Dataset Information

CEACAM6 promotes cisplatin resistance in lung adenocarcinoma and is regulated by microRNA-146a and microRNA-26a.

ABSTRACT: BACKGROUND:Carcinoembryonic antigen (CEA)-related cell adhesion molecule 6 (CEACAM6) is a glycophosphoinositol-anchored glycoprotein which mediates cell-cell interactions. Here, we aimed to explore the specific functions and regulatory mechanisms of CEACAM6 on cisplatin (DDP) in lung adenocarcinoma (LUAD). METHODS:RNA sequencing was performed in the DDP-resistant A549/DDP cell line and parental A549 cell line; miRNA expression profiling of the two cell lines was analyzed using GEO data (GSE43249). Gain- and loss-of-function experiments were used to investigate the biological function of CEACAM6 in vitro. The expression status and prognostic value of CEACAM6 in LUAD were verified using The Cancer Genome Atlas (TCGA) database. RESULTS:CEACAM6 was first screened to be one of the most significantly upregulated genes in the DDP-resistant A549/DDP cell line compared to the parental A549 cell line. Combined with computational prediction of candidate miRNAs that target CEACAM6, miR-146a and miR-26a were selected and verified by qPCR and luciferase reporter assay. The knockdown of CEACAM6 expression in A549/DDP cells inhibited cell proliferation, invasion and migration, decreased the IC50 values of DDP, and caused a significant downregulation of N-cadherin, vimentin, Sox2, Oct4 and GTP-RhoA and upregulation of E-cadherin; while CEACAM6 overexpression in A549 cells resulted in the opposite effects. Of note, both miR-146a and miR-26a could counteract the biological effects of CEACAM6. Furthermore, CEACAM6 mRNA expression was significantly unregulated in DDP-resistant LUAD tissues of TCGA database. CONCLUSIONS:CEACAM6 promotes DDP resistance in LUAD by affecting the epithelial-mesenchymal transition (EMT) phenotype and stemness, which is post-transcriptionally regulated by miR-146a and miR-26a.

SUBMITTER: Du H

PROVIDER: S-EPMC7471054 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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CEACAM6 promotes cisplatin resistance in lung adenocarcinoma and is regulated by microRNA-146a and microRNA-26a.

Du He H Li Yang Y Sun Rongrong R Yuan Yuan Y Sun Sanyuan S Zhang Youwei Y

Thoracic cancer 20200710 9

<h4>Background</h4>Carcinoembryonic antigen (CEA)-related cell adhesion molecule 6 (CEACAM6) is a glycophosphoinositol-anchored glycoprotein which mediates cell-cell interactions. Here, we aimed to explore the specific functions and regulatory mechanisms of CEACAM6 on cisplatin (DDP) in lung adenocarcinoma (LUAD).<h4>Methods</h4>RNA sequencing was performed in the DDP-resistant A549/DDP cell line and parental A549 cell line; miRNA expression profiling of the two cell lines was analyzed using GEO ...[more]

PMID: 32648688

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Project description:The mechanism of RP11-838N2.3 promoting cisplatin resistance in lung adenocarcinoma (LAD) was unclear. The RP11-838N2.3 expression level in cells and LAD tissues was detected by qPCR. We constructed lentivirus-mediated GV303 overexpression and GV248 shRNA vector targeting RP11-838N2.3, then infected A549 and A549/DDP cell and furtherly analyzed cell biology. High-throughput gene chip analysis showed that RP11-838N2.3 was significantly upregulated in A549/DDP (change?fold = 66.056595). The qPCR results showed that the expression level of RP11-838N2.3 in A549/DDP cell was significantly higher than that in A549 cells (P < 0.05), and the expression level of RP11-838N2.3 in LAD tissues was also significantly higher than that in adjacent tissues (P < 0.05). The expression level of RP11-838N2.3 in cisplatin-insensitive LAD tissues was also significantly higher than that in cisplatin-sensitive LAD tissues (P < 0.05). Survival analysis showed that OS (overall survival) and DFS (progression-free survival) of high RP11-838N2.3 expression in the cisplatin-sensitive or cisplatin-insensitive LAD group were lower (P < 0.001 and P < 0.001) than those of low RP11-838N2.3 expression in the cisplatin-sensitive or cisplatin-insensitive LAD group. CCK8 showed that the OD450 value of RP11-838N2.3 overexpression increased significantly at 24?h, 48?h, and 72?h after transfection, while the knockdown of RP11-838N2.3 caused OD450 value at 24?h, 48?h, and 72?h after transfection significantly reduced, under the action of cisplatin that had the same trend (P < 0.05). The cell migration showed that the RP11-838N2.3 overexpression increased significantly migration activity and RP11-838N2.3 knockdown inhibited migration activity at 24?h, 48?h, and 72?h after transfection. The same trend was also observed under the action of cisplatin (P < 0.05). The cell invasion showed that the invasion rate of RP11-838N2.3 overexpression increased significantly, while the invasion rate of RP11-838N2.3 knockdown decreased significantly, and the same trend was observed under the action of cisplatin (P < 0.05). Apoptosis results showed that the apoptosis rate of RP11-838N2.3 overexpressed cells decreased significantly and the apoptosis rate of RP11-838N2.3 knockdown cells increased significantly, and the same trend was also observed under the action of cisplatin (P < 0.05). However, the results of cell cycle showed that there was no significant difference in the proportion of cells in each phase of the cell cycle after RP11-838N2.3 overexpression or knockdown (P > 0.05).RP11-838N2.3 was significantly upregulated in cisplatin-resistant cell and tissues of LAD. RP11-838N2.3 could enhance the proliferation, migration, and invasion and inhibit apoptosis of LAD cisplatin-resistant cell. So RP11-838N2.3 could enhance the cisplatin resistance of LAD cells and was a resistant lncRNA molecule.

Project description:Cisplatin (DDP) resistance has become the major obstacle in the therapy of malignant tumors, including lung adenocarcinoma (LAD). Long non-coding RNAs (lncRNAs) were confirmed to be related to DDP-resistance. Studies have shown that RP3-326I13.1 (also known as PINCR) could promote the progression of colorectal cancer, and RP3-326I13.1 knockdown could induce hypersensitivity to chemotherapy drugs. While the function of RP3-326I13.1 in LAD is unclear, therefore, this study aimed to research the biological function and related molecular mechanisms of RP3-326I13.1 in DDP-resistance of LAD. QPCR analysis found that RP3-326I13.1 was highly expressed in A549/DDP cells and LAD tissues. Cytological assays found that RP3-326I13.1 pro-moted the proliferation, migration, invasion, and DDP-resistance of LAD cell lines. Moreover, knock-down of RP3-326I13.1 could induce G1 phase arrest. Nude mouse xenograft assay confirmed that RP3-326I13.1 could promote tumor growth and DDP-resistance in vivo. Mechanically, RNA pull-down and mass spectrometry analysis indicated that heat shock protein HSP 90-beta (HSP90B) could be combined with RP3-326I13.1. HSP90B knockdown inhibited the effect of RP3-326I13.1 on proliferation, invasion, and promoted LAD cell lines apoptosis. Transcriptome sequencing analysis found that MMP13 was the downstream mRNA of RP3-326I13.1. In conclusion, RP3-326I13.1 could promote DDP-resistance of LAD by binding to HSP90B and upregulating human matrix metalloproteinase-13 (MMP-13) and may serve as a therapeutic target, as well as a biomarker for predicting DDP-resistance in LAD.Abbreviations:DDP: Cisplatin; LAD: Lung adenocarcinoma; LncRNAs: Long non-coding RNAs; qPCR: real-time fluorescent quantitative PCR; HSP90B: Heat shock protein HSP 90-beta; RPMI: Roswell Park Memorial Institute; FBS: Fetal bovine serum; CT: computed tomography; MRI: magnetic resonance imaging; RECIST: Response evaluation criteria in solid tumors; NC: Negative control; OE: overexpression; shRNA: short hairpin RNA; siRNA: small interfering RNA; CCK-8: Cell Counting Kit-8; IC50: The half maximal inhibitory concentration; PBS: Phosphate buffer saline; PI: propidium iodide; SDS-PAGE: sodiumdodecylsulfate-polyacrylamide gel electrophoresis; ceRNA: Competing endogenous RNA; HE: hematoxylin-eosin; ns: no significance.

Dataset Information

CEACAM6 promotes cisplatin resistance in lung adenocarcinoma and is regulated by microRNA-146a and microRNA-26a.

Publications

CEACAM6 promotes cisplatin resistance in lung adenocarcinoma and is regulated by microRNA-146a and microRNA-26a.

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