miR-210-5p promotes epithelial–mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells

Liu, Wei; Jiang, Dongdong; Gong, Fangyi; Huang, Yu‐Min; Luo, Yi; Rong, Yuluo; Wang, Jiaxing; Ge, Xuhui; Ji, Chengyue; Fan, Jin; Cai, Wei

doi:10.1038/s41419-020-2270-1

Cited by 52 publications

(46 citation statements)

References 62 publications

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“…miR-210-3p is the guide-strand that integrates into the RISC (RNA induced silencing complex), whereas miR-210-5p is the passenger-strand that is inactivated through degradation [ 19 , 20 ]. miR-210-5P is up-regulated in several malignant tumors that are associated with a variety of functionally important targets involved in cancers [ 21 ]. However, whether miR-210-5p could regulate mitophagy to participate in drug-sensitivity remains to be examined in depth.…”

Section: Introductionmentioning

confidence: 99%

Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

Wang

Liu

et al. 2020

J Exp Clin Cancer Res

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Background The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients. Mitophagy is the programmed degradation of mitochondria, and is likely involved in drug resistance of cancer cells. Here, we identified hyperactivated mitophagy is essential for sorafenib resistance, and the mitophagy core regulator gene ATAD3A (ATPase family AAA domain containing 3A) was down regulated in hypoxia induced resistant HCC cells. Blocking mitophagy may restore the sorafenib sensitivity of these cells and provide a new treatment strategy for HCC patients. Methods Hypoxia induced sorafenib resistant cancer cells were established by culturing under 1% O2 with increasing drug treatment. RNA sequencing was conducted in transfecting LM3 cells with sh-ATAD3A lentivirus. Subsequent mechanistic studies were performed in HCC cell lines by manipulating ATAD3A expression isogenically where we evaluated drug sensitivity, molecular signaling events. In vivo study, we investigated the combined treatment effect of sorafenib and miR-210-5P antagomir. Results We found a hyperactivated mitophagy regulating by ATAD3A-PINK1/PARKIN axis in hypoxia induced sorafenib resistant HCC cells. Gain- and loss- of ATAD3A were related to hypoxia-induced mitophagy and sorafenib resistance. In addition, ATAD3A is a functional target of miR-210-5p and its oncogenic functions are likely mediated by increased miR-210-5P expression. miR-210-5P was upregulated under hypoxia and participated in regulating sorafenib resistance. In vivo xenograft assay showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice. Conclusions Loss of ATAD3A hyperactivates mitophagy which is a core event in hypoxia induced sorafenib resistance in HCC cells. Targeting miR-210-5P-ATAD3A axis is a novel therapeutic target for sorafenib-resistant HCC.

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Section: Introductionmentioning

confidence: 99%

Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

Wang

Liu

et al. 2020

J Exp Clin Cancer Res

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“…This is consistent with the effect of autophagy on metastasis, as observed by Zhang et al [ 35 ], and Liu et al [ 36 ]. In contrast, Liu et al found that microRNA-210-5p promotes metastasis by suppressing PIK3R5-induced autophagy via the mTOR pathway [ 37 ]. The differences in our conclusions may result from the method of autophagy inhibition: chloroquine suppresses autophagy by blocking autophagosome-lysosome fusion.…”

Section: Discussionmentioning

confidence: 99%

Aurora-B knockdown inhibits osteosarcoma metastasis by inducing autophagy via the mTOR/ULK1 pathway

Liu

Song

et al. 2020

Cancer Cell Int

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Background Autophagy plays an essential role in metastasis of malignancies. Although our studies showed that Aurora-B facilitate pulmonary metastasis in OS, the mechanism of Aurora-B kinase on autophagy and metastasis in OS has not been explored. Methods Clinical-pathological parameters and follow-up information was collected in OS patients. Immunohistochemical staining was performed to detect Aurora-B and LC3 protein in OS tissues. Short hairpin RNA transfection was used to silence Aurora-B in OS cells. Real-time quantitative PCR (RT-qPCR) was performed to detect Aurora-B mRNA expression in OS cells. Aurora-B and autophagy related protein were measured by Western blot. Transmission electron microscopy and laser scanning confocal microscopy were performed to observe the formation of autophagosomes and autolysosomes. Migratory and invasive ability of OS cells were measured by Wound healing and transwell assays. Orthotopic xenograft model was used to evaluate the effect of autophagy mediated by Aurora-B inhibition on pulmonary metastasis of OS. Results The elevated expression of Aurora-B protein in OS tissues negatively associated with the overall survival of OS patients. Further investigation has found that Aurora-B expression was negatively correlative with autophagy related protein LC3 in OS patient tissues. Knockdown Aurora-B stimulates autophagy and inhibits migratory and invasive ability of OS cells. Mechanistically, Aurora-B knockdown suppressed the mTOR/ULK1 signaling pathway and reactivation of the mTOR/ULK1 pathway decreased autophagy level. Furthermore, the inhibition effect of silencing Aurora-B on migration and invasion of OS was reversed by chloroquine and mTOR activator in vitro and vivo. Conclusions Our results suggest that silencing of Aurora-B stimulate autophagy via decreasing mTOR/ULK1 and result in inhibiting OS metastasis. Targeted Aurora-B/mTOR/ULK1 pathway may be a promising treatment strategy for OS patients.

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“…Hence, identifying core molecules associated with tumor proliferation and invasion is crucial for designing new treatment regimens. Increasing evidence unveils that miRNAs perform vital functions in OS progression (Fellenberg et al, 2019; Liu, Jiang et al, 2020; Wang, Shi et al, 2020). According to reports, miRNA containing Exos from OS encourage OS to proliferate and invade via controlling cell‐to‐cell communication in the local and remote microenvironment.…”

Section: Exo‐ncrnas In Osmentioning

confidence: 99%

The potential roles of exosomal noncoding RNAs in osteosarcoma

Wang

2020

Journal Cellular Physiology

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Clinically, it is difficult to efficaciously screen and diagnose osteosarcoma (OS) in advance due to the low sensitivity and poor specificity of the existing tumor markers. Exosomes (Exos) are nanoscale vesicles containing RNAs, lipids, and proteins with a diameter of 30–100 nm. They are multivesicular bodies formed during the invagination of lysosomal particles in cells and released extracellularly after fusing with cell membranes. Besides, Exos are important carriers of cell‐to‐cell communication signals and genetic materials in the tumor microenvironment. During tumorigenesis, the tumor cells interplay with immune cells, endothelial cells, and related fibroblasts through Exos and boost cancer development. After altering the surrounding microenvironment, the Exos drive tumor cells to proliferate, speed up angiogenesis, and boost cancers to develop along with body fluid transportation. Currently, Exos are becoming novel noninvasive tumor diagnostic markers with high sensitivity, exerting pivotal impacts in fundamental research and clinical applications. Here, we review the existing literature on the roles of exosomal noncoding RNAs in OS progression and their potential clinical applications as novel biomarkers and therapeutics.

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miR-210-5p promotes epithelial–mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells

Cited by 52 publications

References 62 publications

Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis

Aurora-B knockdown inhibits osteosarcoma metastasis by inducing autophagy via the mTOR/ULK1 pathway

The potential roles of exosomal noncoding RNAs in osteosarcoma

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