Construction of a circRNA-miRNA-mRNA Regulated Pathway Involved in EGFR-TKI Lung Adenocarcinoma Resistance

Dai, Chenyue; Liu, Bing; Li, Shaolei; Yang, Hong; Si, Jianmin; Xiong, Ying; Wu, Nan; Ma, Yuanyuan

doi:10.1177/15330338211056809

Cited by 5 publications

(5 citation statements)

References 39 publications

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“…Nevertheless, till now, research on the function of circRNAs in NSCLC with gefitinib resistance is still limited. In this study, we focused on circ_0091537, which was previously shown to be upregulated in lung cancer tissues with gefitinib resistance [8]. The data suggested that circ_0091537 dysregulation might be associated with gefitinib resistance in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…With the advance of RNA sequencing technology, an increasing number of circRNAs are identified, and their functions are preliminarily disclosed. Circ_0091537 was previously recorded to be highly expressed in lung cancer cells with gefitinib chemoresistance [8], hinting that circ_0091537 might be involved in NSCLC progression. However, the underlying role of circ_0091537 in NSCLC with gefitinib chemoresistance is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Circ_0091537 promotes gefitinib chemoresistance in non-small cell lung cancer by mediating the miR-520h/YAP1 network

2023

Anti-Cancer Drugs

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Chemoresistance is the leading cause of poor outcomes of non-small cell lung cancer (NSCLC). Circular RNA (circRNA) plays a vital role in NSCLC resistance progression. Our study aimed to uncover the role of circRNA PDZ domain containing 8 (circ_0091537) in NSCLC with gefitinib resistance. The expression of circ_0091537, microRNA-520h (miR-520h), and Yes-associated protein 1 (YAP1) mRNA were detected using quantitative real-time PCR. Cell viability and cell proliferation were assessed by MTT assay and colony formation assay. Colony formation ability was detected by colony formation assay. Cell cycle distribution and cell apoptosis were determined by flow cytometry assay. Cell migration and cell invasion were detected by transwell assay. The potential relationship between miR-520h and circ_0091537 or YAP1 was verified by dual-luciferase reporter assay. Tumor formation assay in nude mice was performed to test the role of circ_0091537 in vivo. Circ_0091537 and YAP1 were upregulated, while miR-520h was downregulated in gefitinib-resistant NSCLC cells. Circ_0091537 knockdown inhibited gefitinib resistance in NSCLC cells and then inhibited NSCLC cell growth, migration, and invasion. MiR-520h was a target of circ_0091537, and miR-520h inhibition reversed the effects of circ_0091537 knockdown. Moreover, YAP1 was a target of miR-520h, and circ_0091537 competitively combined with miR-520h to enrich YAP1 expression. MiR-520h restoration impaired gefitinib resistance and suppressed NSCLC cell proliferation, migration, and invasion by repressing YAP1. Circ_0091537 overexpression weakened gefitinib sensitivity in vivo to promote tumor growth. Circ_0091537 strengthens gefitinib chemoresistance to promote NSCLC progression by mediating the miR-520h/YAP1 network, suggesting that circ_0091537 may be a key indicator in resistance to treatment of NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Circ_0091537 promotes gefitinib chemoresistance in non-small cell lung cancer by mediating the miR-520h/YAP1 network

2023

Anti-Cancer Drugs

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“…Preliminary circRNA/lncRNA-miRNA–mRNA networks have been constructed to shed light on the role of ncRNAs in regulating signaling pathways and drug resistance. 407 …”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

“…Preliminary circRNA/lncRNA- miRNA-mRNA networks have been constructed to shed light on the role of ncRNAs in regulating signaling pathways and drug resistance. 407 Given the complicated and delicate regulatory mechanisms of ncRNAs and their involvement in regulating multiple pathways, ncRNAs are promising therapeutic targets. Some ncRNA drugs have been used in clinical trials but not for treating TKI-resistant tumors.…”

Section: Epigenetic Modificationmentioning

confidence: 99%

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Yang

Wang

et al. 2022

Sig Transduct Target Ther

110

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Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.

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“…In our previous study, we found that circ7312 and MAPK1 were highly expressed in EGFR-TKIresistant PC9 cells but were lowly expressed in the EGFR-TKI-sensitive PC9/ER cells. We also found that the circ7312/miR-764/MAKP1 axis is involved in the development of EGFR-TKI resistance [19]. Therefore, in this study, we aimed to determine the underlying mechanism of this axis in pyroptosis and apoptosis that is involved in EGFR-TKI resistance.…”

Section: Introductionmentioning

confidence: 95%

Hsa_circ_0007312 Promotes Third-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance through Pyroptosis and Apoptosis via the MiR-764/MAPK1 Axis in Lung Adenocarcinoma Cells

Dai¹,

Ma²,

Si³

et al. 2022

J. Cancer

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Purposes: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) used for patients with gefitinib (first-generation EGFR-TKI) resistance, but osimertinib resistance inevitably occurs. Therefore, it is necessary to explore the mechanisms of osimertinib resistance. Materials and Methods: We performed quantitative real-time polymerase chain reaction to detect hsa_circ_0007312 (circ7312), miR-764, and MAPK1 expressions in tissues and cells. Western blotting was used to detect protein levels in cells. Cell Counting Kit-8, apoptotic, and Transwell assays were used to explore biological functions. Luciferase assays were used to identify the interactions between circ7312 and miR-764, MAPK1 and miR-764. A xenograft experiment was performed to clarify the role of circ7312 in vivo. Public datasets were used to identify the relation between circ7312 expression and the cell half maximal inhibitory concentration value of osimertinib in 41 lung adenocarcinoma cell lines. The Student t-test, Kaplan-Meier analysis, and Pearson correlation analysis were used in data analysis. Results: We found that circ7312 knockdown increased miR-764 expression and decreased MAPK1 expression, and circ7312 regulated MAPK1 by sponging miR-764. In addition, high circ7312 expression has significant positive correlation with osimertinib IC50 values, circ7312 knockdown decreased the cell half maximal inhibitory concentration value of osimertinib and increased pyroptosis and apoptosis by sponging the miR-764/MAPK1 axis. We also found that circ7312 and MAPK1 were highly expressed in tumor tissues and related to poor prognosis. Xenograft experiments revealed that circ7312 knockdown decreased osimertinib resistance in vivo. Conclusion:We demonstrated that the inhibition of circ7312 decreased osimertinib resistance by promoting pyroptosis and apoptosis via the miR-764/MAPK1 axis, providing a novel target for osimertinib resistance therapy.

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Construction of a circRNA-miRNA-mRNA Regulated Pathway Involved in EGFR-TKI Lung Adenocarcinoma Resistance

Cited by 5 publications

References 39 publications

Circ_0091537 promotes gefitinib chemoresistance in non-small cell lung cancer by mediating the miR-520h/YAP1 network

Circ_0091537 promotes gefitinib chemoresistance in non-small cell lung cancer by mediating the miR-520h/YAP1 network

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Hsa_circ_0007312 Promotes Third-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance through Pyroptosis and Apoptosis via the MiR-764/MAPK1 Axis in Lung Adenocarcinoma Cells

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