scholarly journals M6A associated TSUC7 inhibition contributed to Erlotinib Resistance in Lung Adenocarcinoma through a Notch Signaling Activation Dependent Way

2021 ◽  
Author(s):  
Kai Li ◽  
Zi-Yang Peng ◽  
Shan Gao ◽  
Qing-Shi Wang ◽  
Rui Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Notch Signaling ◽  
Cancer Progression ◽  
Kinase Inhibitors ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Specific Gene ◽  
Dependent Manner ◽  
Non Coding Rnas ◽  
Signaling Activation

Abstract BackgroundThe small tyrosine kinase inhibitors (TKIs) subversively altered the lung cancer treatments, but patients will inevitably face the therapy resistance and disease recurrence. We aim to explore the potential roles of non-coding RNAs in sensitizing the TKIs effects. MethodsMultiple cellular and molecular detections were applied to confirm the mechanistic regulations and intracellular connections. ResultsWe explored the specific gene features of candidates in association with resistance, and found the miR-146a/Notch signaling was sustained highly activated in a m6A dependent manner, and the m6A regulator of YTHDF2 suppressed TUSC7, and then contributed to the resistant features. Functionally, m6A controlled the stemness of EMT features through METTL3 and YTHDF2, and resulted in resistance in PC9ER and HCC827ER cells. The sponging regulation of TUSC7 toward to miR-146a inhibited Notch signaling functions, and affected the cancer progression and stem cells’ renewal in PC9ER and HCC827ER cells. The Notch signaling functions manipulated the cMYC and DICER inner cytoplasm, and the absence of either cMYC or DICER1 lead to TUSC7 and miR-146a decreasing respectively, formed the closed circle to maintain the balance. ConclusionPC9ER and HCC827ER cells harbored much more stem-like cells, and the resistance could be reversed by Notch signaling inactivation. The intrinsic miR-146 and TUSC7 levels are monitored by m6A effectors, miR-146 and TUSC7 themselves formed the circling loop to sustain the homeostasis. Further in clinics, the combined using of TKIs and Notch specific inhibitory non-coding RNAs will pave the way for yielding the susceptibility to targeted therapy in lung cancer.

scholarly journals M6A associated TSUC7 inhibition contributed to Erlotinib resistance in lung adenocarcinoma through a notch signaling activation dependent way

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Kai Li ◽  
Zi-Yang Peng ◽  
Shan Gao ◽  
Qing-Shi Wang ◽  
Rui Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Notch Signaling ◽  
Cancer Progression ◽  
Kinase Inhibitors ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Specific Gene ◽  
Dependent Manner ◽  
Non Coding Rnas ◽  
Signaling Activation

Abstract Background The small tyrosine kinase inhibitors (TKIs) subversively altered the lung cancer treatments, but patients will inevitably face the therapy resistance and disease recurrence. We aim to explore the potential roles of non-coding RNAs in sensitizing the TKIs effects. Methods: Multiple cellular and molecular detections were applied to confirm the mechanistic regulations and intracellular connections. Results We explored the specific gene features of candidates in association with resistance, and found that m6A controlled the stemness of EMT features through METTL3 and YTHDF2. The miR-146a/Notch signaling was sustained highly activated in a m6A dependent manner, and the m6A regulator of YTHDF2 suppressed TUSC7, both of which contributed to the resistant features. Functionally, the sponge type of TUSC7 regulation of miR-146a inhibited Notch signaling functions, and affected the cancer progression and stem cells’ renewal in Erlotinib resistant PC9 cells (PC9ER) and Erlotinib resistant HCC827 cells (HCC827ER) cells. The Notch signaling functions manipulated the cMYC and DICER inner cytoplasm, and the absence of either cMYC or DICER1 lead to TUSC7 and miR-146a decreasing respectively, formed the closed circle to maintain the balance. Conclusion PC9ER and HCC827ER cells harbored much more stem-like cells, and the resistance could be reversed by Notch signaling inactivation. The intrinsic miR-146 and TUSC7 levels are monitored by m6A effectors, the alternation of either miR-146 or TUSC7 expression could lead to the circling loop to sustain the new homeostasis. Further in clinics, the combined delivery of TKIs and Notch specific inhibitory non-coding RNAs will pave the way for yielding the susceptibility to targeted therapy in lung cancer.

scholarly journals Long non-coding RNAs in lung cancer: implications for lineage plasticity-mediated TKI resistance

2020 ◽  
Author(s):  
Tongyan Liu ◽  
Chencheng Han ◽  
Panqi Fang ◽  
Hongyu Zhu ◽  
Siwei Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Disease Recurrence ◽  
Developmental Pathway ◽  
Mesenchymal Transition ◽  
Histological Transformation ◽  
Tki Resistance ◽  
Intratumoural Heterogeneity ◽  
Non Coding Rnas

Abstract The efficacy of targeted therapy in non-small-cell lung cancer (NSCLC) has been impeded by various mechanisms of resistance. Besides the mutations in targeted oncogenes, reversible lineage plasticity has recently considered to play a role in the development of tyrosine kinase inhibitors (TKI) resistance in NSCLC. Lineage plasticity enables cells to transfer from one committed developmental pathway to another, and has been a trigger of tumor adaptation to adverse microenvironment conditions including exposure to various therapies. More importantly, besides somatic mutation, lineage plasticity has also been proposed as another source of intratumoural heterogeneity. Lineage plasticity can drive NSCLC cells to a new cell identity which no longer depends on the drug-targeted pathway. Histological transformation and epithelial–mesenchymal transition are two well-known pathways of lineage plasticity-mediated TKI resistance in NSCLC. In the last decade, increased re-biopsy practice upon disease recurrence has increased the recognition of lineage plasticity induced resistance in NSCLC and has improved our understanding of the underlying biology. Long non-coding RNAs (lncRNAs), the dark matter of the genome, are capable of regulating variant malignant processes of NSCLC like the invisible hands. Recent evidence suggests that lncRNAs are involved in TKI resistance in NSCLC, particularly in lineage plasticity-mediated resistance. In this review, we summarize the mechanisms of lncRNAs in regulating lineage plasticity and TKI resistance in NSCLC. We also discuss how understanding these themes can alter therapeutic strategies, including combination therapy approaches to overcome TKI resistance.

scholarly journals MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 39
Author(s):  
Crescenzo Massaro ◽  
Elham Safadeh ◽  
Giulia Sgueglia ◽  
Hendrik G. Stunnenberg ◽  
Lucia Altucci ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Hormone Signaling ◽  
Cancer Resistance ◽  
Comprehensive Overview ◽  
Substantial Progress

Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.

scholarly journals Systemic Platelet-activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis

2014 ◽  
Vol 7 ◽  
pp. CGM.S14501 ◽  
Author(s):  
Patrick C. Hackler ◽  
Sarah Reuss ◽  
Raymond L. Konger ◽  
Jeffrey B. Travers ◽  
Ravi P. Sahu
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Lung Tumor ◽  
Platelet Activating Factor ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Melanoma Tumor ◽  
Tumor Growth And Metastasis ◽  
The Impact

Pro-oxidative stressors including cigarette smoke (CS) generate novel lipids with platelet-activated factor-receptor (PAF-R) agonistic activity mediate systemic immunosuppression, one of the most recognized events in promoting carcinogenesis. Our previous studies have established that these oxidized-PAF-R-agonists augment murine B16F10 melanoma tumor growth in a PAF-R-dependent manner because of its effects on host immunity. As CS generates PAF-R agonists, the current studies sought to determine the impact of PAF-R agonists on lung cancer growth and metastasis. Using the murine Lewis Lung Carcinoma (LLC1) model, we demonstrate that treatment of C57BL/6 mice with a PAF-R agonist augments tumor growth and lung metastasis in a PAF-R-dependent manner as these findings were not seen in PAF-R-deficient mice. Importantly, this effect was because of host rather than tumor cells PAF-R dependent as LLC1 cells do not express functional PAF-R. These findings indicate that experimental lung cancer progression can be modulated by the PAF system.

scholarly journals The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating Notch receptor trafficking

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Bo Li ◽  
Chouin Wong ◽  
Shihong Max Gao ◽  
Rulan Zhang ◽  
Rongbo Sun ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Molecular Mechanisms ◽  
Neural Progenitor ◽  
Tumor Formation ◽  
Neural Progenitors ◽  
Notch Receptor ◽  
Dependent Manner ◽  
Cell Fate Decisions ◽  
Retromer Complex ◽  
Signaling Activation

The correct establishment and maintenance of unidirectional Notch signaling are critical for the homeostasis of various stem cell lineages. However, the molecular mechanisms that prevent cell-autonomous ectopic Notch signaling activation and deleterious cell fate decisions remain unclear. Here we show that the retromer complex directly and specifically regulates Notch receptor retrograde trafficking in Drosophila neuroblast lineages to ensure the unidirectional Notch signaling from neural progenitors to neuroblasts. Notch polyubiquitination mediated by E3 ubiquitin ligase Itch/Su(dx) is inherently inefficient within neural progenitors, relying on retromer-mediated trafficking to avoid aberrant endosomal accumulation of Notch and cell-autonomous signaling activation. Upon retromer dysfunction, hypo-ubiquitinated Notch accumulates in Rab7+ enlarged endosomes, where it is ectopically processed and activated in a ligand-dependent manner, causing progenitor-originated tumorigenesis. Our results therefore unveil a safeguard mechanism whereby retromer retrieves potentially harmful Notch receptors in a timely manner to prevent aberrant Notch activation-induced neural progenitor dedifferentiation and brain tumor formation.

scholarly journals Non-Coding RNAs in Lung Tumor Initiation and Progression

2020 ◽  
Vol 21 (8) ◽  
pp. 2774 ◽  
Author(s):  
Ruben Mercado Santos ◽  
Cerena Moreno ◽  
Wen Cai Zhang
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Tumor Suppressors ◽  
Lung Tumor ◽  
Circular Rnas ◽  
Tumor Initiating Cells ◽  
Cancer Initiation ◽  
Non Coding Rnas ◽  
Society Today ◽  
Cell Signaling Pathways

Lung cancer is one of the deadliest forms of cancer affecting society today. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to affect lung cancer tumorigenesis and metastasis. This review will briefly summarize hallmarks involved in lung cancer initiation and progression. For initiation, these hallmarks include tumor initiating cells, immortalization, activation of oncogenes and inactivation of tumor suppressors. Hallmarks involved in lung cancer progression include metastasis and drug tolerance and resistance. The targeting of these hallmarks with non-coding RNAs can affect vital metabolic and cell signaling pathways, which as a result can potentially have a role in cancerous and pathological processes. By further understanding non-coding RNAs, researchers can work towards diagnoses and treatments to improve early detection and clinical response.

Molecular changes in epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) biopsies at time of progression compared to initial biopsy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22066-e22066
Author(s):  
G. Speranza ◽  
V. Cohen ◽  
J. S. Agulnik ◽  
G. Chong ◽  
F. Meilleur ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Missense Mutations ◽  
Molecular Changes ◽  
Mutational Status ◽  
Exon 19 Deletion ◽  
Exon 19

e22066 Background: EGFR mutations predict sensitivity and clinical outcome to tyrosine kinase inhibitors (TKI) in NSCLC. The two most commonly described mutations are Exon 19 deletion and Exon 21 L858R missense mutations. Genetic alterations over time have been described in other tumour types, but studies assessing EGFR genotypic changes with lung cancer progression are lacking. We sought to compare EGFR mutational status from lung tumors at time of recurrence or progression with the primary tumor. Methods: Using the Jewish General Hospital lung cancer database, of all patients diagnosed with NSCLC since 1999, those with biopsies at two different points in time were identified. All tumour samples were genotyped for EGFR exons 19 and 21 mutations using denaturing high performance liquid chromatography (dHPLC). Results: 29 patients were identified. Data for 12 patients, whose time of recurrence or progression varied between 4 months and 6 years, are available at this time. Of 12 patients, one had EGFR exon 19 mutation at time of diagnosis. One patient who initially displayed no EGFR mutation was found to have an exon 19 deletion at time of recurrence. The one with exon 19 at time of initial diagnosis continued to express exon 19 in the second biopsy. Conclusions: To our knowledge, this is the only study assessing changes in molecular genotype using dHPLC between primary and recurrent or progressive lung cancer biopsy specimens. Although sample size is small, it is evident that changes in EGFR mutational status can occur. Further prospective studies are required to determine how commonly molecular changes occur. No significant financial relationships to disclose.

scholarly journals Non-Coding RNAs: Regulating Disease Progression and Therapy Resistance in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1243
Author(s):  
Debashri Manna ◽  
Devanand Sarkar
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Malignant Tumors ◽  
Primary Liver Cancer ◽  
Disease Process ◽  
Therapy Resistance ◽  
Primary Treatment ◽  
Rna Transcripts ◽  
Non Coding Rnas ◽  
Treatment Procedures

Hepatocellular carcinoma (HCC), the primary liver cancer arising from hepatocytes, is a universal health problem and one of the most common malignant tumors. Surgery followed by chemotherapy as well as tyrosine kinase inhibitors (TKIs), such as sorafenib, are primary treatment procedures for HCC, but recurrence of disease because of therapy resistance results in high mortality. It is necessary to identify novel regulators of HCC for developing effective targeted therapies that can significantly interfere with progression of the disease process. Non-coding RNAs (ncRNAs) are an abundant group of versatile RNA transcripts that do not translate into proteins, rather serve as potentially functional RNAs. The role of ncRNAs in regulating diverse aspects of the carcinogenesis process are gradually being elucidated. Recent advances in RNA sequencing technology have identified a plethora of ncRNAs regulating all aspects of hepatocarcinogenesis process and serving as potential prognostic or diagnostic biomarkers. The present review provides a comprehensive description of the biological roles of ncRNAs in disease process and therapy resistance, and potential clinical application of these ncRNAs in HCC.

Non-coding RNAs in Lung Cancer Chemoresistance

2020 ◽  
Vol 20 (13) ◽  
pp. 1023-1032 ◽  
Author(s):  
Priya Mondal ◽  
Jagadish Natesh ◽  
Mohammad Amjad Kamal ◽  
Syed Musthapa Meeran
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Gene Expressions ◽  
Intrinsic Factors ◽  
Non Coding Rnas ◽  
Altered Gene

Background: Lung cancer is the leading cause of cancer-associated death worldwide with limited treatment options. The major available treatment options are surgery, radiotherapy, chemotherapy and combinations of these treatments. In chemotherapy, tyrosine kinase inhibitors and taxol are the first lines of chemotherapeutics used for the treatment of lung cancer. Often drug resistance in the clinical settings hinders the efficiency of the treatment and intrigues the tumor relapse. Drug-resistance is triggered either by intrinsic factors or due to the prolonged cycles of chemotherapy as an acquired-resistance. There is an emerging role of non-coding RNAs (ncRNAs), including notorious microRNAs (miRNAs), proposed to be actively involved in the regulations of various tumor-suppressor genes and oncogenes. Result: The altered gene expression by miRNA is largely mediated either by the degradation or by interfering with the translation of targeted mRNA. Unlike miRNA, other type of ncRNAs, such as long non-coding RNAs (lncRNAs), can target the transcriptional activator or the repressor, RNA polymerase, and even DNA-duplex to regulate the gene expressions. Many studies have confirmed the crucial role of ncRNAs in lung adenocarcinoma progression and importantly, in the acquisition of chemoresistance. Recently, ncRNAs have become early biomarkers and therapeutic targets for lung cancer. Conclusion: Targeting ncRNAs could be an effective approach for the development of novel therapeutics against lung cancer and to overcome the chemoresistance.

scholarly journals Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

2015 ◽  
Vol 112 (22) ◽  
pp. 6955-6960 ◽  
Author(s):  
Hsin-Yung Yen ◽  
Ying-Chih Liu ◽  
Nai-Yu Chen ◽  
Chia-Feng Tsai ◽  
Yi-Ting Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Cancer Progression ◽  
Conformational Changes ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Kinase Activation ◽  
Downstream Signaling ◽  
Egfr Mutant

Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKI-sensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKI-resistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKI-resistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.

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