DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

Geng, Jiawei; Zhang, Rong; Yuan, Xiao; Xu, Haidong; Zhu, Zhou; Wang, Xinxin; Wang, Yan; Xu, Guoqiang; Guo, Wenjie; Wu, Junchao; Qin, Zheng‐Hong

doi:10.1038/s41419-020-02979-9

Cited by 22 publications

(15 citation statements)

References 52 publications

(59 reference statements)

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“… 42 Its acts as a tumor inhibitor in non-small-cell lung carcinoma (NSCLC) by promoting epidermal growth factor receptor (EGFR) lysosome degradation and regulates autophagy as well as cell proliferation by inhibiting the phosphatidylinositol 3-kinase-Akt-mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. 43 , 44 It has been reported that DNER promotes the epithelial-to-mesenchymal transition in breast cancer through the Wnt/β-catenin pathway. 45 DAPL1 was upregulated in hepatoblastoma and could be used as a prognostic biomarker of the disease.…”

Section: Discussionmentioning

confidence: 99%

Development of a seven-gene tumor immune microenvironment prognostic signature for high-risk grade III endometrial cancer

Zheng

Gou

et al. 2021

Molecular Therapy - Oncolytics

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Uterine corpus endometrial carcinoma locally infiltrates numerous immune cells and other tumor immune microenvironment components. These cells are involved in malignant tumor growth and proliferation and the process of resistance toward immunotherapies. Here, we aimed to develop a tumor immune microenvironment-related prognostic signature for high-risk grade III endometrial carcinoma based on The Cancer Genome Atlas. The signature was systematically correlated with immune infiltration characteristics of the tumor microenvironment. The seven-gene Riskscore signature was robust and performed well in training, testing, and Gene Expression Omnibus-independent cohorts. A nomogram comprising the gene signature accurately predicted patient prognosis, with our model performing better than other endometrial cancer-related signatures. Analysis of the IMvigor210 immunotherapy cohort revealed that subgroups with a low Riskscore had a better prognosis than subgroups with a high Riskscore. Subgroups with a low Riskscore exhibited immune cell infiltration and inflammatory profiles, whereas subgroups with a high Riskscore experienced progressive disease. The receiver operating characteristic curve indicated that risk score, neoantigen, and tumor mutation burden models together accurately predicted treatment response. Taken together, we developed a tumor microenvironment-based seven-gene prognostic stratification system to predict the prognosis of patients with high-risk endometrial cancer and guide more effective immunotherapy strategies.

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Section: Discussionmentioning

confidence: 99%

Development of a seven-gene tumor immune microenvironment prognostic signature for high-risk grade III endometrial cancer

Zheng

Gou

et al. 2021

Molecular Therapy - Oncolytics

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“…Moreover, the overexpression of miR-524-5p is associated with a poor prognosis of patients with idiopathic pulmonary fibrosis [ 28 ]. Considering the previously reported findings [ 24 , 28 , 31 ], we examined the role of miR-524-5p in HCC827 and NCI-H1650 cell lines and found that the enrichment of miR-524-5p was significantly lower than EGFR-AS1, and that they were inversely expressed in HCC827 and NCI-H1650 cell lines. Subsequently, the inhibition of miR-524-5p promoted the viability and invasion of HCC827 and NCI-H1650 cell lines.…”

Section: Discussionmentioning

confidence: 94%

“…Emerging evidence suggested that DRAM1 is engaged in the biological functions of cancer cells [ 30 , 43 ]. DRAM1 has been found to play a tumor suppressor role in NSCLC [ 31 ]. However, DRAM1 expression and clinical significance in lung cancer have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…DRAM1 was reported to be decreased in NSCLC and was negatively correlated with EGFR levels. In addition, DRAM1 overexpression inhibited the proliferation, invasion, migration, and EMT of NSCLC cell lines harboring mutant EGFR in vitro and in vivo [ 31 ]. Nevertheless, the underlying mechanism of DRAM1 in the pathogenesis of NSCLC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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EGFR-AS1 Promotes Nonsmall Cell Lung Cancer (NSCLC) Progression via Downregulating the miR-524-5p/DRAM1 Axis and Inhibiting Autophagic Lysosomal Degradation

Yang

Zhang

Hou

et al. 2022

Journal of Oncology

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Nonsmall cell lung cancer (NSCLC) accounts for the majority of lung cancers. Studies have revealed the regulatory role of lncRNAs in cancer pathogenesis and their potential use as diagnostic and prognostic biomarkers. The epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) has been reported to be upregulated in NSCLC tissues, while its detailed mechanism in lung cancer needs to be explored. DNA damage-regulated autophagy modulator 1 (DRAM1) has been known to act as a tumor suppressor in NSCLC, and miR-524-5p has been reported to be a biomarker in idiopathic pulmonary fibrosis and different lung disorders. Our investigation revealed that EGFR-AS1 is highly expressed in lung cancer tissues, and its knockdown inhibited lung cancer cell invasion and viability and reduced tumor growth in vivo. We also found that EGFR-AS1 targets miR-524-5p, and there was a negative correlation between their expressions in lung cancer tissues. Simultaneously, miR-524-5p has been found to promote DRAM1 expression. In addition, the inhibition of miR-524-5p diminished DRAM1 protein expression and promoted lung cancer cell invasion. Our study has revealed that EGFR-AS1 contributes to the pathogenesis of NSCLC by inhibiting autophagic-lysosomal degradation via targeting the miR-524-5p/DRAM1 axis. This finding elucidated for the first time the role of EGFR-AS1 in lung cancer progression and the positive regulatory function of miR-524-5p in regulating DRAM1 protein and suppressing lung cancer progression. This novel mechanism provided a better insight into the pathogenesis of lung cancer and presented a better strategy for the treatment of lung cancer.

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“…Overexpression of DRAM1 has been shown to increase basal levels of autophagosome numbers, indicating that DRAM1 can act early in the autophagy process, contributing to autophagosome formation (Mah et al, 2012). However, the DRAM1 protein predominantly localizes to lysosomes and there is evidence also for functions at later steps in the process, showing that DRAM1 enhances autophagic flux and promotes ATPase activity and lysosomal acidification (Zhang et al ., 2013; Geng et al ., 2020). DRAM1 is thought to mediate crosstalk between autophagy and apoptosis by interacting with the proapoptotic protein BAX (Guan et al ., 2015).…”

Section: Introductionmentioning

confidence: 99%

Dram1 confers resistance toSalmonellainfection

Masud

Zhang

et al. 2021

Preprint

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Dram1 is a stress and infection inducible autophagy modulator that functions downstream of transcription factors p53 and NFκB. Using a zebrafish embryo infection model, we have previously shown that Dram1 provides protection against the intracellular pathogen Mycobacterium marinum by promoting the p62-dependent xenophagy of bacteria that have escaped into the cytosol. However, the possible interplay between Dram1 and other anti-bacterial autophagic mechanisms remains unknown. Recently, LC3-associated phagocytosis (LAP) has emerged as an important host defense mechanism that requires components of the autophagy machinery and targets bacteria directly in phagosomes. Our previous work established LAP as the main autophagic mechanism by which macrophages restrict growth of Salmonella Typhimurium in a systemically infected zebrafish host. We therefore employed this infection model to investigate the possible role of Dram1 in LAP. Morpholino knockdown or CRISPR/Cas9-mediated mutation of Dram1 led to reduced host survival and increased bacterial burden during S. Typhimurium infections. In contrast, overexpression of dram1 by mRNA injection curtailed Salmonella replication and reduced mortality of the infected host. During the early response to infection, GFP-Lc3 levels in transgenic zebrafish larvae correlated with the dram1 expression level, showing over two-fold reduction of GFP-Lc3-Salmonella association in dram1 knockdown or mutant embryos and an approximately 30% increase by dram1 overexpression. Since LAP is known to require the activity of the phagosomal NADPH oxidase, we used a Salmonella biosensor strain to detect bacterial exposure to reactive oxygen species (ROS) and found that the ROS response was largely abolished in the absence of dram1. Together, these results demonstrate the host protective role of Dram1 during S. Typhimurium infection and suggest a functional link between Dram1 and the induction of LAP.

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DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

Cited by 22 publications

References 52 publications

Development of a seven-gene tumor immune microenvironment prognostic signature for high-risk grade III endometrial cancer

Development of a seven-gene tumor immune microenvironment prognostic signature for high-risk grade III endometrial cancer

EGFR-AS1 Promotes Nonsmall Cell Lung Cancer (NSCLC) Progression via Downregulating the miR-524-5p/DRAM1 Axis and Inhibiting Autophagic Lysosomal Degradation

Dram1 confers resistance toSalmonellainfection

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