Dataset Information

Circulating miR-92b and miR-375 for monitoring the chemoresistance and prognosis of small cell lung cancer.

ABSTRACT: miRNAs have been reported to be stably detectable in plasma and to function as potent biomarkers in multiple cancers. The study aimed to evaluate the expression of candidate circulating miRNAs in patients with small cell lung cancer (SCLC) to identify potential noninvasive biomarkers. The expression of five miRNAs (miR-92b, miR-146a, miR-375, miR-1224, and miR-1246) was significantly upregulated in plasma after chemoresistance induction. Receiver operating characteristic curve (ROC) analysis showed that the area under the curve (AUC) values of miR-92b and miR-375 were 0.766 and 0.791, respectively. The data demonstrated that among the five miRNAs assessed, these two miRNAs had better diagnostic accuracy for monitoring drug resistance. In addition, miR-92b and miR-375 levels were decreased after effective chemotherapy. Furthermore, Kaplan-Meier survival analysis confirmed that high expression of miR-92b and miR-375 was closely related to shorter progression-free survival (PFS) in SCLC patients. In conclusion, these findings indicate that circulating miR-92b and miR-375 might be ideal noninvasive biomarkers for monitoring drug resistance during chemotherapy and evaluating the prognosis of patients with SCLC.

SUBMITTER: Li M

PROVIDER: S-EPMC7391689 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Circulating miR-92b and miR-375 for monitoring the chemoresistance and prognosis of small cell lung cancer.

Li Ming M Shan Wulin W Hong Bo B Zou Jinglu J Li Hong H Han Dandan D Zhang Yang Y Li Lailing L Li Dan D Lin Wenchu W

Scientific reports 20200729 1

miRNAs have been reported to be stably detectable in plasma and to function as potent biomarkers in multiple cancers. The study aimed to evaluate the expression of candidate circulating miRNAs in patients with small cell lung cancer (SCLC) to identify potential noninvasive biomarkers. The expression of five miRNAs (miR-92b, miR-146a, miR-375, miR-1224, and miR-1246) was significantly upregulated in plasma after chemoresistance induction. Receiver operating characteristic curve (ROC) analysis sho ...[more]

PMID: 32728103

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Project description:Cisplatin is effective as a single agent or in combination with other drugs for the treatment of non-small cell lung cancer (NSCLC). A concerning clinical challenge with cisplatin-based NSCLC chemotherapy is the intrinsic and acquired chemoresistance to cisplatin. The sterile α motif domain-containing (SAMD9) gene has been reported as a potent tumor suppressor gene that inhibits tumorigenesis and progression of NSCLC. microRNAs (miRNA) have been revealed to play important roles in the regulation of cancer chemoresistance. To the best of our knowledge the present study explored the role of miRNA/SAMD9 signaling in regulating cisplatin chemoresistance in NSCLC for the first time. Out of the several candidate miRNAs predicted to bind the 3'-untranslated region (UTR) of the SAMD9 gene, miRNA-96 (miR-96) demonstrated significant target-sequence-specific inhibition of the SAMD9 3'-UTR luciferase reporter activity in NSCLC cells. In addition, while NSCLC tumor samples exhibited significantly higher expression levels of miR-96 compared with adjacent normal tissues, the expression levels of SAMD9 were significantly lower than those in adjacent normal tissues. miR-96 and SAMD9 were overexpressed and knocked down in the human NSCLC H358 and H23 cell lines and the half maximal inhibitory concentration (IC50) of cisplatin and cell apoptosis rate under cisplatin treatment were used as measures of cisplatin chemoresistance. The present results identified that overexpression of miR-96 in NSCLC cells markedly decreased SAMD9 expression and cisplatin-induced apoptosis, and increased the cisplatin IC50, which could be eliminated by overexpression of SAMD9. By contrast, knocking down miR-96 in NSCLC cells using antagomir-96 significantly increased SAMD9 expression and the cisplatin-induced apoptosis and decreased cisplatin IC50, which could be completely reversed by a knockdown of SAMD9. In conclusion, the current study demonstrates that miR-96 targets and downregulates SAMD9 in NSCLC, which decreases cisplatin-induced apoptosis and induces cisplatin chemoresistance in NSCLC cells. The findings of the present study add novel insights into the function of miR-96 and SAMD9 in cancer, as well as into the molecular mechanisms underlying NSCLC chemoresistance.

Project description:BackgroundHigh incidence of metastasis is the main cause of death for small cell lung cancer (SCLC), with its underlying molecular mechanisms remain unclear. Exosomal miRNAs are important regulators in metastatic processes of various tumors, but their specific role in SCLC metastasis is unknown.MethodsSmall RNA sequencing followed by qRT-PCR verification was used to screen the potential exosomal miRNAs that might mediate SCLC metastasis. SCLC-cell-secreted exosomes were labeled followed by incubating with vascular endothelial cells to evaluate exosome-mediated communication between SCLC cells and vascular endothelial cells. In vitro permeability assay and transendothelial migration assay were applied to investigate the function of exosomal miRNA on vascular endothelial cells. In vivo permeability assay and mouse lung colonization assay were used to verify the effects of exosomal miRNA on vascular barriers and SCLC metastasis in vivo. Proteomics technology, dual-luciferase reporter system together with rescue assays were conducted to excavate the downstream pathways of miRNA.ResultsCompared with 57 healthy volunteers and 46 non-small cell lung cancer patients, we identified that the level of exosomal miR-375-3p in 126 SCLC patients was obviously higher and was positively correlated with patient TNM stages. In vitro functional experiments found that SCLC-cell-secreted exosomal miR-375-3p could increase the permeability of vascular endothelial cells and facilitate the transendothelial migration of SCLC cells. In vivo, miR-375-3p-enriched exosomes also destroyed the barrier structure of lung, liver and brain tissues of mice, leaded to an increased blood vessel permeability and finally promoted SCLC metastasis. Mechanistically, SCLC-cell-secreted exosomal miR-375-3p was transferred to vascular endothelial cells. The internalized miR-375-3p broke the tight junction of vascular endothelial cells by directedly binding to the 3'UTR of tight junction protein claudin-1 and negatively regulating its expression. Overexpressing claudin-1 in vascular endothelial cells could rescue the broken vascular barriers induced by miR-375-3p.ConclusionsOur findings underline the crucial roles of exosomal miRNA-375-3p in regulating vascular endothelial barrier integrity and SCLC metastasis. miRNA-375-3p has a great potential to be a novel biomarker monitoring metastasis and guiding clinical therapeutics of SCLC patients.

Dataset Information

Circulating miR-92b and miR-375 for monitoring the chemoresistance and prognosis of small cell lung cancer.

Publications

Circulating miR-92b and miR-375 for monitoring the chemoresistance and prognosis of small cell lung cancer.

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