{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T20:05:04Z","timestamp":1789502704450,"version":"build-2803163510"},"reference-count":98,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,2]],"date-time":"2020-10-02T00:00:00Z","timestamp":1601596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2018\/02\/X\/NZ3\/00276"],"award-info":[{"award-number":["2018\/02\/X\/NZ3\/00276"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015077","name":"Wydzia\u0142 Lekarski, Uniwersytet Jagiello\u0144ski Collegium Medicum","doi-asserted-by":"publisher","award":["N41\/DBS\/000576"],"award-info":[{"award-number":["N41\/DBS\/000576"]}],"id":[{"id":"10.13039\/100015077","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Helicobacter pylori (Hp)-induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial\u2013mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp-activated gastric fibroblast (Hp-AGF) secretome induced their shift towards plastic LGR5+\/Oct4high\/Sox-2high\/c-Mychigh\/Klf4low phenotype (l.t.EMT+RGM1 cells), while Hp-non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial\u2013myofibroblast transition (EMyoT) of RGM1 cells favoring LGR\u2212\/Oct4high\/Sox2low\/c-Myclow\/Klf4high phenotype (l.t.EMT\u2212RGM1 cells). TGF\u03b21 rich secretome from Hp-reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGF\u03b2R1 and TGF\u03b2R2 activity. In turn, TGF\u03b2R1 activity along with GF-induced TGF\u03b2R2 activation in l.t.EMT\u2212RGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGF\u03b2 signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm.<\/jats:p>","DOI":"10.3390\/microorganisms8101519","type":"journal-article","created":{"date-parts":[[2020,10,2]],"date-time":"2020-10-02T09:39:25Z","timestamp":1601631565000},"page":"1519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Long-Term Helicobacter pylori Infection Switches Gastric Epithelium Reprogramming towards Cancer Stem Cell-Related Differentiation Program in Hp-Activated Gastric Fibroblast-TGF\u03b2 Dependent Manner"],"prefix":"10.3390","volume":"8","author":[{"given":"Gracjana","family":"Krzysiek-Maczka","sequence":"first","affiliation":[{"name":"Department of Physiology, The Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneta","family":"Targosz","sequence":"additional","affiliation":[{"name":"Department of Physiology, The Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urszula","family":"Szczyrk","sequence":"additional","affiliation":[{"name":"Department of Physiology, The Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Wrobel","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, The Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-837 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Strzalka","sequence":"additional","affiliation":[{"name":"Department of Physiology, The Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5805-0065","authenticated-orcid":false,"given":"Tomasz","family":"Brzozowski","sequence":"additional","affiliation":[{"name":"Department of Physiology, The Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6779-7630","authenticated-orcid":false,"given":"Jaroslaw","family":"Czyz","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, The Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-837 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0294-5185","authenticated-orcid":false,"given":"Agata","family":"Ptak-Belowska","sequence":"additional","affiliation":[{"name":"Department of Physiology, The Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/01.sla.0000149300.28588.23","article-title":"Gastric adenocarcinoma: Review and considerations for future directions","volume":"241","author":"Dicken","year":"2005","journal-title":"Ann. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.18632\/oncotarget.14027","article-title":"Outcomes of surgery for gastric cancer with distant metastases: A retrospective study from the SEER database","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"57654","DOI":"10.18632\/oncotarget.14825","article-title":"Targeted therapies for gastric cancer: Failures and hopes from clinical trias","volume":"8","author":"Apicella","year":"2017","journal-title":"Oncotarget"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.imbio.2017.10.016","article-title":"TLR2 Activation induced by H. pylori LPS promotes the differential expression of claudin-4-6-7 and -9 via either STAT3 and ERK1\/2 in AGS cells","volume":"223","year":"2018","journal-title":"Immunobiology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/emmm.200900043","article-title":"Inflammation and EMT: An alliance towards organ fibrosis and cancer progression","volume":"1","author":"Nieto","year":"2009","journal-title":"EMBO Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1478-811X-11-77","article-title":"The functional interplay of Helicobacter pylori factors with gastric epithelial cells induces a multi-step process in pathogenesis","volume":"11","author":"Posselt","year":"2013","journal-title":"Cell Commun. Signal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1128\/IAI.01350-10","article-title":"Complex cellular responses of Helicobacter pylori-colonized gastric adenocarcinoma cells","volume":"79","author":"Schneider","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.tim.2008.05.005","article-title":"Molecular mechanisms of epithelial-barrier disruption by Helicobacter pylori","volume":"16","author":"Wessler","year":"2008","journal-title":"Trends Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.canlet.2013.08.016","article-title":"Helicobacter pylori-induced gastric inflammation and gastric cancer","volume":"345","author":"Wang","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1007\/s00535-014-0952-0","article-title":"Interaction between gastric cancer stem cells and the tumor microenvironment","volume":"49","author":"Ishimoto","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.3748\/wjg.v20.i7.1667","article-title":"Role of the tumor microenvironment in the pathogenesis of gastric carcinoma","volume":"20","author":"Chung","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1053\/j.gastro.2007.01.049","article-title":"Intracellular, intercellular, and stromal invasion of gastric mucosa, preneoplastic lesions, and cancer by Helicobacter pylori","volume":"132","author":"Necchi","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3821","DOI":"10.1038\/s41598-018-20957-2","article-title":"Stromal C-type lectin receptor COLEC12 integrates H. pylori, PGE2-EP2\/4 axis and innate immunity in gastric diseases","volume":"8","author":"Chang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4589","DOI":"10.1182\/blood-2005-10-4169","article-title":"Role of transforming growth factor-beta in hematologic malignancies","volume":"107","author":"Dong","year":"2006","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/cdd.2008.183","article-title":"TGF-\u03b2 induces apoptosis in human B cells via transcriptional regulation of BIK and BCL-XL","volume":"16","author":"Spender","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0092-8674(03)00432-X","article-title":"Mechanisms of TGF-beta signaling from cell membrane to the nucleus","volume":"113","author":"Shi","year":"2003","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2008.07.001","article-title":"TGF\u03b2 in cancer","volume":"134","year":"2008","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ham, I.H., Lee, D., and Hur, H. (2019). Role of cancer-associated fibroblast in gastric cancer progression and resistance to treatments. J. Oncol., 9.","DOI":"10.1155\/2019\/6270784"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.bcp.2013.01.018","article-title":"Fibroblast-Mediated drug resistance in cancer","volume":"85","author":"Paraiso","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nrc1877","article-title":"Fibroblasts in cancer","volume":"6","author":"Kalluri","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.3390\/cancers7040876","article-title":"Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion","volume":"7","author":"Yamaguchi","year":"2015","journal-title":"Cancers"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Krzysiek-Maczka, G., Wrobel, T., Targosz, A., Szczyrk, U., Strzalka, M., Ptak-Belowska, A., Czyz, J., and Brzozowski, T. (2019). Helicobacter pylori-activated gastric fibroblasts induce epithelial-mesenchymal transition of gastric epithelial cells in vitro in a TGF-\u03b2-dependent manner. Helicobacter, 24.","DOI":"10.1111\/hel.12653"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s00441-016-2467-x","article-title":"Fibroblast activation in cancer: When seed fertilizes soil","volume":"365","author":"Kuzet","year":"2016","journal-title":"Cell Tissue Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1172\/JCI39104","article-title":"The basics of epithelial-mesenchymal transition","volume":"119","author":"Kalluri","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yoshida, K., Murata, M., Yamaguchi, T., Matsuzaki, K., and Okazaki, K. (2016). Reversible human TGF-\u03b2 signal shifting between tumor suppression and fibro-carcinogenesis: Implications of Smad phospho-isoforms for hepatic epithelial-mesenchymal transitions. J. Clin. Med., 5.","DOI":"10.3390\/jcm5010007"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1007\/s12272-016-0787-8","article-title":"Inflammatory fibroblasts in cancer","volume":"39","author":"Lim","year":"2016","journal-title":"Arch. Pharm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ebiom.2017.02.019","article-title":"Cancer-Associated fibroblasts promote irradiated cancer cell recovery through autophagy","volume":"17","author":"Wang","year":"2017","journal-title":"EBioMedicine"},{"key":"ref_28","first-page":"3055","article-title":"Cancer-Associated fibroblast regulation of tumor neo-angiogenesis as a therapeutic target in cancer","volume":"17","author":"Wang","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_29","first-page":"1889","article-title":"Therapeutic targeting of the crosstalk between cancer-associated fibroblasts and cancer stem cells","volume":"9","author":"Huang","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.scr.2016.02.005","article-title":"The role of pluripotency factors to drive stemness in gastrointestinal cancer","volume":"16","author":"Hermann","year":"2016","journal-title":"Stem Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Aponte, P.M., and Caicedo, A. (2017). Stemness in cancer: Stem cells, cancer stem cells, and their microenvironment. Stem Cells Int., 1\u201317.","DOI":"10.1155\/2017\/5619472"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4252\/wjsc.v7.i1.27","article-title":"Cancer stem cell plasticity and tumor hierarchy","volume":"7","author":"Cabrera","year":"2015","journal-title":"World J. Stem Cells"},{"key":"ref_33","first-page":"2973","article-title":"Links between cancer stem cells and epithelial-mesenchymal transition","volume":"8","author":"Wang","year":"2015","journal-title":"Onco Targets Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, C.J., Chu, P.Y., Yiang, G.T., and Wu, M.Y. (2019). The molecular mechanism of epithelial-mesenchymal transition for breast carcinogenesis. Biomolecules, 9.","DOI":"10.3390\/biom9090476"},{"key":"ref_35","unstructured":"Krzysiek-Maczka, G., Targosz, A., Szczyrk, U., Strzalka, M., Brzozowski, T., and Ptak-Belowska, A. (2019). Involvement of epithelial-mesenchymal transition-inducing transcription factors in the mechanism of Helicobacter pylori-induced fibroblasts activation. J. Physiol. Pharmacol., 70."},{"key":"ref_36","first-page":"77","article-title":"Molecular alterations in fibroblasts exposed to Helicobacter pylori: A missing link in bacterial inflammation progressing into gastric carcinogenesis?","volume":"64","author":"Targosz","year":"2013","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Krzysiek-Maczka, G., Targosz, A., Szczyrk, U., Strza\u0142ka, M., Sliwowski, Z., Brzozowski, T., Czyz, J., and Ptak-Belowska, A. (2018). Role of Helicobacter pylori infection in cancer-associated fibroblast- induced epithelial-mesenchymal transition in vitro. Helicobacter, 23.","DOI":"10.1111\/hel.12538"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/BF02723056","article-title":"RGM1, a cell line derived from normal gastric mucosa of rat","volume":"32","author":"Kobayashi","year":"1996","journal-title":"In Vitro Cell Dev. Biol. Anim."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"711","DOI":"10.3233\/CBM-170809","article-title":"MicroRNA-152 inhibits tumor cell growth while inducing apoptosis via the transcriptional repression of cathepsin L in gastrointestinal stromal tumor","volume":"21","author":"Lu","year":"2018","journal-title":"Cancer Biomark."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-Step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"Chomczynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1007\/s00109-013-1086-1","article-title":"Glucosamine hydrochloride exerts a protective effect against unilateral ureteral obstruction-induced renal fibrosis by attenuating TGF-\u03b2 signaling","volume":"91","author":"Park","year":"2013","journal-title":"J. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/501327a","article-title":"Tumour heterogeneity","volume":"501","author":"Marte","year":"2013","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s00535-015-1125-5","article-title":"Gastric cancer stem cells: Evidence, potential markers, and clinical implications","volume":"51","author":"Brungs","year":"2016","journal-title":"J. Gastroenterol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1002\/cncr.30538","article-title":"Identifying and targeting cancer stem cells in the treatment of gastric cancer","volume":"123","year":"2017","journal-title":"Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/bcr2789","article-title":"Epithelial-Mesenchymal transition and cancer stem cells: A dangerously dynamic duo in breast cancer progression","volume":"13","author":"May","year":"2011","journal-title":"Breast Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4942","DOI":"10.1158\/1078-0432.CCR-10-2538","article-title":"Cancer stem cells and chemosensitivity","volume":"17","author":"Vigneri","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.cell.2005.02.018","article-title":"Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues","volume":"121","author":"Hochedlinger","year":"2005","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.3892\/ijo.2012.1608","article-title":"Upregulation and inhibition of the nuclear translocation of Oct4 during multistep gastric carcinogenesis","volume":"41","author":"Khoder","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/jso.21270","article-title":"Oct4, a novel marker for human gastric cancer","volume":"99","author":"Chen","year":"2009","journal-title":"J. Surg. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1002\/mc.22656","article-title":"Upregulated miR-132 in Lgr5(+) gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1\/CREB\/ABCG2 signaling pathway","volume":"56","author":"Zhang","year":"2017","journal-title":"Mol. Carcinog."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"19153","DOI":"10.3390\/ijms160819153","article-title":"Current status on stem cells and cancers of the gastric epithelium","volume":"16","author":"Hoffmann","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nature05384","article-title":"Identification and expansion of human colon-cancer-initiating cells","volume":"445","author":"Lombardi","year":"2007","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"13427","DOI":"10.1073\/pnas.0805706105","article-title":"Single-Cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity","volume":"105","author":"Vermeulen","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.devcel.2018.05.027","article-title":"EMT subtype influences epithelial plasticity and mode of cell migration","volume":"45","author":"Aiello","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1084\/jem.20181827","article-title":"Context-Dependent EMT programs in cancer metastasis","volume":"216","author":"Aiello","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zhi, Y., Mou, Z., Chen, J., He, Y., Dong, H., Fu, X., and Wu, Y. (2015). B7H1 expression and epithelial- to-mesenchymal transition phenotypes on colorectal cancer stem-like cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135528"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The epithelial-mesenchymal transition generates cells with properties of stem cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3398","DOI":"10.1158\/0008-5472.CAN-14-3265","article-title":"Diverse targets of \u03b2-catenin during the epithelial-mesenchymal transition define cancer stem cells and predict disease relapse","volume":"75","author":"Chang","year":"2015","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1007\/s10555-015-9589-6","article-title":"Urothelial cancer stem cells and epithelial plasticity: Current concepts and therapeutic implications in bladder cancer","volume":"34","author":"Garg","year":"2015","journal-title":"Cancer Metastasis Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.stemcr.2014.09.008","article-title":"The epithelial-mesenchymal transition factor SNAIL paradoxically enhances reprogramming","volume":"3","author":"Unternaehrer","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.stemcr.2013.09.001","article-title":"L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation","volume":"1","author":"Comes","year":"2013","journal-title":"Stem Cell Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.stem.2011.10.001","article-title":"Nodal\/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy","volume":"9","author":"Lonardo","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1136\/gutjnl-2014-308935","article-title":"Microenvironmental hCAP-18\/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment","volume":"64","author":"Sainz","year":"2015","journal-title":"Gut"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Hermann, P.C., Sancho, P., Canamero, M., Martinelli, P., Madriles, F., Michl, P., Gress, T., De Pascual, R., Gandia, L., and Guerra, C. (2014). Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice. Gastroenterology, 147.","DOI":"10.1053\/j.gastro.2014.08.002"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Hermann, P.C., Trabulo, S.M., Sainz, B., Balic, A., Garcia, E., Hahn, S.A., Vandana, M., Sahoo, S.K., Tunici, P., and Bakker, A. (2013). Multimodal treatment eliminates cancer stem cells and leads to long-term survival in primary human pancreatic cancer tissue xenografts. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066371"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1053\/j.gastro.2009.05.053","article-title":"Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer","volume":"137","author":"Mueller","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.stem.2008.05.007","article-title":"Epithelial-Mesenchymal transition and the stem cell phenotype","volume":"2","author":"Radisky","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1002\/ijc.26311","article-title":"Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells?","volume":"129","author":"Scheel","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6945","DOI":"10.1158\/0008-5472.CAN-10-0785","article-title":"Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness","volume":"70","author":"Giannoni","year":"2010","journal-title":"Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/labinvest.3700427","article-title":"MEK\/ERK signaling is a critical mediator for integrin-induced cell scattering in highly metastatic hepatocellular carcinoma cells","volume":"86","author":"Honma","year":"2006","journal-title":"Lab. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/0092-8674(94)90133-3","article-title":"Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells","volume":"77","author":"Cowley","year":"1994","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1126\/science.8052857","article-title":"Transformation of mammalian cells by constitutively active MAP kinase kinase","volume":"265","author":"Mansour","year":"1994","journal-title":"Science"},{"key":"ref_73","first-page":"317","article-title":"Constitutively active mitogen-activated protein kinase kinase MEK1 disrupts morphogenesis and induces an invasive phenotype in Madin-Darby canine kidney epithelial cells","volume":"10","author":"Montesano","year":"1999","journal-title":"Cell Growth Differ."},{"key":"ref_74","first-page":"4781","article-title":"MEK1 signaling mediates transformation and metastasis of EpH4 mammary epithelial cells independent of an epithelial to mesenchymal transition","volume":"62","author":"Pinkas","year":"2002","journal-title":"Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Voisin, L., Julien, C., Duhamel, S., Gopalbhai, K., Claveau, I., Saba-El-Leil, M.K., Rodrigue-Gervais, I.G., Gaboury, L., Lamarre, D., and Basik, M. (2008). Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors. BMC Cancer, 17.","DOI":"10.1186\/1471-2407-8-337"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/sj.cr.7290179","article-title":"TGF-\u03b21-promoted epithelial- to\u2013mesenchymal transformation and cell adhesion contribute to TGF-\u03b2 1-enhanced cell migration in SMMC-7721 cells","volume":"13","author":"Xu","year":"2003","journal-title":"Cell Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1007\/s00432-014-1840-y","article-title":"The network of epithelial-mesenchymal transition: Potential new targets for tumor resistance","volume":"141","author":"Nantajit","year":"2015","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/cr.2009.5","article-title":"TGF-\u03b2 -induced epithelial to mesenchymal transition","volume":"19","author":"Xu","year":"2009","journal-title":"Cell Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/cr.2008.328","article-title":"Non-Smad pathways in TGF-beta signaling","volume":"19","author":"Zhang","year":"2009","journal-title":"Cell Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"172013","DOI":"10.12703\/P5-17","article-title":"Signal integration in TGF-\u03b2, WNT, and Hippo pathways","volume":"5","author":"Attisano","year":"2013","journal-title":"F1000Prime Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.1038\/onc.2014.258","article-title":"TGF-\u03b2 signaling alters the pattern of liver tumorigenesis induced by Pten inactivation","volume":"34","author":"Morris","year":"2015","journal-title":"Oncogene"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1172\/JCI20513","article-title":"Hepatocyte-Specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas","volume":"113","author":"Horie","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nrc2853","article-title":"TGF\u03b2 signalling: A complex web in cancer progression","volume":"10","author":"Ikushima","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/ncb434","article-title":"Differentiation plasticity regulated by TGF-beta family proteins in development and disease","volume":"9","author":"Derynck","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_85","first-page":"699","article-title":"TGF-\u03b2 signaling: A complex role in tumorigenesis","volume":"17","author":"Shuang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0092-8674(03)00308-8","article-title":"Links between tumor suppressors: p53 is required for TGF-\u03b2 gene responses by cooperating with Smads","volume":"113","author":"Cordenonsi","year":"2003","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8228","DOI":"10.1128\/MCB.00374-07","article-title":"Mutant p53 attenuates the Smad-dependent transforming growth factor \u03b21 (TGF-\u03b21) signaling pathway by repressing the expression of TGF-\u03b2 receptor type II","volume":"27","author":"Kalo","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Wang, Y., Liu, Y., Wang, N., Qi, Y., and Du, J. (2013). Kr\u00fcppel-Like factor 4 transcriptionally regulates TGF-\u03b21 and contributes to cardiac myofibroblast differentiation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063424"},{"key":"ref_89","first-page":"2957","article-title":"Loss of KLF4 and consequential downregulation of Smad7 exacerbate oncogenic TGF-\u03b2 signaling in and promote progression of hepatocellular carcinoma","volume":"36","author":"Sun","year":"2017","journal-title":"Oncotarget"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.1096\/fj.15-272658","article-title":"KLF4 mediates the link between TGF-\u03b21-induced gene transcription and H3 acetylation in vascular smooth muscle cells","volume":"29","author":"He","year":"2015","journal-title":"FASEB J."},{"key":"ref_91","unstructured":"Podolec, J., Baran, J., Siedlinski, M., Urbanczyk, M., Krupinski, M., Bartus, K., Niewiara, L., Podolec, M., Guzik, T., and Tomkiewicz-Pajak, L. (2018). Serum rantes, transforming growth factor-\u03b21 and interleukin-6 levels correlate with cardiac muscle fibrosis in patients with aortic valve stenosis. J. Physiol. Pharmacol., 69."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1158\/0008-5472.CAN-04-3619","article-title":"Drastic down-regulation of Kr\u00fcppel-like factor 4 expression is critical in human gastric cancer development and progression","volume":"65","author":"Wei","year":"2005","journal-title":"Cancer Res."},{"key":"ref_93","first-page":"23","article-title":"Emerging role of KLF4 in human gastrointestinal cancer","volume":"1","author":"Wei","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"17846","DOI":"10.1074\/jbc.M109.076992","article-title":"Kr\u00fcppel-Like factor 4 promotes differentiation by transforming growth factor-beta receptor-mediated Smad and p38 MAPK signaling in vascular smooth muscle cells","volume":"285","author":"Li","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_95","unstructured":"Kim, M., Kim, S.H., Lim, J.W., and Kim, H. (2019). Lycopene induces apoptosis by inhibiting nuclear translocation of \u03b2-catenin in gastric cancer cells. J. Physiol. Pharmacol., 70."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3892\/ol.2016.5499","article-title":"Prognostic significance of KLF4 expression in gastric cancer","volume":"13","author":"Hashimoto","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1126\/science.1135961","article-title":"Integration of TGF-\u03b2 and Ras\/MAPK signaling through p53 phosphorylation","volume":"315","author":"Cordenonsi","year":"2007","journal-title":"Science"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/294097","article-title":"Crosstalk between p53 and TGF-\u03b2 Signalling","volume":"294097","author":"Elston","year":"2012","journal-title":"J. Signal Transduct."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/8\/10\/1519\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:16:02Z","timestamp":1760177762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/8\/10\/1519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,2]]},"references-count":98,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["microorganisms8101519"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms8101519","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,2]]}}}