Hypoxia induced changes in miRNAs and their target mRNAs in extracellular vesicles of esophageal squamous cancer cells

Chen, Fangyu; Chu, Li; Li, Jie; Shi, Yu; Xu, Bing; Gu, Junjie; Yao, Xijuan; Tian, Meng; Yang, Xi; Sun, Xinchen

doi:10.1111/1759-7714.13295

Cited by 32 publications

(31 citation statements)

References 41 publications

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“…To identify novel 5p- and 3p-derived miRNAs and known miRNAs, unique sequences with lengths of ~18–26 nucleotides were mapped to specific species precursors in miRBase 22.0 by BLAST search as previously described ( 37 , 38 ). Briefly, the unique sequence mapping to specific species' mature miRNAs in hairpin arms identified known miRNAs.…”

Section: Methodsmentioning

confidence: 99%

“…Then the unique sequence mapping to the other arm of known specific species precursor hairpin opposite to the annotated mature miRNA-containing arm considered be novel 5p- or 3p-derived miRNA candidates. Furthermore, the remaining sequences were mapped to other selected species' precursors (with the exclusion of specific species) in miRBase 22.0 by BLAST search against the specific genomes, and the sequences containing hairpin RNA structures were predicted from the flank 80-nt sequences using RNAfold software ( http://rna.tbi.univie.ac.at/cgi-bin/RNAfold.cgi ) in order to predict novel candidate miRNAs more accurately ( 37 , 38 ).…”

Section: Methodsmentioning

confidence: 99%

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Development of a Novel Serum Exosomal MicroRNA Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma

Liu

Wang

et al. 2020

Front. Oncol.

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Preoperative prediction of lymph node (LN) metastasis is accepted as a crucial independent risk factor for treatment decision-making for esophageal squamous cell carcinoma (ESCC) patients. Our study aimed to establish a non-invasive nomogram to identify LN metastasis preoperatively in ESCC patients. Construction of the nomogram involved three sequential phases with independent patient cohorts. In the discovery phase ( N = 20), LN metastasis-associated microRNAs (miRNAs) were selected from next-generation sequencing (NGS) assay of human ESCC serum exosome samples. In the training phase ( N = 178), a nomogram that incorporated exosomal miRNA model and clinicopathologic was developed by multivariate logistic regression analysis to preoperatively predict LN status. In the validation phase ( n = 188), we validated the predicted nomogram's calibration, discrimination, and clinical usefulness. Four differently expressed miRNAs (chr 8-23234-3p, chr 1-17695-5p, chr 8-2743-5p, and miR-432-5p) were tested and selected in the serum exosome samples from ESCC patients who have or do not have LN metastasis. Subsequently, an optimized four-exosomal miRNA model was constructed and validated in the clinical samples, which could effectively identify ESCC patients with LN metastasis, and was significantly superior to preoperative computed tomography (CT) report. In addition, a clinical nomogram consisting of the four-exosomal miRNA model and CT report was established in training cohort, which showed high predictive value in both training and validation cohorts [area under the receiver operating characteristic curve (AUC): 0.880 and 0.869, respectively]. The Hosmer–Lemeshow test and decision curve analysis implied the nomogram's clinical applicability. Our novel non-invasive nomogram is a robust prediction tool with promising clinical potential for preoperative LN metastasis prediction of ESCC patients, especially in T1 stage.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Development of a Novel Serum Exosomal MicroRNA Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma

Liu

Wang

et al. 2020

Front. Oncol.

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“…Because miRNAs are important intercellular signalling molecules encapsulated by EVs, we inferred that they may be associated with H-EV-induced radioresistance in OSCC. We previously reported highthroughput miRNA-seq results in EVs derived from both normoxic and hypoxic conditions of OSCC cells, nding that miR-340-5p is highly expressed in H-EVs derived from OSCC cells (15). Previous studies have reported that miR-340-5p plays a dual role in cancer development and progression.…”

Section: Mir-340-5p Is Highly Expressed In H-evs and Promotes Radiorementioning

confidence: 99%

Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10

Chen

et al. 2020

Preprint

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Background: Radiotherapy resistance is a major obstacle in the treatment of oesophageal squamous cell carcinoma (OSCC). Hypoxia is a critical cause of radioresistance. However, the communication between hypoxic cells and aerobic cells via exosomes during the transfer of radiation resistance remains unclear. Methods: Exo-miR-340-5p levels were analysed by RNA-seq and qRT-PCR. We co-cultured OSCC cells with isolated normoxic and hypoxic exosomes to study their impact on radiosensitivity. We used a specific exo-miR-340-5p mimic and knock-down retrovirus to explore the role of this miRNA in the transfer of radioresistance from hypoxic to normoxic cells. Dual-luciferase reporter and RIP assays were used to verify KLF10 as a putative target of miR-340-5p. Several in vitro assays were conducted and xenograft models were established to investigate the effect of exo-miR-340-5p on OSCC radiosensitivity. The plasma exo-miR-340-5p levels in OSCC patients were analysed to study the clinical value of this parameter.Results: Hypoxic exosomes alleviated radiation-induced apoptosis and accelerated DNA damage repair. miR-340-5p was highly expressed in hypoxic exosomes and was transferred into normoxic cells, where it induced radioresistance. Overexpression of miR-340-5p in normoxic OSCC cells mimicked the radioresistance of cells co-cultured with hypoxic exosomes. Knockdown of miR-340-5p in hypoxic exosomes reversed the radioresistance effect, indicating that exo-miR-340-5p is critical for hypoxic EV-transferred radioresistance. KLF10 was identified as the direct target of miR-340-5p. Moreover, metformin was found to increase the expression of KLF10 and enhance the radiosensitivity of OSCC. Higher levels of miR-340-5p in the plasma exosomes from OSCC patients are related to a poorer radiotherapy response and prognosis. Conclusions: Hypoxic tumour cell-derived exosomal miR-340-5p confers radioresistance in OSCC by targeting KLF10/UVRAG, suggesting that miR-340-5p could be a potential biomarker and therapeutic target for the enhancement of radiosensitivity in OSCC. Metformin can increase KLF10 expression, which ameliorates the radioresistance induced by exo-miR-340-5p transfer. Therefore, metformin could be further investigated as a therapeutic option for the treatment of OSCC.

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“…Fifty miRNA was up-regulated and 34 miRNA was down-regulated significantly in hypoxictreated cell lines, and these differentially expressed miRNAs are mainly involved in cancer-related and phospholipase D signaling pathways. 64 Base on the studies of kidney cancer and breast cancer cells, it was speculated that the enhanced phospholipase D activity was necessary for stable expression of HIF-1 and HIF-2 and aerobic glycolysis of cells. [65][66][67] Exosomes are special types of EVs with a diameter of 50-200nm.…”

Section: Hypoxia Acidosis and Nutrient Depletion Are The Basic Charmentioning

confidence: 99%

<p>Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche</p>

Han¹,

Cao²,

Huang³

et al. 2020

CMAR

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Esophageal cancer (EC) is the sixth most deadly cancer, and its incidence is still increasing year by year. Although the researches on the molecular mechanisms of EC have been widely carried out and incremental progress has been made, its overall survival rate is still low. There is cumulative evidence showing that the esophageal microenvironment plays a vital role in the development of EC. In precancerous lesions of the esophagus, high-risk environmental factors can promote the development of precancerous lesions by inducing the production of inflammatory factors and the recruitment of immune cells. In the tumor microenvironment, tumor-promoting cells can inhibit anti-tumor immunity and promote tumor progression through a variety of pathways, such as bone marrow-derived suppressor cells (MDSCs), tumor-associated fibroblasts (CAFs), and regulatory T cells (Tregs). The formation of extracellular hypoxia and acidic microenvironment and the change of extracellular matrix stiffness are also important factors affecting tumor progression and metastasis. Simultaneously, primary tumor-derived cytokines and bone marrow-derived immune cells can also promote the formation of pre-metastasis niche of EC lymph nodes, which are beneficial to EC lymph node metastasis. Further research on the specific mechanism of these processes in the occurrence, development, and metastasis of each EC subtype will support us to grasp the overall pre-cancerous prevention, targeted treatment, and metastatic assessment of EC.

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Hypoxia induced changes in miRNAs and their target mRNAs in extracellular vesicles of esophageal squamous cancer cells

Cited by 32 publications

References 41 publications

Development of a Novel Serum Exosomal MicroRNA Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma

Development of a Novel Serum Exosomal MicroRNA Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma

Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10

<p>Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche</p>

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