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Transforming growth factor-?1 activates ?Np63/c-Myc to promote oral squamous cell carcinoma.

ABSTRACT: During the development of oral squamous cell carcinoma (OSCC), the transformed epithelial cells undergo increased proliferation resulting in tumor growth and invasion. Interestingly, throughout all phases of differentiation and progression to OSCC, transforming growth factor-?1 (TGF)-?1 induces cell cycle arrest or apoptosis; however, the role of TGF-?1 in promoting cancer cell proliferation has not been explored in detail. The purpose of this study was to identify the effect of TGF-?1 on OSCC cell proliferation.Using both human OSCC samples and cell lines (UMSCC38 and UMSCC11B), we assessed protein, mRNA, gene expression, and protein-DNA interactions during OSCC progression.Our results showed that TGF-?1 increased OSCC cell proliferation by upregulating the expression of ?Np63 and c-Myc oncogenes. Although the basal OSCC cell proliferation is sustained by activating ?Np63, increased induction of c-Myc causes unregulated OSCC cell proliferation. Following induction of the cell cycle by ?Np63 and c-Myc, cancer cells that halt c-Myc activity undergo epithelial mesenchymal transition or invasion while those that continue to express ?Np63/c-Myc undergo unlimited progression through the cell cycle.OSCC proliferation is manifested by the induction of c-Myc in response to TGF-?1 signaling, which is essential for OSCC growth. Our data highlight the potential role of TGF-?1 in the induction of cancer progression and invasion of OSCC.

SUBMITTER: Hu L

PROVIDER: S-EPMC5892788 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Transforming growth factor-β1 activates ΔNp63/c-Myc to promote oral squamous cell carcinoma.

Hu Lihua L Liu Jingpeng J Li Zhi Z Wang Chunling C Nawshad Ali A

Oral surgery, oral medicine, oral pathology and oral radiology 20160608 4

<h4>Objective</h4>During the development of oral squamous cell carcinoma (OSCC), the transformed epithelial cells undergo increased proliferation resulting in tumor growth and invasion. Interestingly, throughout all phases of differentiation and progression to OSCC, transforming growth factor-β1 (TGF)-β1 induces cell cycle arrest or apoptosis; however, the role of TGF-β1 in promoting cancer cell proliferation has not been explored in detail. The purpose of this study was to identify the effect o ...[more]

PMID: 27567435

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Project description:Fibroblasts are major cellular components of the tumor microenvironment, regulating tumor cell behavior in part through secretion of extracellular matrix proteins, growth factors, and angiogenic factors. In previous studies, conditional deletion of the type II transforming growth factor-beta (TGF-beta) receptor in fibroblasts (Tgfbr2FspKO) was shown to promote mammary tumor metastasis in fibroblast-epithelial cell cotransplantation studies in mice, correlating with increased expression of hepatocyte growth factor (HGF). Here, we advance our findings to show that Tgfbr2(FspKO) fibroblasts enhance HGF/c-Met and HGF/Ron signaling to promote scattering and invasion of mammary carcinoma cells. Blockade of c-Met and Ron by small interfering RNA silencing and pharmacologic inhibitors significantly reduced mammary carcinoma cell scattering and invasion caused by Tgfbr2FspKO fibroblasts. Moreover, neutralizing antibodies to c-Met and Ron significantly inhibited HGF-induced cell scattering and invasion, correlating with reduced Stat3 and p42/44MAPK phosphorylation. Investigation of the signal transducer and activator of transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) signaling pathways by pharmacologic inhibition and small interfering RNA silencing revealed a cooperative interaction between the two pathways to regulate HGF-induced invasion, scattering, and motility of mammary tumor cells. Furthermore, whereas c-Met was found to regulate both the Stat3 and MAPK signaling pathways, Ron was found to regulate Stat3 but not MAPK signaling in mammary carcinoma cells. These studies show a tumor-suppressive role for TGF-beta signaling in fibroblasts, in part by suppressing HGF signaling between mammary fibroblasts and epithelial cells. These studies characterize complex functional roles for HGF and TGF-beta signaling in mediating tumor-stromal interactions during mammary tumor cell scattering and invasion, with important implications in the metastatic process.

Dataset Information

Transforming growth factor-?1 activates ?Np63/c-Myc to promote oral squamous cell carcinoma.

Publications

Transforming growth factor-β1 activates ΔNp63/c-Myc to promote oral squamous cell carcinoma.

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