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LncRNA H19 is involved in TGF-?1-induced epithelial to mesenchymal transition in bovine epithelial cells through PI3K/AKT Signaling Pathway.

ABSTRACT: Increased levels of long noncoding RNA H19 (H19) have been observed in many inflammatory and organ fibrosis diseases including ulcerative colitis, osteoarthritis, liver fibrosis, renal fibrosis and pulmonary fibrosis. However, the role of H19 in bovine mastitis and mastitis-caused fibrosis is still unclear. In our study, H19 was characterized as a novel regulator of EMT induced by transforming growth factor-?1 (TGF-?1) in bovine mammary alveolar cell-T (MAC-T) cell line. We found that H19 was highly expressed in bovine mastitis tissues and inflammatory MAC-T cells induced by virulence factors of pathogens. TGF-?1 was also highly expressed in inflammatory MAC-T cells, and exogenous TGF-?1 could induce EMT, enhance extracellular matrix protein expression, and upregulate H19 expression in epithelial cells. Stable expression of H19 significantly promotes EMT progression and expression of ECM protein induced by TGF-?1 in MAC-T cells. Furthermore, by using a specific inhibitor of the PI3K/AKT pathway, we demonstrated that TGF-?1 upregulated H19 expression through PI3K/AKT pathway. All these observations imply that the lncRNA H19 modulated TGF-?1-induced epithelial to mesenchymal transition in bovine epithelial cells through PI3K/AKT signaling pathway, which suggests that mammary epithelial cells might be one source for myofibroblasts in vivo in the mammary glands under an inflammatory condition, thereby contributing to mammary gland fibrosis.

SUBMITTER: Yang W

PROVIDER: S-EPMC5649593 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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lncRNA H19 is involved in TGF-<i>β</i>1-induced epithelial to mesenchymal transition in bovine epithelial cells through PI3K/AKT Signaling Pathway.

Yang Wei W Li Xuezhong X Qi Shaopei S Li Xueru X Zhou Kun K Qing Suzhu S Zhang Yong Y Gao Ming-Qing MQ

PeerJ 20171017

Increased levels of long noncoding RNA H19 (H19) have been observed in many inflammatory and organ fibrosis diseases including ulcerative colitis, osteoarthritis, liver fibrosis, renal fibrosis and pulmonary fibrosis. However, the role of H19 in bovine mastitis and mastitis-caused fibrosis is still unclear. In our study, H19 was characterized as a novel regulator of EMT induced by transforming growth factor-β1 (TGF-β1) in bovine mammary alveolar cell-T (MAC-T) cell line. We found that H19 was hi ...[more]

PMID: 29062612

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Project description:BackgroundTumor microenvironments (TMEs) activate various axes/pathways, predominantly inflammatory and hypoxic responses, impact tumorigenesis, metastasis and therapeutic resistance significantly. Although molecular pathways of individual TME are extensively studied, evidence showing interaction and crosstalk between hypoxia and inflammation remain unclear. Thus, we examined whether interferon (IFN) could modulate both inflammatory and hypoxic responses under normoxia and its relation with cancer development.MethodsIFN was used to induce inflammation response and HIF-1α expression in various cancer cell lines. Corresponding signaling pathways were then analyzed by a combination of pharmacological inhibitors, immunoblotting, GST-Raf pull-down assays, dominant-negative and short-hairpin RNA-mediated knockdown approaches. Specifically, roles of functional HIF-1α in the IFN-induced epithelial-mesenchymal transition (EMT) and other tumorigenic propensities were examined by knockdown, pharmacological inhibition, luciferase reporter, clonogenic, anchorage-independent growth, wound-healing, vasculogenic mimicry, invasion and sphere-formation assays as well as cellular morphology observation.ResultsWe showed for the first time that IFN induced functional HIF-1α expression in a time- and dose- dependent manner in various cancer cell lines under both hypoxic and normoxic conditions, and then leading to an activated HIF-1α pathway in an IFN-mediated pro-inflammatory TME. IFN regulates anti-apoptosis activity, cellular metastasis, EMT and vasculogenic mimicry by a novel mechanism through mainly the activation of PI3K/AKT/mTOR axis. Subsequently, pharmacological and genetic modulations of HIF-1α, JAK, PI3K/AKT/mTOR or p38 pathways efficiently abrogate above IFN-induced tumorigenic propensities. Moreover, HIF-1α is required for the IFN-induced invasiveness, tumorigenesis and vasculogenic mimicry. Further supports for the HIF-1α-dependent tumorigenesis were obtained from results of xenograft mouse model and sphere-formation assay.ConclusionsOur mechanistic study showed an induction of HIF-1α and EMT ability in an IFN-mediated inflammatory TME and thus demonstrating a novel interaction between inflammatory and hypoxic TMEs. Moreover, targeting HIF-1α may be a potential target for inhibiting tumor tumorigenesis and EMT by decreasing cancer cells wound healing and anchorage-independent colony growth. Our results also lead to rationale guidance for developing new therapeutic strategies to prevent relapse via targeting TME-providing IFN signaling and HIF-1α programming.

Dataset Information

LncRNA H19 is involved in TGF-?1-induced epithelial to mesenchymal transition in bovine epithelial cells through PI3K/AKT Signaling Pathway.

Publications

lncRNA H19 is involved in TGF-<i>β</i>1-induced epithelial to mesenchymal transition in bovine epithelial cells through PI3K/AKT Signaling Pathway.

Similar Datasets

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