Lenalidomide Up-Regulates SPARC and Inhibits In Vitro Growth of the Malignant Clone in Myelodysplastic Syndrome Patients with 5q Deletion.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 855-855
Author(s):  
Andrea Pellagatti ◽  
Martin Jädersten ◽  
Ann-Mari Forsblom ◽  
Helen Cattan ◽  
Birger Christensson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myelodysplastic Syndrome ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Activin A ◽  
Healthy Controls ◽  
Erythroid Progenitors ◽  
Normal Cells

Abstract The immunomodulatory drug lenalidomide induces cytogenetic remissions in 75% of patients with myelodysplastic syndrome (MDS) and del(5)(q31) through unknown mechanisms. We investigated the in vitro effects of lenalidomide on growth and maturation in differentiating erythroblasts from MDS patients with del(5)(q31) (n=13) and from healthy controls (n=10). Lenalidomide selectively inhibited growth of del(5q) erythroblasts, while not affecting normal cells, including cytogenetically normal cells from MDS del(5q) patients. The inhibitory effect was more pronounced in erythroid than in myeloid cells. In order to gain insight into the mode of action of lenalidomide and to identify the molecular targets of this drug, we have investigated the gene expression profiles of the lenalidomide-treated and untreated intermediate erythroblasts from MDS del(5q) patients (n=9) and from healthy controls (n=8). GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix), covering over 47,000 transcripts representing 39,000 human genes, were used. Treatment with lenalidomide significantly influenced the pattern of gene expression in del(5q) intermediate erythroblasts, with up-regulation of VSIG4, PPIC, TPBG, and SPARC in all samples, and down-regulation of many genes involved in erythropoiesis, including HBA2, GYPA, and KLF1, in most samples. Up-regulation of SPARC (median 4.4-fold, range 2.4–9.5) is of particular interest since SPARC, a gene with known tumor suppressor functions, is both anti-proliferative and anti-angiogenic, and is located at 5q31–q32, within the commonly deleted region in MDS 5q- syndrome. Activin A was one of the most significant differentially expressed genes between lenalidomide-treated cells of MDS del(5q) patients and healthy controls. Activin A is a member of the transforming growth factor-beta superfamily, with pleiotropic functions including apoptosis of hemopoietic cells. We conclude that lenalidomide specifically inhibits growth of del(5q) erythroid progenitors, while not affecting cytogenetically normal cells. These novel findings suggest that up-regulation of SPARC and Activin A may underlie the potent effects of lenalidomide, in particular growth inhibition and anti-angiogenesis, in MDS with del(5)(q31). The localization of the SPARC gene to the CDR of the 5q- syndrome is intriguing and, in relation to the findings of the present study, we suggest that SPARC may well play a role in the molecular pathogenesis of the 5q- syndrome.

Lenalidomide Selectively Inhibits In Vitro Growth of the Malignant Clone in Myelodysplastic Syndrome (MDS) Patients with 5q Deletion.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3438-3438 ◽  
Author(s):  
Martin Jädersten ◽  
Andrea Pellagatti ◽  
Ann-Mari Forsblom ◽  
Emma K. Emanuelsson ◽  
Mats Merup ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Myelodysplastic Syndrome ◽  
Fold Increase ◽  
Healthy Controls ◽  
In Vitro Growth ◽  
Normal Cells ◽  
Hematopoietic Stem ◽  
5Q Deletion

Abstract The immunomodulatory drug lenalidomide induces 82% complete cytogenetic remissions in patients with myelodysplastic syndrome (MDS) and 5q31 deletion. Lenalidomide has multiple effects, but the causal mechanisms of action are unknown. In this study we assessed the direct effect of lenalidomide on hematopoietic cells from eight MDS patients with del(5)(q31) and from five healthy controls. Lenalidomide titrated up to 500 μM caused no growth inhibition of mononuclear cells from healthy controls. Selected CD34+ hematopoietic stem cells were then cultured with or without 10 μM of lenalidomide in a 14-day model for pure erythroblast differentiation in a medium containing IL-3, IL-6, and SCF, and with addition of Epo during the second week. Cell count and viability was monitored regularly, and FISH and FACS analyses were performed at day 0, 7, and 14. The median proportion of 5q- cells by FISH at day 7 was 98% (range 86–99), dropping to 88% (range 35–98) at day 14 due to a variable outgrowth of cytogenetically normal cells. Day 7 cells, the majority still being 5q-, were used for gene expression analyses. In erythroblast cultures with cells from healthy controls, lenalidomide had no inhibitory effect on fold increase of cell counts (P=0.92). However, in cultures with cells from 5q- patients, the clone with 5q deletion showed significant inhibition of fold increase at day 14 (P=0.009), while the cytogenetically normal progenitors were not inhibited (P=0.83). Gene expression profiling was performed using Affymetrix Human Genome U133 Plus 2.0 Arrays. A group of genes was found whose expression was affected by the addition of lenalidomide to the cultures of both normal erythroblasts and 5q- erythroblasts. Furthermore, lenalidomide decreased the proportion of cells expressing late erythroid markers on FACS analysis at day 14. We conclude that lenalidomide selectively inhibits in vitro growth of 5q- hematopoietic stem cells, while not affecting growth of cytogenetically normal cells from MDS patients with 5q deletion or from healthy controls. In addition, we see that lenalidomide affects cell differentiation and induces changes in gene expression.

scholarly journals Identification of key biomarkers associated with development and prognosis in patients with ovarian carcinoma: evidence from bioinformatic analysis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiayu Shen ◽  
Shuqian Yu ◽  
Xiwen Sun ◽  
Meichen Yin ◽  
Jing Fei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Transforming Growth Factor Beta ◽  
Cell Adhesion Molecules ◽  
Cellular Response ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Regulation Of Transcription ◽  
Hub Genes

Abstract Background Ovarian cancer (OC) is the deadliest cause in the gynecological malignancies. Most OC patients are diagnosed in advanced stages with less than 40% of women cured. However, the possible mechanism underlying tumorigenesis and candidate biomarkers remain to be further elucidated. Results Gene expression profiles of GSE18520, GSE54388, and GSE27651 were available from Gene Expression Omnibus (GEO) database with a total of 91 OC samples and 22 normal ovarian (OV) tissues. Three hundred forty-nine differentially expressed genes (DEGs) were screened between OC tissues and OV tissues via GEO2R and online Venn software, followed by KEGG pathway and gene ontology (GO) enrichment analysis. The enriched functions and pathways of these DEGs contain male gonad development, cellular response to transforming growth factor beta stimulus, positive regulation of transcription from RNA polymerase II promoter, calcium independent cell-cell adhesion via plasma membrane cell adhesion molecules, extracellular matrix organization, pathways in cancer, cell cycle, cell adhesion molecules, PI3K-AKT signaling pathway, and progesterone mediated oocyte maturation. The protein-protein network (PPI) was established and module analysis was carried out using STRING and Cytoscape. Next, with PPI network analyzed by four topological methods in Cytohubba plugin of Cytoscape, 6 overlapping genes (DTL, DLGAP5, KIF15, NUSAP1, RRM2, and TOP2A) were eventually selected. GEPIA and Oncomine were implemented for validating the gene expression and all the six hub genes were highly expressed in OC specimens compared to normal OV tissues. Furthermore, 5 of 6 genes except for DTL were associated with worse prognosis using Kaplan Meier-plotter online tool and 3 of 6 genes were significantly related to clinical stages, including RRM2, DTL, and KIF15. Additionally, cBioPortal showed that TOP2A and RRM2 were the targets of cancer drugs in patients with OC, indicating the other four genes may also be potential drug targets. Conclusion Six hub genes (DTL, DLGAP5, KIF15, NUSAP1, RRM2, and TOP2A) present promising predictive value for the development and prognosis of OC and may be used as candidate targets for diagnosis and treatment of OC.

During ontogeny primitive (CD34+CD38−) hematopoietic cells show altered expression of a subset of genes associated with early cytokine and differentiation responses of their adult counterparts

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4160-4168 ◽  
Author(s):  
Il-Hoan Oh ◽  
Aster Lau ◽  
Connie J. Eaves
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Fetal Liver ◽  
Expression Profiles ◽  
Hematopoietic Cells ◽  
Altered Expression ◽  
Short Term Exposure ◽  
Activated State

Abstract Comparison of gene expression profiles in closely related subpopulations of primitive hematopoietic cells offers a powerful first step to elucidating the molecular basis of their different biologic properties. Here we present the results of a comparative quantitative analysis of transcript levels for various growth factor receptors, ligands, and transcription factor genes in CD34+CD38− and CD34+CD38+ cells purified from first trimester human fetal liver, cord blood, and adult bone marrow (BM). In addition, adult BM CD34+CD38− cells were examined after short-term exposure to various growth factors in vitro. Transcripts for 19 of the 24 genes analyzed were detected in unmanipulated adult BM CD34+CD38− cells. Moreover, the levels of transforming growth factor beta (TGF-β), gp130, c-fos, and c-jun transcripts in these cells were consistently and significantly different (higher) than in all other populations analyzed, including phenotypically similar but biologically different cells from fetal or neonatal sources, as well as adult BM CD34+ cells still in G0 after 2 days of growth factor stimulation. We have thus identified a subset of early response genes whose expression in primitive human hematopoietic cells is differently regulated during ontogeny and in a fashion that is recapitulated in growth factor-stimulated adult BM CD34+CD38− cells, before their cell cycle progression and independent of their subsequent differentiation response. These findings suggest a progressive alteration in the physiology of primitive hematopoietic cells during development such that these cells initially display a partially “activated” state, which is not maximally repressed until after birth.

scholarly journals Gene expression in mouse ovarian follicle development in vivo versus an ex vivo alginate culture system

Reproduction ◽  
2011 ◽  
Vol 142 (2) ◽  
pp. 309-318 ◽  
Author(s):  
Elizabeth M Parrish ◽  
Anaar Siletz ◽  
Min Xu ◽  
Teresa K Woodruff ◽  
Lonnie D Shea
Keyword(s):  
Gene Expression ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Expression Profiles ◽  
Ovarian Follicle ◽  
Gene Expression Profiles ◽  
Follicle Development ◽  
Α Subunit

Ovarian follicle maturation results from a complex interplay of endocrine, paracrine, and direct cell–cell interactions. This study compared the dynamic expression of key developmental genes during folliculogenesis in vivo and during in vitro culture in a 3D alginate hydrogel system. Candidate gene expression profiles were measured within mouse two-layered secondary follicles, multi-layered secondary follicles, and cumulus–oocyte complexes (COCs). The expression of 20 genes involved in endocrine communication, growth signaling, and oocyte development was investigated by real-time PCR. Gene product levels were compared between i) follicles of similar stage and ii) COCs derived either in vivo or by in vitro culture. For follicles cultured for 4 days, the expression pattern and the expression level of 12 genes were the same in vivo and in vitro. Some endocrine (cytochrome P450, family 19, subfamily A, polypeptide 1 (Cyp19a1) and inhibin βA subunit (Inhba)) and growth-related genes (bone morphogenetic protein 15 (Bmp15), kit ligand (Kitl), and transforming growth factor β receptor 2 (Tgfbr2)) were downregulated relative to in vivo follicles. For COCs obtained from cultured follicles, endocrine-related genes (inhibin α-subunit (Inha) and Inhba) had increased expression relative to in vivo counterparts, whereas growth-related genes (Bmp15, growth differentiation factor 9, and kit oncogene (Kit)) and zona pellucida genes were decreased. However, most of the oocyte-specific genes (e.g. factor in the germline α (Figla), jagged 1 (Jag1), and Nlrp5 (Mater)) were expressed in vitro at the same level and with the same pattern as in vivo-derived follicles. These studies establish the similarities and differences between in vivo and in vitro cultured follicles, guiding the creation of environments that maximize follicle development and oocyte quality.

During ontogeny primitive (CD34+CD38−) hematopoietic cells show altered expression of a subset of genes associated with early cytokine and differentiation responses of their adult counterparts

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4160-4168 ◽  
Author(s):  
Il-Hoan Oh ◽  
Aster Lau ◽  
Connie J. Eaves
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Fetal Liver ◽  
Expression Profiles ◽  
Hematopoietic Cells ◽  
Altered Expression ◽  
Short Term Exposure ◽  
Activated State

Comparison of gene expression profiles in closely related subpopulations of primitive hematopoietic cells offers a powerful first step to elucidating the molecular basis of their different biologic properties. Here we present the results of a comparative quantitative analysis of transcript levels for various growth factor receptors, ligands, and transcription factor genes in CD34+CD38− and CD34+CD38+ cells purified from first trimester human fetal liver, cord blood, and adult bone marrow (BM). In addition, adult BM CD34+CD38− cells were examined after short-term exposure to various growth factors in vitro. Transcripts for 19 of the 24 genes analyzed were detected in unmanipulated adult BM CD34+CD38− cells. Moreover, the levels of transforming growth factor beta (TGF-β), gp130, c-fos, and c-jun transcripts in these cells were consistently and significantly different (higher) than in all other populations analyzed, including phenotypically similar but biologically different cells from fetal or neonatal sources, as well as adult BM CD34+ cells still in G0 after 2 days of growth factor stimulation. We have thus identified a subset of early response genes whose expression in primitive human hematopoietic cells is differently regulated during ontogeny and in a fashion that is recapitulated in growth factor-stimulated adult BM CD34+CD38− cells, before their cell cycle progression and independent of their subsequent differentiation response. These findings suggest a progressive alteration in the physiology of primitive hematopoietic cells during development such that these cells initially display a partially “activated” state, which is not maximally repressed until after birth.

A phorbol ester-regulated ribonuclease system controlling transforming growth factor beta 1 gene expression in hematopoietic cells

1990 ◽  
Vol 10 (11) ◽  
pp. 5983-5990
Author(s):  
R E Wager ◽  
R K Assoian
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Fold Increase ◽  
Mrna Levels ◽  
Tgf Beta ◽  
Growth Factor Beta

12-Tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of U937 promonocytes leads to a 30-fold increase in transforming growth factor beta 1 (TGF-beta 1) gene expression, and this effect results from a stabilized mRNA. Similar up-regulation was detected in TPA-treated K562 erythroblasts but was absent from cell lines that do not differentiate in response to TPA. Related studies in vitro showed that postnuclear extracts of U937 promonocytes contain a ribonuclease system that degrades TGF-beta 1 mRNA selectively and that this system is completely blocked by prior treatment of the cells with TPA. These data identify a new mechanism for regulating TGF-beta 1 mRNA levels and allow us to establish the overall basis for control of TGF-beta 1 gene expression by activation of protein kinase C. Our results also provide a new basis for understanding the long-term up-regulation of TGF-beta 1 gene expression that can accompany hematopoietic cell differentiation.

scholarly journals A phorbol ester-regulated ribonuclease system controlling transforming growth factor beta 1 gene expression in hematopoietic cells.

1990 ◽  
Vol 10 (11) ◽  
pp. 5983-5990 ◽  
Author(s):  
R E Wager ◽  
R K Assoian
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Fold Increase ◽  
Mrna Levels ◽  
Tgf Beta ◽  
Growth Factor Beta

12-Tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of U937 promonocytes leads to a 30-fold increase in transforming growth factor beta 1 (TGF-beta 1) gene expression, and this effect results from a stabilized mRNA. Similar up-regulation was detected in TPA-treated K562 erythroblasts but was absent from cell lines that do not differentiate in response to TPA. Related studies in vitro showed that postnuclear extracts of U937 promonocytes contain a ribonuclease system that degrades TGF-beta 1 mRNA selectively and that this system is completely blocked by prior treatment of the cells with TPA. These data identify a new mechanism for regulating TGF-beta 1 mRNA levels and allow us to establish the overall basis for control of TGF-beta 1 gene expression by activation of protein kinase C. Our results also provide a new basis for understanding the long-term up-regulation of TGF-beta 1 gene expression that can accompany hematopoietic cell differentiation.

scholarly journals OP0136 THE INFLUENCE OF LONG-TERM EXERCISE AND IN VITRO EXERCISE-MIMICKING STIMULATION ON THE PRODUCTION OF MYOKINES AND CYTOKINES IN MYOTUBES OF PATIENTS WITH CHRONIC IDIOPATHIC INFLAMMATORY MYOPATHIES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 88.2-88
Author(s):  
M. Vokurková ◽  
L. Vernerová ◽  
M. Špiritović ◽  
H. Štorkánová ◽  
S. Oreska ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Cytokines ◽  
Culture Medium ◽  
Muscle Cells ◽  
Activin A ◽  
Idiopathic Inflammatory Myopathies ◽  
Healthy Controls ◽  
Inflammatory Myopathies

Background:It has been demonstrated several times that endurance exercise has beneficial effects on the condition of patients with idiopathic inflammatory myopathies (IIM). Muscle contraction during exercise is a major stimulus for the release of myokines that are supposed to take part in the beneficial adaption to exercise.Objectives:The aim of this study was to find out how a six-month physiotherapy andin vitroexercise-mimicking treatment affect myokine and cytokine production in myotubes of IIM patients.Methods:Seven patients with chronic IIM took part in a six-month physiotherapy (stretching and strengthening), which significantly improved their muscle strength and endurance. IIM patients (n=7) before and after the six months exercise and their respective healthy counterparts (HC, n=9) underwent amusculus vastus lateralisbiopsy. Isolated skeletal muscle cells were grown, differentiated into myotubes, which were treated with a pharmacological cocktail: palmitate, forskolin and ionomycin (PFI) to mimic exercise-stimulated contractions in vitro. Myokine and cytokine concentrations produced by myotubes to the culture medium were analyzed with ELISA and the multiplex immunoassay, respectively. RT-PCR was used for the evaluation of myokine gene expression in the cultured myotubes.Results:Compared to myotubes of healthy controls, myotubes of IIM patient released more myostatin and activin A into the medium. The myostatin gene was expressed significantly more in muscle cells of patients than in healthy controls’ cells (p<0.05). After a six-month rehabilitation program, activin A secretion was four-fold reduced in myotubes of patients with IIM, while myostatin release and gene expression remained unchanged. In myotubes of IIM patients, less follistatin and more follistatin like 3 were detected in the culture medium compared to HC myotubes. Myotubes derived from IIM patients after six months of rehabilitation secreted twice as much follistatin and half the amount of follistatin like 3 into the medium than myotubes derived from IIM patients prior to rehabilitation (p<0.05). There was no difference in secretion of interleukin (IL) 6, IL-17, tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF) between myotubes of IIM patients and myotubes of HC. However, six-month exercise significantly (p<0.05) reduced release of IL-6, TNF and VEGF in myotubes of IIM patients. Contrary to our expectation, stimulation of PFI had no effect on the release of myostatin, activin A, follistatin and follistatin like 3, or the expression of their genes. PFI treatment significantly (p<0.05) increased IL-6 secretion in myotubes from HC and IIM patients prior to six months of rehabilitation. On the other hand, it was observed that myotubes of HC and IIM patients exposed to the PFI cocktail secreted significantly less inflammatory cytokines IL-17, TNF and VEGF into the medium compared to unstimulated myotubes (p<0.05).Conclusion:In conclusion, long-term exercise influenced the production of myokines and decreased release of inflammatory cytokines in myotubes of IIM patients.In vitroexercise-mimicking treatment increased the secretion of IL-6 and decreased the release of inflammatory cytokines as IL-17, TNF-α and VEGF in myotubes of patients with IIM and healthy individuals.Acknowledgments:This work was supported by the Ministry of Health of the Czech Republic grants nr. 16-33746A and donation 140.0000008.Disclosure of Interests:None declared

scholarly journals Circulating Exosomal miR-17 Inhibits the Induction of Regulatory T Cells via Suppressing TGFBR II Expression in Rheumatoid Arthritis

2018 ◽  
Vol 50 (5) ◽  
pp. 1754-1763 ◽  
Author(s):  
Liping Wang ◽  
Chunyan Wang ◽  
Xuqiang Jia ◽  
Jing Yu
Keyword(s):  
Rheumatoid Arthritis ◽  
Flow Cytometry ◽  
T Cells ◽  
Regulatory T Cells ◽  
Mirna Expression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Luciferase Reporter

Background/Aims: A reduced prevalence of circulating regulatory T cells (Tregs)is a hallmark of inflammatory rheumatoid arthritis (RA). However, the underlying mechanisms of alterations of Tregs are unclear. Methods: The ratio of Tregs in peripheral blood of healthy controls (HCs) and patients with RA was determined by flow cytometry. MicroRNA (miRNA) expression profiles in exosomes derived from RA patients (RA-exosomes) and in those from HCs (HC-exosomes) were detected by microarray analysis, and miR-17 was measured by quantitative real-time PCR. Transforming growth factor beta receptor II (TGFBR II) expressed by T cells was measured by flow cytometry. The interaction between miR-17 and TGFBR II was evaluated by dual-luciferase reporter assay. Results: We found that RA-exosomes can selectively affect Treg differentiation in vitro. Several miRNAs are more abundant in the RA-exosomes than in HC-exosomes. Among those upregulated in patients with RA, miR-17 can suppress Treg induction by inhibiting the expression of TGFBR II. Conclusion: Our findings imply that altered miRNA expression in RA-exosomes may contribute to the pathogenesis of RA by disrupting the homeostasis of Tregs.

scholarly journals TGF-β and microRNA Interplay in Genitourinary Cancers

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1619 ◽  
Author(s):  
Joanna Boguslawska ◽  
Piotr Kryst ◽  
Slawomir Poletajew ◽  
Agnieszka Piekielko-Witkowska
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
In Vivo Studies ◽  
Genitourinary Cancers

Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the “TGF-β paradox” in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.

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