cell AR was to a direct target of miR-224-5p. we have identified that miR-224-5p can in exosomes, to cells, cell proliferation and metastasis through directly AR in Meanwhile, our results that miR-224-5p tumor growth in that the and are associated with the incidence and clinical outcomes of lung R. R. et and non-small cell lung cancer: in tumor Cancer 2018; PubMed Scopus Google X. Y. Wang Z. S. R. H. promote NSCLC by the receptor a biology PubMed Scopus Google Scholar receptor been to to modulate growth receptor and to promote NSCLC X. Y. Wang Z. S. R. H. promote NSCLC by the receptor a biology PubMed Scopus Google Scholar was to by F. C. I. NSCLC to by Cancer Res. 2018; PubMed Scopus Google Scholar and with of EGFR in Z. Li Z. X. Z. Liu Z. T. J. J. M. J. et outcomes of treatment in NSCLC patients with EGFR 2015; PubMed Scopus Google Scholar the potential and therapeutic of the receptor in clinical management of a in the of the and of AR in NSCLC are and C. G. R. and survival in patients with lung Cancer. 2015; PubMed Scopus Google R. F. A. A. T. A. M. A. M. Z. et in lung and in by PubMed Scopus Google Scholar our we that AR was in NSCLC tissues tumor and Meanwhile, NSCLC patients with a high of AR a survival experiments that AR cell proliferation and and cell in NSCLC AR as in by or of of androgen C. H. N. in 2017; PubMed Scopus Google Scholar Moreover, the AR is through cancer, AR can by in extracellular or L. D. G. S. M. S. A. F. I. L. et receptor in cancer: a potential target for the Rev. 2018; 68: Full Text Full Text PDF PubMed Scopus Google Scholar cancer, AR with and and and Z. Yang S. Zhou Q. Wang G. Song J. Li Z. Z. J. K. Y. et of exosome-derived in tumor Cancer. 2018; PubMed Scopus Google Scholar by upregulated AR in of cell which the for targeting the AR in are extracellular vesicles that can deliver nucleic acids, proteins, and lipids to neighboring or distant cells. from the by the formation of R. The and of PubMed Scopus Google Scholar have the of as novel of have that or secreted by tumor cells through exosomes are in the the tumor and et T. Lv H. Lv G. Li T. Wang C. Han Q. Yu L. Su B. Guo L. Huang S. et al.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.Nat. Commun. 2018; 9: 191Crossref PubMed Scopus (456) Google Scholar that exosomal miR-1247-3p lung metastasis of tumor cells and of which are to the tumor microenvironment or modulate by as Z. Yang S. Zhou Q. Wang G. Song J. Li Z. Z. J. K. Y. et of exosome-derived in tumor Cancer. 2018; PubMed Scopus Google L. J. C. Liu B. Y. Liu F. Sun Li et promotes in cancer by as a Cell. Full Text Full Text PDF PubMed Scopus Google from our have that C. X. Wang Liu B. as by directly targeting in lung 2017; 8: PubMed Scopus Google Scholar H. Z. Liu X. C. Y. L. Wang J. S. Li Y. is for non-small cell lung cancer by Scopus Google Scholar Y. Wang D. Li X. Y. Y. Yu H. Z. non-small cell lung cancer via targeting Cancer. PubMed Scopus (39) Google Scholar and Li Y. Liu X. X. Sun Q. Z. non-small cell lung cancer via J. PubMed Scopus Google Scholar have a the of NSCLC. revealed that the of associated with the tumorigenesis of lung our that miR-224-5p was exosomes and exosomal miR-224-5p was cells, cell proliferation and of NSCLC or human lung cells. exosomes are as to target to to and from miR-224-5p by the and to recipient cells or L. G. and of 2017; PubMed Scopus Google Scholar the exosomes and tumorigenesis to exosome-derived miR-224-5p as a and target for our that miR-224-5p-enriched exosomes promote tumorigenesis of NSCLC by directly targeting novel potential targets for and treatment of and and cell with with and of human NSCLC The was by the of of all in are in human NSCLC cell and from the The lung and cell from the of and cell in and cells in with and the of and in a and with was was with The and to of and and as the for and was with by the for of and are in and the was the with and and as for with or cells. The for and for and with a The of or and cells. the cells for via a to the miR-224-5p overexpression cell to the for and cells with miR-224-5p or the and The of or was or and the experiments proliferation the cells a a of cells to was of with of in the for the of was nm a formation cells a a of cells and for the with for and with for the and cells a a of cells and by a in the of was with with for or the cell was and cell assay was cells to the of in of and of with was to the of the and and the cell and to the of cell to the cells cells to in the cells by with with of for and with for in the the cells for via a and was from the cells or and with a of by and to a the was in for with AR and with the with a to for with with a and and we cells to that the cell the with cell and for to for and for and for with The of the and exosomes The of exosomes, was by the and size of exosomes by or of miR-224-5p-enriched exosomes exosomes and with NSCLC and for the cells to of miR-224-5p in NSCLC was by The of exosomes proliferation and of NSCLC was as of AR of miR-224-5p was of the in the and as the by with the of the by are in cells in the cell the cells with a of miR-224-5p or of or and of the as the for the for the of the cells The to and as the in tumor xenograft assay and from the and in a cells with or in of the of the with cells in of via the Tumor with a and tumor the and the xenograft and lung tissues tumor tissues and lung tissues to and or by the and of tumor tissues with in and of and by and the subsequently with the in for and in for in the the with and AR to by of with a and a are as the a with set as was to was with IntroductionLung cancer is the most common malignant cancer and the leading cause of cancer-related deaths worldwide.1Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 2018; 68: 394-424Crossref PubMed Scopus (47594) Google Scholar,2Chen Z. Fillmore C.M. Hammerman P.S. Kim C.F. Wong K.K. Non-small-cell lung cancers: a heterogeneous set of diseases.Nat. Rev. Cancer. 2014; 14: 535-546Crossref PubMed Scopus (1025) Google Scholar More than 85% of lung cancer cases are classified as non-small cell lung cancer (NSCLC), with the predicted 5-year survival rate remaining below 15%.2Chen Z. Fillmore C.M. Hammerman P.S. Kim C.F. Wong K.K. Non-small-cell lung cancers: a heterogeneous set of diseases.Nat. Rev. Cancer. 2014; 14: 535-546Crossref PubMed Scopus (1025) Google Scholar,3Herbst R.S. Morgensztern D. Boshoff C. The biology and management of non-small cell lung cancer.Nature. 2018; 553: 446-454Crossref PubMed Scopus (1747) Google Scholar There are many factors associated with the high incidence and mortality of NSCLC, such as late diagnosis, smoking history,4Reck M. Blais N. Juhasz E. Gorbunova V. Jones C.M. Urban L. Orlov S. Barlesi F. Kio E. Keilholz U. et al.Smoking history predicts sensitivity to PARP inhibitor veliparib in patients with advanced non-small cell lung cancer.J. Thorac. Oncol. 2017; 12: 1098-1108Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar age differences,5Hansen O. Schytte T. Nielsen M. Brink C. Age dependent prognosis in concurrent chemo-radiation of locally advanced NSCLC.Acta Oncol. 2015; 54: 333-339Crossref PubMed Scopus (11) Google Scholar and sex.6Harichand-Herdt S. Ramalingam S.S. Gender-associated differences in lung cancer: clinical characteristics and treatment outcomes in women.Semin. Oncol. 2009; 36: 572-580Crossref PubMed Scopus (39) Google ScholarExosomes are extracellular vesicles with a size range of 30–150 nm in diameter that are secreted from almost all types of cells, including cancer cells.7Ruivo C.F. Adem B. Silva M. Melo S.A. The biology of cancer exosomes: insights and new perspectives.Cancer Res. 2017; 77: 6480-6488Crossref PubMed Scopus (322) Google Scholar Cancer-derived exosomes can deliver nucleic acids,8Fang T. Lv H. Lv G. Li T. Wang C. Han Q. Yu L. Su B. Guo L. Huang S. et al.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.Nat. Commun. 2018; 9: 191Crossref PubMed Scopus (456) Google Scholar proteins,9Zhang H. Deng T. Liu R. Bai M. Zhou L. Wang X. Li S. Wang X. Yang H. Li J. et al.Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis.Nat. Commun. 2017; 8: 15016Crossref PubMed Scopus (320) Google Scholar and lipids10Skotland T. Sandvig K. Llorente A. Lipids in exosomes: current knowledge and the way forward.Prog. Lipid Res. 2017; 66: 30-41Crossref PubMed Scopus (532) Google Scholar to neighboring or distant cells and subsequently modulate recipient cells. Recently, high levels of microRNAs (miRNAs) have been identified in cancer-derived exosomes, which provide a favorable microenvironment that contribute to tumorigenesis,11Melo S.A. Sugimoto H. O’Connell J.T. Kato N. Villanueva A. Vidal A. Qiu L. Vitkin E. Perelman L.T. Melo C.A. et al.Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis.Cancer Cell. 2014; 26: 707-721Abstract Full Text Full Text PDF PubMed Scopus (1069) Google Scholar tumor metastasis,8Fang T. Lv H. Lv G. Li T. Wang C. Han Q. Yu L. Su B. Guo L. Huang S. et al.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.Nat. Commun. 2018; 9: 191Crossref PubMed Scopus (456) Google Scholar,9Zhang H. Deng T. Liu R. Bai M. Zhou L. Wang X. Li S. Wang X. Yang H. Li J. et al.Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis.Nat. Commun. 2017; 8: 15016Crossref PubMed Scopus (320) Google Scholar angiogenesis,12Zeng Z. Li Y. Pan Y. Lan X. Song F. Sun J. Zhou K. Liu X. Ren X. Wang F. et al.Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by and Commun. 2018; 9: PubMed Scopus Google Scholar Z. Y. Y. X. A. J. L. J. D. from induced by treatment promotes lung 2017; 36: PubMed Scopus Google Scholar and Y. H. Li X. X. Li Y. Liu D. J. Liu F. L. Y. Y. to the therapeutic of cells 2017; PubMed Scopus Google Scholar miR-224-5p been to in NSCLC and tumor and R. Sun Kim T. Z. M. Li B. C. Y. et promotes tumor in cell lung 2015; PubMed Scopus Google S. J. Y. Wang F. Y. X. and metastasis by targeting in non-small cell lung cancer 2018; Google Scholar Meanwhile, the high of exosomal miR-224-5p can promote the proliferation and of liver cancer cells, which may as a and of Y. Liu Zhou Y. of exosomal in of and and J. PubMed Scopus Google Scholar cancer-derived exosomal miR-224-5p is in NSCLC tumorigenesis been and are to the survival rate of lung cancer R. R. et and non-small cell lung cancer: in tumor Cancer 2018; PubMed Scopus Google K. T. E. T. T. S. L.T. S. of receptor and in non-small cell lung PubMed Scopus Google D. C. O. F. The of tumor cell of and androgen receptor in patients for cell lung PubMed Scopus Google Scholar The androgen receptor (AR) to the receptor as a the of androgen AR to the or of C. H. N. in 2017; PubMed Scopus Google M. T. B. D. receptor and androgen in cancer: a Oncol. 2017; PubMed Scopus Google Scholar the of AR for is as a and potential therapeutic target in E. S. A. A. J. et microRNAs provide and therapeutic targets in advanced PubMed Scopus Google Scholar J. H. receptor in 2017; 9: Scopus Google Scholar and M. T. B. D. receptor and androgen in cancer: a Oncol. 2017; PubMed Scopus Google B. A. et receptor and cancer results from the Cancer PubMed Scopus Google Scholar the of AR in the of cancers a and NSCLC patients to androgen associated with a survival C. G. R. and survival in patients with lung Cancer. 2015; PubMed Scopus Google Scholar the survival rate of NSCLC patients with levels of AR was than that in NSCLC patients with AR R. F. A. A. T. A. M. A. M. Z. et in lung and in by PubMed Scopus Google Scholar AR in the outcomes and of NSCLC to our results showed that miR-224-5p-enriched exosomes can to and cells, human lung cells or NSCLC cell proliferation and by targeting

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