Hypoxia-induced exosomes promote hepatocellular carcinoma proliferation and metastasis via miR-1273f transfer

You, Yu; Zou, Min; Zhou, Zhihang; Mao, Lin-Hong; Tao, Ran; Liu, Yan; He, Song

doi:10.1016/j.yexcr.2019.111649

Cited by 86 publications

(51 citation statements)

References 43 publications

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“…Although the functional signi cances of ve miRNAs remain unknown, the correlation between these miRNAs and various cancers has been reported in some studies. The expression of miR-1273f was signi cantly elevated within exosomes released by hypoxic hepatocellular carcinoma cells than that by normoxic cells, and it could activate the Wnt/β-catenin signaling pathway (29). Meanwhile, the exosome and plasma levels of miR-619-5p were signi cantly higher in non-small cell lung cancer (30) and prostate cancer cases(31) than in the HCs, whereas the expression level of miR-619-5p was signi cantly lower in colorectal cancer tissues than in normal tissues (32).…”

Section: Discussionmentioning

confidence: 99%

Urinary microRNA Biomarkers for Detecting the Presence of Esophageal Cancer

Okuda

Shimura

Iwasaki

et al. 2020

Preprint

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Background: Esophageal cancer (EC) including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) generally exhibits poor prognosis; hence, a noninvasive biomarker enabling early detection is necessary. Thus, this study aimed to establish novel urinary miRNA biomarkers for diagnosing EC.Methods: Out of 343 patients (299 healthy controls [HCs] and 44 ESCCs), 150 HCs and 43 patients with ESCC, which were both age- and sex-matched, were analyzed and randomly divided into two groups: 9 patients (6 HCs and 3 ESCCs) in the discovery cohort for microarray analysis and 184 patients (144 HCs and 40 ESCCs) in the training/test cohort with cross-validation for qRT-PCR analysis. Using 152 urine samples (144 HCs and 8 EACs), we validated the urinary miRNA biomarkers for EAC diagnosis.Results: Eight miRNAs were selected as biomarker candidates in the discovery cohort. In the training/test cohort, five of the eight miRNAs (miR-1273f, miR-619-5p, miR-150-3p, miR-4327, and miR-3135b) in the ESCC group had significantly higher urinary levels than those in the HC group. Consistently, these five urinary miRNAs were significantly different between HC and ESCC in both training and test sets. Especially, urinary miR-1273f and miR-619-5p showed excellent values of area under the curve (AUC) ≥ 0.80 for diagnosing stage I ESCC. Consistent with the ESCC group, the EAC group had significantly higher urinary levels of these five miRNAs than the HC group, and it also exhibited AUC values of approximately 0.80.Conclusion: The present study established novel urinary miRNA biomarkers that can early detect ESCC and EAC.

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Section: Discussionmentioning

confidence: 99%

Urinary microRNA Biomarkers for Detecting the Presence of Esophageal Cancer

Okuda

Shimura

Iwasaki

et al. 2020

Preprint

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“…In addition, 3D-O showed that there was a higher amount of secreted extracellular vesicles generated as a result of the threedimensional environment when compared to 2D and these changes were further enhanced in response to oxygen deprivation. Extracellular vesicle yield in 3D cultures has already been shown to be higher than in 2D models (95), as well as that hypoxic conditions can lead cells to express increased vesicle yield (96). The increased expression for each of the studied ECMs in the presence of lower oxygen could either be accounted for by an absolute increase in new ECM generation or by an enhanced enzymatic functional cascade resulting in enhanced alignment of the ECMs already present in the matrix environment.…”

Section: Immune Cell Infiltration Into 3d Matrices Has Been Observed mentioning

confidence: 90%

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Bhattacharya

Calar

Evans

et al. 2019

Preprint

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Oxygen deprivation within tumors is one of the most prevalent causes of resilient cancer cell survival and increased immune evasion in breast cancer (BCa). Current in vitro models do not adequately mimic physiological oxygen levels relevant to breast tissue and its tumor-immune interactions. Here, we propose an approach to engineer a three-dimensional (3D) model (named 3D engineered oxygen, 3D-O) that supports growth of BCa cells and generates physio-and pathophysiological oxygen levels. Low oxygen-induced changes within the 3D-O model supported known tumor hypoxia characteristics such as reduced BCa cell proliferation, increased extracellular matrix protein expression, increased extracellular vesicle secretion and enhanced immune surface marker expression on BCa cells. We further demonstrated that low oxygeninduced changes mimicked tumor-immune interactions leading to immune evasion mechanisms. CD8+ T cell infiltration was significantly impaired under pathophysiological oxygen levels andwe were able to establish that hypoxia inhibition re-sensitize BCa cells to cytotoxic CD8+ T cells.Therefore, our novel 3D-O model could serve as a promising platform for the evaluation of immunological events and as a drug-screening platform tool to overcome hypoxia-driven immune evasion.

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“…Hypoxia is an important feature of the microenvironment of solid tumors, and promotes malignancy. [32][33][34][35][36]44 In several previous studies microRNAs have reportedly mediated the cancer-promoting effects of hypoxia in various tumor types. 54 Zheng et al 41 suggested that hypoxia could drive tumorigenesis and metastasis in HCC by downregulating miR-196-5p.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia is a main feature of HCC, and strong evidence suggests that it may promote HCC progression by regulating characteristics associated with malignancy, including cancer stem-like properties, 32 proliferation, 33,34 metastasis, 35,36 and epithelial-mesenchymal transition 37,38 in both hypoxia-inducible factor 1-alpha (HIF1-α)-dependent and HIF1-α-independent manners. Dou et al 39 reported that hypoxia contributed to growth and metastasis by increasing the expression of tuftelin 1, which is an HCC oncoprotein.…”

Section: Introductionmentioning

confidence: 99%

<p>Hypoxia-Induced Placenta-Specific microRNA (miR-512-3p) Promotes Hepatocellular Carcinoma Progression by Targeting Large Tumor Suppressor Kinase 2</p>

Zhang

Huang²,

Tu³

et al. 2020

OTT

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Background: Sustained proliferation and active metastasis are hallmarks of cancer, and they pose major challenges to the development of treatments and a cure for hepatocellular carcinoma (HCC). Thus, the mechanisms of proliferation, migration, and invasion of cancer cells need to be investigated. Many studies indicate that dysregulation of microRNA plays important roles in the progression of HCC, but the role of placenta-specific microRNA (miR-512-3p) in HCC has not been systematically investigated. Purpose: In the current study, the expression, biological function, and mechanisms of miR-512-3p involvement in HCC were investigated. Methods: Real-time quantitative polymerase chain reaction assays were conducted to determine miR-512-3p levels in HCC tissues and cell lines. The StarBase V3.0 online platform was used to compare miR-512-3p levels in HCC tissues with TCGA data and to identify potential miR-512-3p target genes. Associations between miR-512-3p and clinicopathological characteristics were analyzed statistically. MTT, ethynyl deoxyuridine, and transwell assays were performed to assess cell viability, proliferation, migration, and invasion. The luciferase reporter gene assay was used to verify target genes. Recuse assays were performed to confirm whether large tumor suppressor kinase 2 (LATS2) participated in the regulatory effects of miR-512-3p on HCC cell proliferation and motility, and whether miR-512-3p mediated the tumor-promoting effects of hypoxia. Results: miR-512-3p was upregulated in HCC and it was associated with worse survival and unfavorable clinicopathological characteristics. Functional assays indicated that miR-512-3p contributed to HCC cell proliferation, migration, and invasion. Mechanistically, LATS2-a downstream target of miR-512-3p-mediated the tumor-promoting effects of miR-512-3p in HCC. Hypoxia could elevate miR-512-3p levels in HCC cells, and miR-512-3p partially mediated the tumor-promoting effects of hypoxia. Conclusion: Hypoxia-induced miR-512-3p contributes to HCC cell proliferation, migration, and invasion by targeting LATS2 and inhibiting the Hippo/yes-associated protein 1 pathways.

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Hypoxia-induced exosomes promote hepatocellular carcinoma proliferation and metastasis via miR-1273f transfer

Cited by 86 publications

References 43 publications

Urinary microRNA Biomarkers for Detecting the Presence of Esophageal Cancer

Urinary microRNA Biomarkers for Detecting the Presence of Esophageal Cancer

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

<p>Hypoxia-Induced Placenta-Specific microRNA (miR-512-3p) Promotes Hepatocellular Carcinoma Progression by Targeting Large Tumor Suppressor Kinase 2</p>

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