AEG-1/MTDH-activated autophagy enhances human malignant glioma susceptibility to TGF-β1-triggered epithelial-mesenchymal transition

Zou, Meijuan; Zhu, Wei; Wang, Li; Shi, Lei; Gao, Rui; Ou, Yingwei; Chen, Xuguan; Wang, Zhongchang; Jiang, Aiqin; Liu, Kunmei; Xiao, Ming; Ni, Ping; Wu, Dandan; He, Wenping; Sun, Geng; Li, Ping; Zhai, Sulan; Wang, Xuerong; Hu, Gang

doi:10.18632/oncotarget.7536

Cited by 41 publications

(48 citation statements)

References 39 publications

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“…An EMT promoting effect of autophagy was shown in different cancer cells. 43,44 On the other hand, an anti-EMT role of autophagy sustaining the epithelial phenotype has been described in hepatocytes and in different organs during embryogenesis. 45,46 We found reduced signs of epithelial dedifferentiation in post-ischemic kidneys when Atg5 was conditionally ablated from proximal tubular S3 segments.…”

Section: Discussionmentioning

confidence: 99%

The impact of autophagy on the development of senescence in primary tubular epithelial cells

et al. 2016

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Autophagy and senescence are 2 distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the 2 processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC. Specific inhibition of autophagy by silencing autophagy-related 5 (Atg5) counteracted the occurrence of senescence hallmarks under baseline conditions. Reduced senescent features were also observed in Atg5 silenced PTEC after g-irradiation and during H-Ras induced oncogenic senescence, but the response was less uniform in these stress models. Senescence inhibition was paralleled by better preservation of a mature epithelial phenotype in PTEC. Interestingly, treatment with rapamycin, which acts as an activator of autophagy, also counteracted the occurrence of senescence features in PTEC. While we interpret the anti-senescent effect of rapamycin as an autophagy-independent effect of mTOR-inhibition, the more specific approach of Atg5 silencing indicates that overactivated autophagy can have pro-senescent effects in PTEC. These results highlight the complex interaction between cell culture dependent stress mechanisms, autophagy and senescence.

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Section: Discussionmentioning

confidence: 99%

The impact of autophagy on the development of senescence in primary tubular epithelial cells

et al. 2016

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“…Interestingly, STAT3 may also suppress the recognition of GBM cells by the immune system (Ciaglia et al, 2015). Recent observations suggest that cellular metabolic adaptations such as in choline homeostasis or autophagy can trigger or support the induction of mesenchymal transcription factors in GBM (Koch et al, 2016;Zou et al, 2016).…”

Section: Regulators Of Mt and Gbm Progressionmentioning

confidence: 99%

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

2017

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The epithelial‐to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment‐derived stimuli that provoke EMT‐like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal‐to‐epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/MET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets.

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“…EMT is the process in which epithelial cells with polarity transform into freely moving mesenchymal cells under specific physiological and pathological conditions and is the most important step in the induction of tumor cell invasion and metastasis in situ (18). …”

Section: Introductionmentioning

confidence: 99%

Metadherin regulates actin cytoskeletal remodeling and enhances human gastric cancer metastasis via epithelial-mesenchymal transition

Jiang

Song

et al. 2017

International Journal of Oncology

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Metadherin (MTDH) can be recruited to mature tight junction complexes, and it regulates mesenchymal marker protein expression in many tumors and promote cancer metastasis. This study investigated the influence of MTDH expression on gastric cancer and to elucidate the potential mechanisms by which MTDH regulates actin cytoskeletal remodeling and enhances human gastric cancer metastasis via epithelial-mesenchymal transition (EMT). Relative MTDH mRNA expression levels were assessed by quantitative real-time PCR (Q-PCR), and MTDH protein expression levels and localization were evaluated via immunohistochemical (ICH) staining. We studied the role of MTDH in cancer cell migration and invasion by modulating MTDH expression in the gastric cancer cell lines MKN45 and AGS. We also confirmed the functions of MTDH through in vivo experiments. We found that MTDH expression levels were correlated with lymph node metastasis, TNM stages and decreased OS (P=0.002, <0.001 and 0.010, respectively) in human gastric cancer and that MTDH upregulation promoted EMT in vitro. Consistent with this finding, MTDH downregulation inhibited cell migration and invasion in vitro and suppressed tumor growth and metastasis in vivo. Furthermore, MTDH knockdown regulated actin cytoskeletal remodeling and inhibited EMT. Overall, our results provide a novel role for MTDH in regulating gastric cancer metastasis.

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AEG-1/MTDH-activated autophagy enhances human malignant glioma susceptibility to TGF-β1-triggered epithelial-mesenchymal transition

Cited by 41 publications

References 39 publications

The impact of autophagy on the development of senescence in primary tubular epithelial cells

The impact of autophagy on the development of senescence in primary tubular epithelial cells

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

Metadherin regulates actin cytoskeletal remodeling and enhances human gastric cancer metastasis via epithelial-mesenchymal transition

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