Pleiotropic Roles of Non-Coding RNAs in TGF-β-Mediated Epithelial-Mesenchymal Transition and Their Functions in Tumor Progression.
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ABSTRACT:
SUBMITTER: Grelet S
PROVIDER: S-EPMC5532611 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:Epithelial to mesenchymal transition (EMT) is a course of action that enables a polarized epithelial cell to undertake numerous biochemical alterations that allow it to adopt features of mesenchymal cells such as high migratory ability, invasive properties, resistance to apoptosis, and importantly higher-order formation of extracellular matrix elements. EMT has important roles in implantation and gastrulation of the embryo, inflammatory reactions and fibrosis, and transformation of cancer cells, their invasiveness and metastatic ability. Regarding the importance of EMT in the invasive progression of cancer, this process has been well studies in in this context. Non-coding RNAs (ncRNAs) have been shown to exert critical function in the regulation of cellular processes that are involved in the EMT. These processes include regulation of some transcription factors namely SNAI1 and SNAI2, ZEB1 and ZEB2, Twist, and E12/E47, modulation of chromatin configuration, alternative splicing, and protein stability and subcellular location of proteins. In the present paper, we describe the influence of ncRNAs including microRNAs and long non-coding RNAs in the EMT process and their application as biomarkers for this process and cancer progression and their potential as therapeutic targets.
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Project description:Epithelial-mesenchymal transition is a change of cellular plasticity critical for embryonic development and tumor metastasis. CDK5 is a proline-directed serine/threonine kinase playing important roles in cancer progression. Here we show that CDK5 is commonly overexpressed and significantly correlated with several poor prognostic parameters of breast cancer. We found that CDK5 participated in TGF-?1-induced EMT. In MCF10A, TGF-?1 upregulated the CDK5 and p35 expression, and CDK5 knockdown inhibited TGF-?1-induced EMT. CDK5 overexpression also exhibited a potential synergy in promoting TGF-?1-induced EMT. In mesenchymal breast cancer cells MDA-MB-231 and BT549, CDK5 knockdown suppressed cell motility and tumorigenesis. We further demonstrated that CDK5 modulated cancer cell migration and tumor formation by regulating the phosphorylation of FAK at Ser-732. Therefore, CDK5-FAK pathway, as a downstream step of TGF-?1 signaling, is essential for EMT and motility in breast cancer cells. This study implicates the potential value of CDK5 as a molecular marker for breast cancer.
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Project description:Transforming growth factor-β (TGF-β) has received much attention as a major inducer of epithelial-mesenchymal transition (EMT) during cancer progression, mainly by activating a set of pleiotropic transcription factors including SNAI2/Slug. However, the involvement of long non-coding RNAs (lncRNAs) in TGF-β-induced Slug activation and EMT remains largely unknown. Methods: In this study, we used microarray analysis to compare lncRNA expression profiles between TGF-β treated and untreated breast cancer cells. Then, the clinical significance of lncRNAs in breast cancer was investigated by qPCR and Kaplan-Meier survival analysis. The molecular mechanisms and EMT-promoting effects in vitro were analyzed by confocal laser microscopy, Western blotting, chromosome conformation capture (3C), chromatin isolation by RNA purification (ChIRP), ChIP, luciferase reporter assay and transwell migration assay. Lastly, the pro-metastatic effects in vivo were evaluated by bioluminescent imaging and hematoxylin and eosin (H&E) staining. Results: We observed that TGF-β induced genome-wide changes in lncRNA levels in breast cancer cells, among which AC026904.1 and UCA1 were highly expressed in metastatic breast cancer and closely associated with poor prognosis. Mechanistic study revealed that AC026904.1 and UCA1 were upregulated by non-canonical and canonical TGF-β pathways, respectively. Further analysis showed that AC026904.1 functions as an enhancer RNA in the nucleus, whereas UCA1 exerts a competitive endogenous RNA (ceRNA) activity in the cytoplasm. In addition, the biological functions of these two lncRNAs converged on the activation and maintenance of Slug, constituting a one-two punch in promoting EMT and tumor metastasis. Conclusion: These findings uncover for the first time that AC026904.1 and UCA1 could cooperatively upregulate Slug expression at both transcriptional and post-transcriptional levels, exerting critical roles in TGF-β-induced EMT. The present work provides new evidence that lncRNAs function as key regulators of EMT and hold great promise to be used as novel biomarkers and therapeutic targets for metastatic breast cancer.
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Project description:Transforming growth factor ? (TGF-?) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF-? plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well as in maintaining adult tissue homeostasis. TGF-? elicits a broad range of context-dependent cellular responses, and consequently, alterations in TGF-? signaling have been implicated in many diseases, including cancer. During the early stages of tumorigenesis, TGF-? acts as a tumor suppressor by inducing cytostasis and the apoptosis of normal and premalignant cells. However, at later stages, when cancer cells have acquired oncogenic mutations and/or have lost tumor suppressor gene function, cells are resistant to TGF-?-induced growth arrest, and TGF-? functions as a tumor promotor by stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT). The latter leads to metastasis and chemotherapy resistance. TGF-? further supports cancer growth and progression by activating tumor angiogenesis and cancer-associated fibroblasts and enabling the tumor to evade inhibitory immune responses. In this review, we will consider the role of TGF-? signaling in cell cycle arrest, apoptosis, EMT and cancer cell metastasis. In particular, we will highlight recent insights into the multistep and dynamically controlled process of TGF-?-induced EMT and the functions of miRNAs and long noncoding RNAs in this process. Finally, we will discuss how these new mechanistic insights might be exploited to develop novel therapeutic interventions.
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