Suppression of endothelial miR-22 mediates non-small cell lung cancer cell-induced angiogenesis

Abstract

MicroRNAs (miRNAs) expressed in endothelial cells (ECs) are powerful regulators of angiogenesis, which is essential for tumor growth and metastasis. Here, we demonstrated that miR-22 is preferentially and highly expressed in ECs, while its endothelial level is significantly downregulated in human non-small cell lung cancer (NSCLC) tissues when compared to matched nontumor lung tissues. This reduction of endothelial miR-22 is possibly induced by NSCLC cell-secreted interleukin-1β and subsequently activated transcription factor nuclear factor-κB. Endothelial miR-22 functions as a potent angiogenesis inhibitor that inhibits all of the key angiogenic activities of ECs and consequently NSCLC growth through directly targeting sirtuin 1 and fibroblast growth factor receptor 1 in ECs, leading to inactivation of AKT/mammalian target of rapamycin signaling. These findings provide insight into the molecular mechanisms of NSCLC angiogenesis and indicate that endothelial miR-22 represents a potential target for the future antiangiogenic treatment of NSCLC. MicroRNAs (miRNAs) expressed in endothelial cells (ECs) are powerful regulators of angiogenesis, which is essential for tumor growth and metastasis. Here, we demonstrated that miR-22 is preferentially and highly expressed in ECs, while its endothelial level is significantly downregulated in human non-small cell lung cancer (NSCLC) tissues when compared to matched nontumor lung tissues. This reduction of endothelial miR-22 is possibly induced by NSCLC cell-secreted interleukin-1β and subsequently activated transcription factor nuclear factor-κB. Endothelial miR-22 functions as a potent angiogenesis inhibitor that inhibits all of the key angiogenic activities of ECs and consequently NSCLC growth through directly targeting sirtuin 1 and fibroblast growth factor receptor 1 in ECs, leading to inactivation of AKT/mammalian target of rapamycin signaling. These findings provide insight into the molecular mechanisms of NSCLC angiogenesis and indicate that endothelial miR-22 represents a potential target for the future antiangiogenic treatment of NSCLC. IntroductionAngiogenesis, i.e., the formation of new blood vessels from preexisting ones, is essential for tumor growth and metastasis. Accordingly, excessive angiogenesis is a poor prognostic indicator for the aggressiveness of different cancer types such as non-small cell lung cancer (NSCLC).1Fontanini G. Lucchi M. Vignati S. Mussi A. Ciardiello F. De Laurentiis M. De Placido S. Basolo F. Angeletti C.A. Bevilacqua G. Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study.J. Natl. Cancer Inst. 1997; 89: 881-886Crossref PubMed Scopus (298) Google Scholar Tumor angiogenesis is tightly regulated by the balance between pro- and antiangiogenic factors, which involves the dynamic communication between tumor cells and endothelial cells (ECs). Tumor cells are capable of releasing different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF, FGF2), epidermal growth factor (EGF), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8.2Bielenberg D.R. Zetter B.R. The contribution of angiogenesis to the process of metastasis.Cancer J. 2015; 21: 267-273Crossref PubMed Scopus (265) Google Scholar,3Rajabi M. Mousa S.A. The role of angiogenesis in cancer treatment.Biomedicines. 2017; 5: 34Crossref PubMed Scopus (329) Google Scholar The binding of these factors to their receptors located on ECs activates pivotal downstream angiogenesis-related signaling pathways such as phosphoinositide 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) signaling.4Hoeben A. Landuyt B. Highley M.S. Wildiers H. Van Oosterom A.T. De Bruijn E.A. Vascular endothelial growth factor and angiogenesis.Pharmacol. Rev. 2004; 56: 549-580Crossref PubMed Scopus (1429) Google Scholar Consequently, ECs are stimulated to degrade their basement membrane, proliferate, migrate toward tumor cells, and interconnect with each other to form new microvascular networks.2Bielenberg D.R. Zetter B.R. The contribution of angiogenesis to the process of metastasis.Cancer J. 2015; 21: 267-273Crossref PubMed Scopus (265) Google Scholar,4Hoeben A. Landuyt B. Highley M.S. Wildiers H. Van Oosterom A.T. De Bruijn E.A. Vascular endothelial growth factor and angiogenesis.Pharmacol. Rev. 2004; 56: 549-580Crossref PubMed Scopus (1429) Google ScholarPrevious studies have shown that sirtuin (SIRT) 1 plays a crucial role in the regulation of angiogenesis.5Potente M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google Scholar SIRT1 is a prototype member of the sirtuin family of nicotinamide adenine dinucleotide-dependent class III histone deacetylases. Loss of SIRT1 results in a significant reduction of EC sprouting and branching activity.5Potente M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google Scholar Moreover, endothelial SIRT1 deletion impairs angiogenesis within ischemic hindlimbs and the M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google R. S. J. B. M. J. R. F. J. M.S. Endothelial sirtuin 1 through of to of vascular PubMed Scopus Google Scholar The proangiogenic of SIRT1 is by of its that SIRT1 which to leading to the of the of signaling by its in and PubMed Scopus Google Scholar SIRT1 the transcription factor and its antiangiogenic activity.5Potente M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google Scholar SIRT1 the of by the transcription of a of target of rapamycin in impairs signaling and results in and PubMed Scopus Google (miRNAs) are that through binding to the of leading to and D. M. MicroRNAs in and Rev. PubMed Scopus Google Scholar the as powerful regulators of to tumor and of miR-22 within different human and tumor tissues are to of for the and of types of cancer such as M. R. J. inhibits cell and and by targeting in 2017; PubMed Scopus Google Scholar is located on and highly J. of in human and PubMed Scopus Google Scholar to expressed in different types of R. M. MicroRNAs in the tumor controls on the Google Scholar its role in tumor angiogenesis the we the regulation of endothelial miR-22 by NSCLC the of miR-22 in basic angiogenic EC and The antiangiogenic of miR-22 in and in we the of endothelial miR-22 on NSCLC angiogenesis and growth in a tumor SIRT1 and receptor as of miR-22 in miR-22 is downregulated in human NSCLC the of miR-22 in tumor endothelial cells and endothelial cells ECs the blood vessels in tumor tissues and matched nontumor lung tissues from with lung by of of ECs by by a of the EC and receptor as as a of the and and the in and when compared to that in lung and NSCLC and These ECs for to the level of we that miR-22 is significantly downregulated in ECs from NSCLC tissues when compared to from matched nontumor lung tissues the between endothelial miR-22 and of NSCLC to the of the level of endothelial the NSCLC into a miR-22 and a miR-22 tumor tumor and vascular compared between the that a of endothelial miR-22 with vascular of NSCLC miR-22 to preferentially and highly expressed in types of ECs, i.e., human microvascular endothelial cells and human endothelial cells when compared to NSCLC cells and and other cell types in the tumor such as from and human This a of miR-22 in ECs cells miR-22 in tumor cells are capable of the angiogenic of ECs by and we a to the of miR-22 in is regulated by NSCLC of with cells, The of and in the and as by a and a reduction of miR-22 in with cells and cells when compared to of we with NSCLC cells between these cell types in a with cells a in the miR-22 level of that factors by the tumor cells to the of endothelial This by the of with cells, which significantly the endothelial of miR-22 by studies the of NSCLC cells to proangiogenic factors, and S. M. M. M. et of lung cancer cell between their and the in and in 2007; PubMed Scopus Google S. A. S. of from human tumor cell and of and its on survival of tumor PubMed Scopus Google F. F. J. E. R. S. B. E. E. et and and of Natl. PubMed Scopus Google B. M. A. E. and human tumor cells J. PubMed Scopus Google Scholar of these factors the NSCLC reduction of endothelial stimulated with each factor for that the of miR-22 is significantly by and is by and of with significantly the of miR-22 in induced by with cells This that NSCLC cells endothelial miR-22 through the that is of nuclear factor which the transcription of a of and and target of transcription PubMed Scopus Google E. M. G. R. E. of signaling in the regulation of on in PubMed Scopus Google Scholar we inhibits the transcription of miR-22 in to the inhibitor for This in a of miR-22 when compared to controls that is by the of endothelial miR-22 induced by NSCLC cells, we the of in with cells of we demonstrated that the nuclear of a of is significantly in with tumor cells and of signaling with the reduction of endothelial miR-22 induced by with cells inhibits the angiogenic of the of miR-22 in EC angiogenic we with miR-22 and miR-22 inhibitor to and the level of with the of the of inhibitor as the of these the of and by shown in and with significantly the miR-22 level by while miR-22 by to the of with significantly the of of This of for in ECs The of miR-22 on EC by the cell of The cell significantly in when compared to controls and This with in the of cells and These results that miR-22 inhibits EC and by the cells in the inhibits and and of of with and as by the to the cells in and for and of The cells with and indicate the and of by the of with and as by the to and of The cells with and and formation of of with and as by the formation are the of miR-22 in EC and of with the of and and the of cells by and of with significantly and and cell by and we formation to the of miR-22 in the of with the of by when compared to controls and significantly EC formation by and miR-22 angiogenesis and in miR-22 is in endothelial we that the of vascular sprouting from is significantly by with and and significantly by with and angiogenesis and in and of which with and and in for and of of that with and as by to and of human in with and with to cell and of of with and as by to are in we in a reduction of the when compared to controls and cells with a cells and miR-22 inhibits tumor angiogenesis and findings demonstrated that NSCLC cells the level of miR-22 in ECs and miR-22 as a potent angiogenesis we that tumor cells angiogenesis through endothelial miR-22 we in tumor communication by cells with into the of and to the of the that of with significantly inhibits tumor between to when compared to controls and Accordingly, a tumor of miR-22 in significantly the tumor of human within the the angiogenic of from the and demonstrated that tumor cells when compared to controls This that miR-22 in tumor ECs inhibits the of tumor cells and their cell miR-22 inhibits tumor angiogenesis and of as by of a on the of tumor as as on and of on of on and The of are by of as by on and to of human and in on with to cell of human and in on and of human tumor cells within and cells of the of within are SIRT1 and in the of miR-22 that its antiangiogenic in ECs, we the human target of miR-22 to the of and that are in angiogenesis and have as miR-22 which tumor necrosis factor receptor vascular endothelial growth factor kinase kinase and kinase of these downregulated in when compared to controls These findings indicate that these the of miR-22 and is that through D. M. MicroRNAs in and Rev. PubMed Scopus Google H. D. J. is the of by the 56: PubMed Scopus Google SIRT1 and in of of and human target of miR-22 in as by of and in with level of of and as by of in cells with and a as by the of and in with and of of and as by are we the human of on the and angiogenesis-related These factor of cell viral oncogene homolog and the of SIRT1 and to significantly in when compared to controls the of SIRT1 and by miR-22 as by and et L. miR-22 and PubMed Scopus Google Scholar that miR-22 in human in is a highly cell and is for target a by and with deletion of into the that significantly the of the reduction with the that SIRT1 and are of the pivotal angiogenesis we to the of in and with the of and by and inhibits angiogenesis through targeting SIRT1 and studies role of SIRT1 and in angiogenesis.5Potente M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google M. S. E. R. M. growth growth factor receptor in Rev. PubMed Scopus Google Scholar miR-22 inhibits the angiogenic of ECs through targeting SIRT1 and the SIRT1 inhibitor and the inhibitor in of in of a we that of and of significantly the of 3 of treatment and Accordingly, to of these we a of each inhibitor of and of for the and formation These that to and and formation inhibits angiogenesis through targeting SIRT1 and and of of that for to of and as by the of of that with and with of of for as by the of by the of that with and with of of for as by the to formation of of that with and with of of for as by the formation of of that with and with of for as by the of by the of that with and with of for as by the formation of of that with and with of for as by the formation and level of SIRT1 of in that for to of 1 of as by and level of SIRT1 of in that with cells in a in the of 1 of for as by are and we miR-22 functions through which is a downstream of SIRT1 and the highly inhibitor a inhibits the angiogenic of endothelial cells by targeting and J. PubMed Scopus Google Scholar we that of significantly 3 of Accordingly, to of by the and formation we that of and formation we that NSCLC cells endothelial miR-22 by possibly we the regulation of the miR-22 in we the of SIRT1 and in as as with that significantly the of SIRT1 that of and the of and Moreover, of with cells significantly the endothelial of SIRT1 and of with and in as a tumor oncogene by the and of different types of tumor J. of in human and PubMed Scopus Google Scholar on the of miR-22 on the angiogenic of miR-22 to endothelial cell and its into vascular endothelial cell by targeting PubMed Scopus Google H. L. M. A. J. G. and angiogenesis targeting 2017; PubMed Scopus Google Scholar the and of miR-22 in ECs findings that miR-22 is preferentially and highly expressed in ECs and the of endothelial miR-22 NSCLC blood NSCLC cells endothelial possibly releasing and the of miR-22 in This the angiogenic of ECs, miR-22 functions as a potent angiogenesis inhibitor by targeting SIRT1 and cancer is the cancer and the leading of cancer in A. Cancer Cancer J. PubMed Scopus Google Scholar cell and cell for of all lung cancer in and with NSCLC have treatment and a poor Mousa S.A. cell lung treatment and future Cancer 5: PubMed Scopus Google Scholar in the we on tumor and miR-22 to significantly downregulated in ECs from human NSCLC tissues when compared to that from matched nontumor lung tissues. we a significantly downregulated of miR-22 in directly with cells when compared to EC This is in with a that miR-22 in human microvascular ECs is by with J. S. J. R. growth factor receptor in angiogenic endothelial PubMed Scopus Google Scholar endothelial miR-22 to regulated by different types of cells directly with ECs receptors and ECs by factors and into the as as by the and in the J. cell and of Google Scholar that NSCLC cells endothelial miR-22 through The is as a proangiogenic E. The role in 5: PubMed Scopus Google Scholar its functions through binding to the in and activates the inhibitor of kinase The of to the of into the the transcription of and and target of transcription PubMed Scopus Google E. M. G. R. E. of signaling in the regulation of on in PubMed Scopus Google Scholar a binding in the miR-22 that the of miR-22 in cancer B. D. J. R. M. E. role of miR-22 by in cancer cells to by targeting and and of PubMed Scopus Google Scholar results that the of to the inhibitor significantly miR-22 that miR-22 is by in tumor cells in the of endothelial miR-22 on angiogenesis and tumor a of in angiogenesis we that miR-22 is a angiogenesis inhibitor that all of the of the angiogenic EC and the of miR-22 on these directly on each This is by the that inhibits and formation within the of the in results by and in The that the is on the angiogenic sprouting of murine ECs that the antiangiogenic of miR-22 is in ECs of different the of endothelial miR-22 on NSCLC we in tumor communication by with cells into the of is to that tumor the of miR-22 in human ECs these ECs the into new and tumor Accordingly, the of miR-22 on NSCLC studies that the of with their in cell types and to the of J. H. of mechanisms of and PubMed Scopus Google A. R. M. of regulation from to J. PubMed Scopus Google Scholar in the to the of miR-22 in we the and human target of the SIRT1 and to downregulated in the that miR-22 its in a is a member of the family of receptor and expressed on M. S. E. R. M. growth growth factor receptor in Rev. PubMed Scopus Google Scholar of by and the angiogenic of ECs in and in M. S. E. R. M. growth growth factor receptor in Rev. PubMed Scopus Google Scholar to target for the antiangiogenic treatment of to the of SIRT1 the antiangiogenic of we to the SIRT1 inhibitor the inhibitor These molecular of SIRT1 we in that the of and is in are of is the of the of NSCLC to the between endothelial miR-22 and the with the of the This by the of for of into ECs in M. for PubMed Scopus Google Scholar This to directly into to and to the and of in and of and viral to these in the that of endothelial miR-22 significantly to NSCLC in NSCLC to its receptors located on ECs, the of in endothelial miR-22 miR-22 the pivotal proangiogenic regulators SIRT1 and which results in the of signaling and of the of miR-22 results in and that endothelial miR-22 a target for the treatment of cells angiogenesis by endothelial which SIRT1 and the as in in the and of to the of endothelial miR-22 in NSCLC of endothelial miR-22 to significantly downregulated in human NSCLC from the studies and in human ECs and NSCLC cells to the regulation of endothelial miR-22 by NSCLC a of in to the of miR-22 on angiogenic EC and and inhibitor of miR-22 into ECs to and a and a tumor to the in of miR-22 on angiogenesis and tumor and to and the target of the on and each in with to the and of the are as cell the in each These in all of the by the to in the and inhibitor SIRT1 inhibitor and inhibitor from The inhibitor from NSCLC tissues and matched nontumor lung tissues from with lung The of these are shown in by in and in This by the and the of lung and matched nontumor lung with a of on and with and a ECs and into the of the of blood cells from ECs from each This by in endothelial cell growth in from of and and human cells in with of and of in growth The human NSCLC cell and in with of and of cells in a and to the of tumor cells on endothelial miR-22 1 with cells into and in endothelial cell for a human to the the cells with and in of of and of by for 1 of the cells by in 1 of and the in the of a The with 3 of and from the The ECs with of by the into the and for and with which factors cells to of 1 NSCLC cells the and in the for in in the of for the of on in a and cells the in for in for with for and with for the cells with a for 1 by the with a for 1 with The of in of of each with a the of miR-22 in the cells with for to to the with as cell to the in and for the of into each of the of each by a with as the The a of the of the cells with a for by with a and with of miR-22 in cell regulation by as E. angiogenesis by of J. 2017; PubMed Scopus Google Scholar and for The cells and by with and with the cell with the and the of cells with EC different the in the cell with a to and with to to the as as The and expressed as a of as D. of a of the PubMed Scopus Google Scholar in of into of with and of with to the to migrate for and with by the of cells in a and expressed as a of formation the of ECs, into each of a with of for the formation of formation by the of by endothelial with of and expressed as a of the of miR-22 in from for with of 1 of and and in in a with into each and from the to for by with sprouting by the of the sprouting and expressed as a of by the and to the for and the for the and of the in of miR-22 in angiogenesis, a as inhibits the angiogenic of endothelial cells by targeting and J. PubMed Scopus Google Scholar in with the of growth and with 1 of 1 of and of of with into to The for of endothelial miR-22 in tumor angiogenesis and growth in a tumor cells in with in of and into the of of the on and by of a The tumor the the and the of tumor in PubMed Scopus Google Scholar The tumor a and with a on and The of by of a the of the on the and for of and in and the of the and the with a a by a a with The subsequently a by the of in of each the and of tumor cells, with a a by a and The by with the with The of and tumor cells in on each with a a the the for the transcription by a is that of ECs by the the and in a the The of and the with and nuclear as are in for and from S. J. M. H. B. S. et a potent role with potential in PubMed Scopus Google Scholar cell on and to The and with a a a a a a This by the and a The of of target a target with of into cells of and activities with the a by the to that of and expressed as a of between with the the of the between by by the are expressed as of IntroductionAngiogenesis, i.e., the formation of new blood vessels from preexisting ones, is essential for tumor growth and metastasis. Accordingly, excessive angiogenesis is a poor prognostic indicator for the aggressiveness of different cancer types such as non-small cell lung cancer (NSCLC).1Fontanini G. Lucchi M. Vignati S. Mussi A. Ciardiello F. De Laurentiis M. De Placido S. Basolo F. Angeletti C.A. Bevilacqua G. Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study.J. Natl. Cancer Inst. 1997; 89: 881-886Crossref PubMed Scopus (298) Google Scholar Tumor angiogenesis is tightly regulated by the balance between pro- and antiangiogenic factors, which involves the dynamic communication between tumor cells and endothelial cells (ECs). Tumor cells are capable of releasing different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF, FGF2), epidermal growth factor (EGF), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8.2Bielenberg D.R. Zetter B.R. The contribution of angiogenesis to the process of metastasis.Cancer J. 2015; 21: 267-273Crossref PubMed Scopus (265) Google Scholar,3Rajabi M. Mousa S.A. The role of angiogenesis in cancer treatment.Biomedicines. 2017; 5: 34Crossref PubMed Scopus (329) Google Scholar The binding of these factors to their receptors located on ECs activates pivotal downstream angiogenesis-related signaling pathways such as phosphoinositide 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) signaling.4Hoeben A. Landuyt B. Highley M.S. Wildiers H. Van Oosterom A.T. De Bruijn E.A. Vascular endothelial growth factor and angiogenesis.Pharmacol. Rev. 2004; 56: 549-580Crossref PubMed Scopus (1429) Google Scholar Consequently, ECs are stimulated to degrade their basement membrane, proliferate, migrate toward tumor cells, and interconnect with each other to form new microvascular networks.2Bielenberg D.R. Zetter B.R. The contribution of angiogenesis to the process of metastasis.Cancer J. 2015; 21: 267-273Crossref PubMed Scopus (265) Google Scholar,4Hoeben A. Landuyt B. Highley M.S. Wildiers H. Van Oosterom A.T. De Bruijn E.A. Vascular endothelial growth factor and angiogenesis.Pharmacol. Rev. 2004; 56: 549-580Crossref PubMed Scopus (1429) Google ScholarPrevious studies have shown that sirtuin (SIRT) 1 plays a crucial role in the regulation of angiogenesis.5Potente M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google Scholar SIRT1 is a prototype member of the sirtuin family of nicotinamide adenine dinucleotide-dependent class III histone deacetylases. Loss of SIRT1 results in a significant reduction of EC sprouting and branching activity.5Potente M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google Scholar Moreover, endothelial SIRT1 deletion impairs angiogenesis within ischemic hindlimbs and the M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google R. S. J. B. M. J. R. F. J. M.S. Endothelial sirtuin 1 through of to of vascular PubMed Scopus Google Scholar The proangiogenic of SIRT1 is by of its that SIRT1 which to leading to the of the of signaling by its in and PubMed Scopus Google Scholar SIRT1 the transcription factor and its antiangiogenic activity.5Potente M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. Haendeler J. Mione M. Dejana E. Alt F.W. et al.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev. 2007; 21: 2644-2658Crossref PubMed Scopus (487) Google Scholar SIRT1 the of by the transcription of a of target of rapamycin in impairs signaling and results in and PubMed Scopus Google (miRNAs) are that through binding to the of leading to and D. M. MicroRNAs in and Rev. PubMed Scopus Google Scholar the as powerful regulators of to tumor and of miR-22 within different human and tumor tissues are to of for the and of types of cancer such as M. R. J. inhibits cell and and by targeting in 2017; PubMed Scopus Google Scholar is located on and highly J. of in human and PubMed Scopus Google Scholar to expressed in different types of R. M. MicroRNAs in the tumor controls on the Google Scholar its role in tumor angiogenesis the we the regulation of endothelial miR-22 by NSCLC the of miR-22 in basic angiogenic EC and The antiangiogenic of miR-22 in and in we the of endothelial miR-22 on NSCLC angiogenesis and growth in a tumor SIRT1 and receptor as of miR-22 in

Topics & Concepts