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TGF-? signaling promotes tube-structure-forming growth in pancreatic duct adenocarcinoma.

ABSTRACT: Tube-forming growth is an essential histological feature of pancreatic duct adenocarcinoma (PDAC) and of the pancreatic duct epithelium; nevertheless, the nature of the signals that start to form the tubular structures remains unknown. Here, we showed the clonal growth of PDAC cell lines in a three-dimensional (3D) culture experiment that modeled the clonal growth of PDAC. At the beginning of this study, we isolated the sphere- and tube-forming clones from established mouse pancreatic cancer cell lines via limiting dilution culture using collagen gel. Compared with cells in spherical structures, the cells in the formed tubes exhibited a lower CK19 expression in 3D culture and in the tumor that grew in the abdominal cavity of nude mice. Conversely, the expression of the transforming growth factor ? (TGF-?)-signaling target mRNAs was higher in the formed tube vs the spherical structures, suggesting that TGF-? signaling is more active in the tube-forming process than the sphere-forming process. Treatment of sphere-forming clones with TGF-?1 induced tube-forming growth, upregulated the TGF-?-signaling target mRNAs, and yielded electron microscopic findings of a fading epithelial phenotype. In contrast, the elimination of TGF-?-signaling activation by treatment with inhibitors diminished the tube-forming growth and suppressed the expression of the TGF-?-signaling target mRNAs. Moreover, upregulation of the Fn1, Mmp2, and Snai1 mRNAs, which are hallmarks of tube-forming growth in PDAC, was demonstrated in a mouse model of carcinogenesis showing rapid progression because of the aggressive invasion of tube-forming cancer. Our study suggests that the tube-forming growth of PDAC relies on the activation of TGF-? signaling and highlights the importance of the formation of tube structures.

SUBMITTER: Yamaguchi T

PROVIDER: S-EPMC6677751 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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TGF-β signaling promotes tube-structure-forming growth in pancreatic duct adenocarcinoma.

Yamaguchi Takashi T Ikehara Sanae S Akimoto Yoshihiro Y Nakanishi Hayao H Kume Masahiko M Yamamoto Kazuo K Ohara Osamu O Ikehara Yuzuru Y

Scientific reports 20190802 1

Tube-forming growth is an essential histological feature of pancreatic duct adenocarcinoma (PDAC) and of the pancreatic duct epithelium; nevertheless, the nature of the signals that start to form the tubular structures remains unknown. Here, we showed the clonal growth of PDAC cell lines in a three-dimensional (3D) culture experiment that modeled the clonal growth of PDAC. At the beginning of this study, we isolated the sphere- and tube-forming clones from established mouse pancreatic cancer cel ...[more]

PMID: 31375695

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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.

Dataset Information

TGF-? signaling promotes tube-structure-forming growth in pancreatic duct adenocarcinoma.

Publications

TGF-β signaling promotes tube-structure-forming growth in pancreatic duct adenocarcinoma.

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