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Moustakas, AristidisORCID iD iconorcid.org/0000-0001-9131-3827
Publications (10 of 106) Show all publications
Kolliopoulos, C., Lin, C.-Y., Heldin, C.-H., Moustakas, A. & Heldin, P. (2019). Has2 natural antisense RNA and Hmga2 promote Has2 expression during TGFβ-induced EMT in breast cancer. Matrix Biology, 80, 29-45
Open this publication in new window or tab >>Has2 natural antisense RNA and Hmga2 promote Has2 expression during TGFβ-induced EMT in breast cancer
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2019 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 80, p. 29-45Article in journal (Refereed) Published
Abstract [en]

The glycosaminoglycan hyaluronan has a crucial role in tissue organization and cell signaling. Hyaluronan accumulates in conjunction with rapid tissue remodeling during embryogenesis, as well as in inflammatory conditions and cancer. We report a negative correlation between the expression of genes encoding hyaluronan synthase HAS2, its natural antisense transcript HAS2-AS, the chromatin modulating factor HMGA2 and transforming growth factor-β (TGFβ), and survival of patients with invasive breast carcinomas. In mouse mammary epithelial cells, TGFβ activates Smad and non-Smad signaling pathways, resulting in the transcriptional induction of Has2, Has2as (the mouse ortholog of HAS2-AS) and Hmga2, as well as epithelial-mesenchymal transition (EMT)-promoting transcription factors, such as Snail. Importantly, Has2as abrogation suppressed the TGFβ induction of EMT markers, including Snai1, Hmga2, Fn1, and suppressed the mesenchymal phenotype. TGFβ induction of Hmga2, Has2as and Has2, and synthesis of hyaluronan were accompanied with activation of Akt and Erk1/2 MAP-kinase signaling and were required for breast cancer cell motility. Importantly, the hyaluronan receptor Cd44, but not Hmmr, was required for TGFβ-mediated EMT phenotype. Interestingly, Has2as was found to contribute to the maintenance of stem cell factors and breast cancer stemness. Our findings show that Has2as has a key role in TGFβ- and HAS2-induced breast cancer EMT, migration and acquisition of stemness.

Keywords
Cancer, EMT, Hyaluronan, Stemness, lncRNA
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-372431 (URN)10.1016/j.matbio.2018.09.002 (DOI)000471739100003 ()30194979 (PubMedID)
Funder
Swedish Cancer Society, 15 0778Swedish Research Council, 15 02757
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-08-15Bibliographically approved
Morén, A., Bellomo, C., Tsubakihara, Y., Kardassis, D., Mikulits, W., Heldin, C.-H. & Moustakas, A. (2019). LXR alpha limits TGF beta-dependent hepatocellular carcinoma associated fibroblast differentiation. Oncogenesis, 8, Article ID 36.
Open this publication in new window or tab >>LXR alpha limits TGF beta-dependent hepatocellular carcinoma associated fibroblast differentiation
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2019 (English)In: Oncogenesis, E-ISSN 2157-9024, Vol. 8, article id 36Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) is deposited in the extracellular space of diverse tissues. Resident fibroblasts respond to TGF beta and undergo myofibroblastic differentiation during tissue wound healing and cancer progression. Cancer-associated fibroblasts (CAFs) communicate with tumor cells during cancer progression, under the guidance of TGF beta signaling. We report that agonist-activated liver X receptors (LXR) limit the expression of key components of myofibroblast differentiation, including the a-smooth muscle actin (alpha SMA) gene in liver cancer cells. CAFs derived from hepatocellular carcinoma (HCC) express high aSMA and low LXR alpha levels, whereas hepatocarcinoma cells exhibit an inverse expression pattern. All hepatoma cells analyzed responded to the LXR alpha agonist T0901317 by inducing fatty acid synthase (FASN) expression. On the other hand, T0901317 antagonized TGF beta-induced fibroblastic marker responses, such as fibronectin and calponin, in a subset of hepatoma cells and all CAFs analyzed. Mechanistically, LXR alpha antagonized TGF beta signaling at the transcriptional level. Smad3 and LXR alpha were recruited to adjacent DNA motifs of the ACTA2 promoter. Upon cloning the human ACTA2 promoter, we confirmed its transcriptional induction by TGF beta stimulation, and LXR alpha overexpression repressed the promoter activity. Hepatosphere formation by HCC cells was enhanced upon co-culturing with CAFs. T0901317 suppressed the positive effects exerted on hepatosphere growth by CAFs. Taken together, the data suggest that LXR alpha agonists limit TGF beta-dependent CAF differentiation, potentially limiting primary HCC growth.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-387277 (URN)10.1038/s41389-019-0140-4 (DOI)000468075200001 ()31097694 (PubMedID)
Funder
Swedish Research Council, K2013-66 x - 14936-10-5Swedish Research Council, 2017-01588Swedish Research Council, 2018-02757Swedish Research Council, 2015-02757EU, FP7, Seventh Framework ProgrammeEU, European Research Council, 787472
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Zhang, Y., Valsala Madhavan Unnithan, R., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., . . . Olsson, A.-K. (2019). TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells. The FASEB Journal, 33(7), 7822-7832
Open this publication in new window or tab >>TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 7, p. 7822-7832Article in journal (Refereed) Published
Abstract [en]

Platelets can promote several stages of the metastatic process and thus contribute to malignant progression. As an example, platelets promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study, we show that tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-kappa B activator (TANK)-binding kinase 1 (TBK1) is a previously unknown mediator of platelet-induced EMT in mammary carcinoma cells. Coculture of 2 mammary carcinoma cell lines, Ep5 from mice and MCF10A(MII) from humans, with isolated platelets induced morphologic as well as molecular changes characteristic of EMT, which was paralleled with activation of TBK1. TBK1 depletion using small interfering RNA impaired platelet-induced EMT in both Ep5 and MCF10A(MII) cells. Furthermore, platelet-induced activation of the NF-kappa B subunit p65 was suppressed after TBK1 knockdown, demonstrating that TBK1 mediates platelet-induced NF-kappa B signaling and EMT. Using an in vivo metastasis assay, we found that depletion of TBK1 from mammary carcinoma cells during in vitro preconditioning with platelets subsequently suppressed the formation of lung metastases in mice. Altogether, these results suggest that TBK1 contributes to tumor invasiveness and may be a driver of metastatic spread in breast cancer.-Zhang, Y., Unnithan, R. V. M., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., Cedervall, J., Olsson, A.-K. TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells.

Keywords
platelets, cancer, TBK1, NF-kappa B, metastasis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-392047 (URN)10.1096/fj.201801936RRR (DOI)000476234700004 ()30912981 (PubMedID)
Funder
Swedish Research Council, 2016-03036Swedish Cancer Society, CAN 2017/522Swedish Society of Medicine, SLS-683851
Note

Ragaseema Valsala Madhavan Unnithan and Anahita Hamidi contributed equally to this work.

Jessica Cedervall and Anna-Karin Olsson contributed equally to this work.

Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved
Papoutsoglou, P., Tsubakihara, Y., Caja, L., Morén, A., Pallis, P., Ameur, A., . . . Moustakas, A. (2019). The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity. Cell reports, 28(12), 3182-3198.ell
Open this publication in new window or tab >>The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 28, no 12, p. 3182-3198.ellArticle in journal (Refereed) Published
Abstract [en]

Molecular processes involving lncRNAs regulate cell function. By applying transcriptomics, we identify lncRNAs whose expression is regulated by transforming growth factor beta (TGF-beta). Upon silencing individual lncRNAs, we identify several that regulate TGF-beta signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-beta through Smad and protein kinase pathways and resides in the nucleus. Depleting TGFB2-AS1 enhances TGF-beta/Smad-mediated transcription and expression of hallmark TGF-beta-target genes. Increased dose of TGFB2-AS1 reduces expression of these genes, attenuates TGF-beta-induced cell growth arrest, and alters BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1, mainly via its 3' terminal region, binds to the EED adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me(3) modifications at TGF-beta-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity partially rescues TGFB2-AS1-mediated gene repression. Thus, the TGF-beta-induced TGFB2-AS1 lncRNA exerts inhibitory functions on TGF-beta/BMP signaling output, supporting auto-regulatory negative feedback that balances TGF-beta/BMP-mediated responses.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-395306 (URN)10.1016/j.celrep.2019.08.028 (DOI)000486389400014 ()31533040 (PubMedID)
Funder
Swedish Cancer Society, CAN2015/438Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757EU, European Research Council, 787472
Available from: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-18Bibliographically approved
Kolliopoulos, C., Raja, E., Razmara, M., Heldin, P., Heldin, C.-H., Moustakas, A. & van der Heide, L. P. (2019). Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output. Journal of Biological Chemistry, 294(11), 4119-4136
Open this publication in new window or tab >>Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output
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2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 294, no 11, p. 4119-4136Article in journal (Refereed) Published
Abstract [en]

TGFβ signaling via SMAD proteins and protein kinase pathways up- or down-regulates the expression of many genes and thus affects physiological processes, such as differentiation, migration, cell cycle arrest, and apoptosis during developmental or adult tissue homeostasis. We here report that NUAK family kinase 1 (NUAK1) and NUAK2 are two TGFβ target genes. NUAK1/2 belong to the AMP-activated protein kinase (AMPK) family, whose members control central and protein metabolism, polarity and overall cellular homeostasis. We found that TGFβ-mediated transcriptional induction of NUAK1 and NUAK2 requires SMAD family members 2, 3 and 4 (SMAD2/3/4) and mitogen activated protein kinase (MAPK) activities, which provided immediate and early signals for the transient expression of these two kinases. Genomic mapping identified an enhancer element within the first intron of the NUAK2 gene that can recruit SMAD proteins, which, when cloned, could confer induction by TGFβ.  Furthermore, NUAK2 formed protein complexes with SMAD3 and the TGFβ type I receptor. Functionally, NUAK1 suppressed and NUAK2 induced TGFβ signaling. This was evident during TGFβ-induced epithelial cytostasis, mesenchymal differentiation and myofibroblast contractility, in which NUAK1 or NUAK2 silencing enhanced or inhibited these responses, respectively. In conclusion, we have identified a bifurcating loop during TGFβ signaling, whereby transcriptional induction of NUAK1 serves as a negative checkpoint and NUAK2 induction positively contributes to signaling and terminal differentiation responses to TGFβ activity.

Keywords
AMP-activated kinase (AMPK), SMAD transcription factor, cell cycle, epithelial-mesenchymal transition (EMT), myofibroblast, signal transduction, transforming growth factor beta (TGF-B)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-378698 (URN)10.1074/jbc.RA118.004984 (DOI)000461854400024 ()30622137 (PubMedID)
Funder
Swedish Research Council, K2010-67X-14936-07-3Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757
Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-04-17Bibliographically approved
Batool, T., Fang, J., Jansson, V., Zhao, H., Gallant, C. J., Moustakas, A. & Li, J.-P. (2019). Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells. Cellular Signalling, 54, 122-129
Open this publication in new window or tab >>Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells
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2019 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 54, p. 122-129Article in journal (Refereed) Published
Abstract [en]

Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of glucuronic acid to iduronic acid in the process of heparan sulfate biosynthesis. Targeted interruption of the gene, Glce,in mice resulted in neonatal lethality with varied defects in organ development. To understand the molecular mechanisms of the phenotypes, we used mouse embryonic fibroblasts (MEF) as a model to examine selected signaling pathways. Our earlier studies found reduced activities of FGF-2, GDNF, but increased activity of sonic hedgehog in the mutant cells. In this study, we focused on the bone morphogenetic protein (BMP) signaling pathway. Western blotting detected substantially elevated endogenous Smad1/5/8 phosphorylation in the Hsepi mutant (KO) MEF cells, which is reverted by re-expression of the enzyme in the KO cells. The mutant cells displayed an enhanced proliferation and elevated alkaline phosphatase activity, marking higher differentiation, when cultured in osteogenic medium. The high level of Smad1/5/8 phosphorylation was also found in primary calvarial cells isolated from the KO mice. Analysis of the genes involved in the BMP signaling pathway revealed upregulation of a number of BMP ligands, but reduced expression of several Smads and BMP antagonist (Grem1) in the KO MEF cells. The results suggest that Hsepi expression modulates BMP signaling activity, which, at least partially, is associated with defected molecular structure of heparan sulfate expressed in the cells.   

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
BMP signaling, Heparan sulfate, MEF cells, Smad, Glucuronyl C5-epimerase, Bone Morphogenetic Protein
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-363254 (URN)10.1016/j.cellsig.2018.11.010 (DOI)000456752900013 ()30458230 (PubMedID)
Funder
Swedish Cancer Society, CAN2015/496Swedish Research Council, 2015-02595Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2019-02-12Bibliographically approved
Tsubakihara, Y. & Moustakas, A. (2018). Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor. International Journal of Molecular Sciences, 19(11), Article ID 3672.
Open this publication in new window or tab >>Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor
2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 11, article id 3672Article, review/survey (Refereed) Published
Abstract [en]

Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor (TGF). The power of TGF to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGF, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGF signaling and EMT facilitate tumor cell dissemination.

Keywords
epithelial-mesenchymal transition, micro-RNA, non-coding RNA, signal transduction, transcription factor, transforming growth factor, tumor invasiveness
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-372518 (URN)10.3390/ijms19113672 (DOI)000451528500388 ()30463358 (PubMedID)
Funder
Swedish Research Council, K2013-66X-14936-10-5
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Maturi, V., Morén, A., Enroth, S., Heldin, C.-H. & Moustakas, A. (2018). Genomewide binding of transcription factor Snail1 in triple-negative breast cancer cells. Molecular Oncology, 12(7), 1153-1174
Open this publication in new window or tab >>Genomewide binding of transcription factor Snail1 in triple-negative breast cancer cells
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2018 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 12, no 7, p. 1153-1174Article in journal (Refereed) Published
Abstract [en]

Transcriptional regulation mediated by the zinc finger protein Snail1 controls early embryogenesis. By binding to the epithelial tumor suppressor CDH1 gene, Snail1 initiates the epithelial-mesenchymal transition (EMT). The EMT generates stem-like cells and promotes invasiveness during cancer progression. Accordingly, Snail1 mRNA and protein is abundantly expressed in triple-negative breast cancers with enhanced metastatic potential and phenotypic signs of the EMT. Such high endogenous Snail1 protein levels permit quantitative chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. Snail1 associated with 185 genes at cis regulatory regions in the Hs578T triple-negative breast cancer cell model. These genes include morphogenetic regulators and signaling components that control polarized differentiation. Using the CRISPR/Cas9 system in Hs578T cells, a double deletion of 10bp each was engineered into the first exon and into the second exon-intron junction of Snail1, suppressing Snail1 expression and causing misregulation of several hundred genes. Specific attention to regulators of chromatin organization provides a possible link to new phenotypes uncovered by the Snail1 loss-of-function mutation. On the other hand, genetic inactivation of Snail1 was not sufficient to establish a full epithelial transition to these tumor cells. Thus, Snail1 contributes to the malignant phenotype of breast cancer cells via diverse new mechanisms.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
bone morphogenetic protein, breast cancer, chromatin immunoprecipitation, epithelial-mesenchymal transition, transforming growth factor beta
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-360496 (URN)10.1002/1878-0261.12317 (DOI)000436942300011 ()29729076 (PubMedID)
Funder
Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757Swedish National Infrastructure for Computing (SNIC), b2013260Swedish Cancer Society, CAN 2012/438Swedish Cancer Society, CAN 2015/438Swedish Cancer Society, CAN 2016/445
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Maturi, V., Enroth, S., Heldin, C.-H. & Moustakas, A. (2018). Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells. Journal of Cellular Physiology, 233(10), 7113-7127
Open this publication in new window or tab >>Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells
2018 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 233, no 10, p. 7113-7127Article in journal (Refereed) Published
Abstract [en]

Zinc finger E-box binding homeobox 1 (ZEB1) is a transcriptional regulator involved in embryonic development and cancer progression. ZEB1 induces epithelial-mesenchymal transition (EMT). Triple-negative human breast cancers express high ZEB1 mRNA levels and exhibit features of EMT. In the human triple-negative breast cancer cell model Hs578T, ZEB1 associates with almost 2,000 genes, representing many cellular functions, including cell polarity regulation (DLG2 and FAT3). By introducing a CRISPR-Cas9-mediated 30bp deletion into the ZEB1 second exon, we observed reduced migratory and anchorage-independent growth capacity of these tumor cells. Transcriptomic analysis of control and ZEB1 knockout cells, revealed 1,372 differentially expressed genes. The TIMP metallopeptidase inhibitor 3 and the teneurin transmembrane protein 2 genes showed increased expression upon loss of ZEB1, possibly mediating pro-tumorigenic actions of ZEB1. This work provides a resource for regulators of cancer progression that function under the transcriptional control of ZEB1. The data confirm that removing a single EMT transcription factor, such as ZEB1, is not sufficient for reverting the triple-negative mesenchymal breast cancer cells into more differentiated, epithelial-like clones, but can reduce tumorigenic potential, suggesting that not all pro-tumorigenic actions of ZEB1 are linked to the EMT.

Keywords
ZEB1, EMT, ChIP-seq, CRISPR-Cas9
National Category
Cell Biology
Research subject
Biochemistry; Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-334438 (URN)10.1002/jcp.26634 (DOI)000438352300071 ()29744893 (PubMedID)
Funder
Swedish Research Council, 2015-02757Swedish Research Council, K2013-66X-14936-10-5Swedish Cancer Society, CAN 2012/438Swedish Cancer Society, CAN 2015/438Swedish Cancer Society, CAN 2016/445
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-09-24Bibliographically approved
Bouris, P., Manou, D., Sopaki-Valalaki, A., Kolokotroni, A., Moustakas, A., Kapoor, A., . . . Theocharis, A. D. (2018). Serglycin promotes breast cancer cell aggressiveness: Induction of epithelial to mesenchymal transition, proteolytic activity and IL-8 signaling. Matrix Biology, 74, 35-51
Open this publication in new window or tab >>Serglycin promotes breast cancer cell aggressiveness: Induction of epithelial to mesenchymal transition, proteolytic activity and IL-8 signaling
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2018 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 74, p. 35-51Article in journal (Refereed) Published
Abstract [en]

Serglycin is an intracellular proteoglycan that is expressed and constitutively secreted by numerous malignant cells, especially prominent in the highly-invasive, triple-negative MDA-MB-231 breast carcinoma cells. Notably, de novo expression of serglycin in low aggressive estrogen receptor alpha (ER alpha)-positive MCF7 breast cancer cells promotes an aggressive phenotype. In this study, we discovered that serglycin promoted epithelial to mesenchymal transition (EMT) in MCF7 cells as shown by increased expression of mesenchymal markers vimentin, fibronectin and EMT-related transcription factor Snail2. These phenotypic traits were also associated with the development of drug resistance toward various chemotherapy agents and induction of their proteolytic potential as shown by the increased expression of matrix metalloproteinases, including MMP-1, MMP-2, MMP-9, MT1-MMP and up-regulation of urokinase-type plasminogen activator. Knockdown of serglycin markedly reduced the expression of these proteolytic enzymes in MDA-MB-231 cells. In addition, serglycin expression was closely linked to a pro-inflammatory gene signature including the chemokine IL-8 in ER alpha-negative breast cancer cells and tumors. Notably, serglycin regulated the secretion of IL-8 in breast cancer cells independently of their ER alpha status and promoted their proliferation, migration and invasion by triggering IL-8/CXCR2 downstream signaling cascades including PI3K, Src and Rac activation. Thus, serglycin promotes the establishment of a pro-inflammatory milieu in breast cancer cells that evokes an invasive mesenchymal phenotype via autocrine activation of IL-8/CXCR2 signaling axis.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
Proteoglycans, Serglycin, Interleukin-8, Breast cancer, Signaling
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-373024 (URN)10.1016/j.matbio.2018.05.011 (DOI)000452933100003 ()29842969 (PubMedID)
Funder
EU, Horizon 2020, 645756
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9131-3827

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