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TGF-? autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.

ABSTRACT: Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-? (TGF-?) cytokines. In early-stage breast cancers, TGF-? exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-? promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-? are not fully understood. The present study validates the role of TGF-? signaling in cancer progression and explores mediators of pro-oncogenic TGF-? activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-? receptors decreased both basal and TGF-?-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-? stimulation of cell motility and invasion. TGF-? disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-?. Blockade of Raf-MEK signaling enhanced TGF-? induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-? rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-? stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-? receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-? signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-?-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-? signaling.

SUBMITTER: Daroqui MC

PROVIDER: S-EPMC3981025 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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TGF-β autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.

Daroqui María Cecilia MC Vazquez Paula P Bal de Kier Joffé Elisa E Bakin Andrei V AV Puricelli Lydia I LI

Oncology reports 20120514 2

Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-β (TGF-β) cytokines. In early-stage breast cancers, TGF-β exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-β promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-β are not fully underst ...[more]

PMID: 22614218

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Project description:BackgroundLung cancer has the highest case fatality rate among cancers because of uncontrolled proliferation and early metastasis of cancer cells in the lung tissue. This study aimed to clarify the role of the non-SMC condensin I complex, subunit G (NCAPG) in lung adenocarcinoma (LUAD), explore the mechanisms of its progression, and lay the foundation for the search for new biological markers.MethodsWe analyzed overlapping differentially expressed genes (DEGs) from three datasets; a protein-protein interaction (PPI) network was subsequently constructed and analyzed using Cytoscape. We then selected NCAPG for validation because of its poor prognosis and because it has not been sufficiently studied in the context of LUAD. Immunohistochemical analysis was used to detect the expression of NCAPG in LUAD tissues, and the relationships between NCAPG and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to verify the role of NCAPG in LUAD. Finally, we studied the specific mechanism of action of NCAPG in LUAD.ResultsThrough comprehensive analysis of the GSE43458, GSE75037, and The Cancer Genome Atlas databases, we identified 517 overlapping DEGs. Among them, NCAPG was identified as a hub gene. Immunohistochemical analysis revealed that NCAPG was strongly associated with the clinical stage, M-classification, and N-classification. Univariate and multivariate Cox regression analyses indicated that NCAPG was a prognostic risk factor for LUAD, while the in vitro experiments showed that NCAPG overexpression promoted proliferation, migration, invasion, and epithelial-mesenchymal transition. Furthermore, knockdown of NCAPG inhibited LUAD progression, both in vitro and in vivo. Mechanistically, NCAPG overexpression increased p-Smad2 and p-Smad3 expressions in the transforming growth factor β (TGF-β) signaling pathway. Additionally, rescue experiments indicated that TGF-β signaling pathway inhibitors could restore the effect of NCAPG overexpression in LUAD cells.ConclusionsNCAPG may promote proliferation and migration via the TGF-β signaling pathway in LUAD.

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TGF-? autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.

Publications

TGF-β autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.

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