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MTS assay (A, B), colony forming assay (C) and flow cytometry (D) were applied to measure the effects of hsa_circ_0005576 knockdown and miR‐512‐5p inhibition on osimertinib sensitivity in H1975OR and HCC827OR cells. *P < .05
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Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for lung adenocarcinoma (LUAD) harboring activating mutations, but patients ultimately develop acquired resistance. Circular RNAs are involved in EGFR-TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remain...
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To investigate the role of SLITRK6 in lung adenocarcinoma (LUAD) and the underlying mechanism in it, clinical tissues and tissue microarray of LUAD were used to detect the expression of SLITRK6. In vitro cell viability assay and colony formation assay in LUAD cells were conducted to investigate SLITRK6 related biological functions. In vivo subcutan...
Citations
... Previous data suggested that circRANGAP1 [12] and SOD2 [27] functions as oncogenes, while miR-512-5p acts as a tumor suppressor [28,29]. However, whether these three genes interact with each other to regulate NSCLC progression is unknown. ...
Non-small cell lung cancer (NSCLC) is the most prevalent histology type of lung cancer worldwide, accounting for 18% of total cancer-related deaths estimated by GLOBOCAN in 2020. CircRNAs have emerged as potent regulators of NSCLC development. CircRANGAP1 (hsa_circ_0001235/hsa_circ_0063526) is a potential biomarker for NSCLC identified by microarray dataset analysis. Here, we investigated the biological functions of circRANGAP1 in NSCLC development and elucidated the associated competing endogenous RNA (ceRNA) mechanisms. We found that circRANGAP1 expression was upregulated in NSCLC tissues and cells, which was inversely correlated with carcinogenesis and poor clinical outcome of NSCLC patients. CircRANGAP1 knockdown inhibited NSCLC migration by regulating miR-512-5p/SOD2 axis. In conclusion, circRANGAP1 facilitated NSCLC tumorigenesis and development by sponging miR-512-5p to upregulate SOD2 expression. Suppression of circRANGAP1 expression by si-circRANGAP1 treatment could be a strategy to inhibit NSCLC development and metastasis.
... circPVT1 is related with the cisplatin and pemetrexed insensitivity of patients with lung adenocarcinoma; notably, circPVT1 contributes to cisplatin and pemetrexed chemotherapy resistance through the miR-145-5p/ABcc1 axis (42). Hsa_circ_0005576 promotes osimertinib resistance through the miR-512-5p/IGF1R axis in lung adenocarcinoma cells (43). Inhibition of circ7312 reduces osimertinib resistance by promoting pyroptosis and Figure 7. downregulation of circPPP4R1 increase the sensitivity of H1975-OR cells to osimertinib. ...
Drug resistance is an urgent problem to be solved in the treatment of non‑small‑cell lung cancer (NSCLC). Osimertinib is a third‑generation EGFR‑tyrosine kinase inhibitor, which can improve the efficacy and quality of life of patients; however, the inevitable resistance after long‑term use of osimertinib often leads to treatment failure. Cell lines are key tools for basic and preclinical studies. At present, few osimertinib‑resistant cell lines (HCC827‑OR and H1975‑OR) have been established. In the present study, osimertinib‑resistant cell lines were established by gradually increasing the drug concentration. Half‑maximal inhibitory concentration (IC50), cell morphology, whole exon sequencing, Cell Counting Kit‑8 assay, EdU staining and flow cytometry were used to evaluate the osimertinib‑resistant cell lines. Western blot analysis was used to detect the expression levels of key proteins involved in osimertinib resistance. The circular RNA (circRNA) expression profile was identified by RNA sequencing (RNA‑seq) analysis of HCC827, HCC827‑OR, H1975 and H1975‑OR cells. Subsequently, the biological roles of differentially expressed circRNAs were explored in in vitro studies. Osimertinib‑resistant cell lines were successfully established via treatment with an increasing concentration of osimertinib. Osimertinib IC50 and proliferation of resistant cells were much higher than those of sensitive cells. Notably, phosphorylated (p)‑AKT and p‑ERK were markedly activated in resistant cells, and the inhibitory effect of osimertinib on p‑AKT and p‑ERK was weaker in resistant cells than that in parental cells. RNA‑seq analysis identified differentially expressed circRNAs in HCC827, HCC827‑OR, H1975 and H1975‑OR cells. The most dysregulated circRNAs (circPDLIM5 and circPPP4R1) were selected for further functional study. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the host genes of differentially expressed circRNAs were associated with 'endocytosis' and 'regulation of autophagy'. In conclusion, the present study established osimertinib‑resistant cell lines and revealed that circRNAs may serve as a promising biomarker in NSCLC osimertinib resistance.
... In addition, acquired resistance to both irreversible and reversible EGFR-TKIs, including osimertinib and gefitinib, has been reported in NSCLC and lung adenocarcinoma due to both EGFR-dependent and EGFR-independent mechanisms. These include mutations in the EGFR kinase domain duplication (EGFR-KDD) [123] or in the EGFR gene [121], mutations in KRAS exon 3 (R68S) [124], and the involvement of hsa_circ_0005576 via miR-512-5p/IGF1R signaling [125]. Acquired drug resistance in EGFR-mutant NSCLC patients is a common reason for the limited long-term efficacy of targeted therapy [126]. ...
Targeted therapy is a new cancer treatment approach, involving drugs that particularly target specific proteins in cancer cells, such as receptor tyrosine kinases (RTKs) which are involved in promoting growth and proliferation, Therefore inhibiting these proteins could impede cancer progression. An understanding of RTKs and the relevant signaling cascades, has enabled the development of many targeted drug therapies employing RTK inhibitors (RTKIs) some of which have entered clinical application. Here we discuss RTK structures, activation mechanisms and functions. Moreover, we cover the potential effects of combination drug therapy (including chemotherapy or immunotherapy agents with one RTKI or multiple RTKIs) especially for drug resistant cancers.
... Hsa_circ_0005576 was markedly increased in osimertinib-resistant LUAD cells. Knockdown of hsa_circ_0005576 recovered osimertinib sensitivity via the miR-512-5p/IGF1 receptor pathway (114). In addition, hsa_circ_0007312 (circ7312) was positively correlated with osimertinib IC 50 values and xenograft experiments indicated that knockdown of circ7312 decreased resistance to osimertinib in vivo. ...
Lung cancer is one of the most common malignant tumor types and the leading cause of cancer‑associated death worldwide. Different types of lung cancer exhibit differences in terms of pathophysiology and pathogenesis, and also treatment and prognosis. Accumulating evidence has indicated that circular RNAs (circRNAs) are abnormally expressed among different types of lung cancer and confer important biological functions in progression and prognosis. However, studies comparing different circRNAs in lung cancer subtypes are scarce. Furthermore, circRNAs have an important role in drug resistance and are related to clinicopathological features in lung cancer. Summaries of the association of circRNAs with drug resistance are also scarce in the literature. The present study outlined the biological functions of circRNAs and focused on discriminating differential circRNA patterns and mechanisms in three different types of lung cancer. The emerging roles of circRNAs in the resistance to chemotherapy, targeted therapy, radiotherapy and immunotherapy were also highlighted. Understanding these aspects of circRNAs sheds light on novel physiological and pathophysiological processes of lung cancer and suggests the application of circRNAs as biomarkers for diagnosis and prognosis, as well as therapeutic resistance.
... Accumulating evidence has shown the important role of circRNAs in regulating the biological events of LUAD, such as proliferation, metastasis, and glycolysis [31][32][33]. However, only one paper focused on the role of circRNAs in the osimertinib resistance of LUAD, suggesting that circ_0005576 promotes osimertinib resistance of LUAD by miR-512-5P/IGF1R axis [34]. Herein, we confirmed the elevation of circKRT17 in osimertinib-resistant LUAD, and circKRT17 knockdown could increase the sensitivity of LUAD cells to osimertinib. ...
Background:
Circular RNAs (circRNAs) play a key role in regulating the drug resistance of numerous human tumors. However, whether circKRT17 involves in the osimertinib resistance of lung adenocarcinoma (LUAD) remains undetermined.
Methods:
Relative mRNA/circRNA and protein levels were detected by qRT-PCR and western blotting. Localization of circKRT17 and YAP1 was determined by FISH and immunofluorescence staining. Cell growth and apoptosis were evaluated using colony formation, EdU assays, and flow cytometry. The N6-methyladenosine (m6A) modification was analyzed by MeRIP. The interplay between EIF4A3 and circKRT17 or YAP1 was verified by RNA pull-down or/and RIP assays. Subcutaneous tumor growth was monitored in nude mice, and Ki-67 and TUNEL staining were carried out to evaluate cell proliferation and apoptosis, respectively.
Results:
CircKRT17 and METTL3 were elevated in osimertinib-insensitive LUAD tissues and cells. Knockdown of circKRT 17 and METTL3 increased the sensitivity of LUAD cells to osimertinib. Knockdown of METTL3 decreased the expression of circKRT17 by inhibiting m6A modification. CircKRT17 promoted the stability and nuclear transportation of YAP1 by recruiting EIF4A3 in LUAD cells. Overexpression of YAP1 abolished the impacts of circKRT17 knockdown on the osimertinib sensitivity of LUAD cells. CircKRT17 knockdown increased the repressive effects of osimertinib on tumor growth in vivo by inhibiting YAP1 signaling.
Conclusion:
METTL3 initiated the m6A modification of circKRT17, thus promoting osimertinib resistance of LUAD by enhancing YAP1 stability through EIF4A4 recruitment.
... Regarding the functions of circRNAs in the resistance of osimertinib, a third-generation EGFR-TKI, Liu et al. demonstrated that has_circ_0005576 promoted osimertinib resistance by regulating miR-512-5p/IGF1R axis in LUAD cells (119). Another report clearly showed that has_circ_0002130 expression was considerably increased in osimertinib-resistant NSCLC cells and serum exosomes from osimertinib-resistant NSCLC patients, suggesting circ_0002130 may promote osimertinib resistance. ...
... It has been documented that circRNAs control cellular processes through several mechanisms which include modulating transcription (23), serving as sponge for miRNAs (134), acting as a platform or sponge for proteins (65), regulating splicing at the same locus (22), forming functional circRNA-protein complexes (65), directly binding to mRNAs to regulate their expression, outcompeting linear mRNAs for protein binding and encoding peptides (5,146). However, a vast majority of reports in drug resistance-associated circRNAs have focused on their function as miRNA sponge (107,119). Further investigations are needed to elucidate involvement of other molecular mechanisms of circRNAs in NSCLC drug resistance. ...
Due to the characteristics of aggressiveness and high risk of postoperative recurrence, non-small cell lung cancer (NSCLC) is a serious hazard to human health, accounting for 85% of all lung cancer cases. Drug therapies, including chemotherapy, targeted therapy and immunotherapy, are effective treatments for NSCLC in clinics. However, most patients ultimately develop drug resistance, which is also the leading cause of treatment failure in cancer. To date, the mechanisms of drug resistance have yet to be fully elucidated, thus original strategies are developed to overcome this issue. Emerging studies have illustrated that circular RNAs (circRNAs) participate in the generation of therapeutic resistance in NSCLC. CircRNAs mediate the modulations of immune cells, cytokines, autophagy, ferroptosis and metabolism in the tumor microenvironment (TME), which play essential roles in the generation of drug resistance of NSCLC. More importantly, circRNAs function as miRNAs sponges to affect specific signaling pathways, directly leading to the generation of drug resistance. Consequently, this review highlights the mechanisms underlying the relationship between circRNAs and drug resistance in NSCLC. Additionally, several therapeutic drugs associated with circRNAs are summarized, aiming to provide references for circRNAs serving as potential therapeutic targets in overcoming drug resistance in NSCLC.
... Beyond tumorigenesis, recent studies have investigated dysregulated ncRNAs in EGFR TKI-resistant lung cancer and partially elucidated their diverse mechanisms. To date, research has mainly focused on specific ncRNAs involved in crucial signaling pathways downstream of EGFR and parallel pathways instead of the mechanisms of ncRNA dysregulation [32][33][34]. Remarkably, a minority of studies have shown that EGFR mutations might lead naturally to ncRNAs [35]. MiR-21, for example, a miRNA activated by EGFR, has been proven to negatively modulate TNF expression. ...
... Thus, the PI3K/AKT pathway is enhanced, causing resistance to gefitinib, afatinib, erlotinib and osimertinib [49,50]. In a similar manner, ncRNAs such as miR-223, lncRNA GAS5 and hsa_circ_0005576 regulate IGF1R expression and subsequently influence the resistance of lung cancer cells to EGFR TKIs [32,[51][52][53]. ...
Lung cancer accounts for the majority of malignancy-related mortalities worldwide. The introduction of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment and significantly improved the overall survival (OS) of lung cancer. Nevertheless, almost all EGFR-mutant patients invariably acquire TKI resistance. Accumulating evidence has indicated that noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), have a central role in the tumorigenesis and progression of lung cancer by regulating crucial signaling pathways, providing a new approach for exploring the underlying mechanisms of EGFR-TKI resistance. Therefore, this review comprehensively describes the dysregulation of ncRNAs in EGFR TKI-resistant lung cancer and its underlying mechanisms. We also underscore the clinical application of ncRNAs as prognostic, predictive and therapeutic biomarkers for EGFR TKI-resistant lung cancer. Furthermore, the barriers that need to be overcome to translate the basic findings of ncRNAs into clinical practice are discussed.
... 399,400 CircRNA hsa_-circ_0005576 directly interacts with miR-512-5p in LUAD cell lines and upregulates miR-512-5p/IGF-1R pathway, leading to osimertinib resistance. 401 In addition, circRNA-SORE binds to Y-box binding protein 1 (YBX1) to block the interaction between YBX1 and the pre-mRNA-processing factor 19 (PRP19) (an E3 ubiquitin ligase). 402 Consequently, PRP19-mediated YBX degradation is inhibited, and high YBX is related to the apoptosis resistance. ...
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.
... HSCC is a common malignant tumor originating from the mucous epithelium of the upper aerodigestive tract, accounting for about 5-15% of head and neck squamous Anti-PD-L1 therapy resistance Promotes tumor immune evasion [186] YTHDF2 Increases m6A-modified circASK1 degradation ...
... Liu's group revealed that hsa_circ_0005576 could elevate the mRNA level of insulin-like growth factor 1 receptor (IGF1R) by sponging miR-512-5p in osimertinib-resistant LUAD cells. IGF1R has been demonstrated to promote proliferation and anti-apoptosis through PI3K/AKT and MAPK/ ERK1/2 signaling activation, resulting in osimertinib resistance in LUAD [186]. Besides, ASK1/JNK/p38 signaling pathway is tightly related to apoptosis [196,197]. ...
The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying mechanisms of therapeutic resistance may provide new strategies for overcoming cancer resistance. N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotes, and is involved in the regulation of RNA splicing, translation, transport, degradation, stability and processing, thus affecting several physiological processes and cancer progression. As a novel type of multifunctional non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been demonstrated to play vital roles in anticancer therapy. Currently, accumulating studies have revealed the mutual regulation of m6A modification and circRNAs, and their interaction can further influence the sensitivity of cancer treatment. In this review, we mainly summarized the recent advances of m6A modification and circRNAs in the modulation of cancer therapeutic resistance, as well as their interplay and potential mechanisms, providing promising insights and future directions in reversal of therapeutic resistance in cancer.
This review article presents an in-depth analysis of the current state of research on receptor tyrosine kinase regulatory non-coding RNAs (RTK-RNAs) in solid tumors. RTK-RNAs belong to a class of non-coding RNAs (nc-RNAs) responsible for regulating the expression and activity of receptor tyrosine kinases (RTKs), which play a critical role in cancer development and progression. The article explores the molecular mechanisms through which RTK-RNAs modulate RTK signaling pathways and highlights recent advancements in the field. This include the identification of potential new RTK-RNAs and development of therapeutic strategies targeting RTK-RNAs. While the review discusses promising results from a variety of studies, encompassing in vitro, in vivo, and clinical investigations, it is important to acknowledge the challenges and limitations associated with targeting RTK-RNAs for therapeutic applications. Further studies involving various cancer cell lines, animal models, and ultimately, patients are necessary to validate the efficacy of targeting RTK-RNAs. The specificity of ncRNAs in targeting cellular pathways grants them tremendous potential, but careful consideration is required to minimize off-target effects, the article additionally discusses the potential clinical applications of RTK-RNAs as biomarkers for cancer diagnosis, prognosis, and treatment. In essence, by providing a comprehensive overview of the current understanding of RTK-RNAs in solid tumors, this review emphasizes their potential as therapeutic targets for cancer while acknowledging the associated challenges and limitations.
