The Role of Non-Coding RNA Editing in MET Signaling in NSCLC

非编码 RNA 编辑在 NSCLC MET 信号转导中的作用

基本信息

批准号：
10573620
负责人：
Mario Acunzo
金额：
$ 22.49万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573620
关键词：
Adenosine Apoptosis Asian population Bioinformatics Biological Cancer Biology Cancer Etiology Cancer Patient Cancer cell line Cancerous Cell Line Cells Cessation of life Chemoresistance Circulation Code Coupled DNA Sequence Alteration DRADA2b protein Dedications Disease Disease Progression Drug resistance Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event Extracellular Signal Regulated Kinases Future Gefitinib Genes Genetic Transcription Glioblastoma Human Genome Inosine MAPK3 gene MET gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Messenger RNA MicroRNAs Modernization Modification Molecular Molecular Target Mutate Mutation Names Non-Small-Cell Lung Carcinoma Nucleotides Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Positioning Attribute Post-Transcriptional RNA Processing Protein Family RNA RNA Editing RNA Primary Transcript Receptor Protein-Tyrosine Kinases Regulation Reporting Repression Research Personnel Resistance Resistance development Role Signal Repression Signal Transduction Somatic Mutation Structure Structure of parenchyma of lung Technology Testing Therapeutic Uses Tissues Transfection Tyrosine Kinase Inhibitor Untranslated RNA cancer drug resistance combat computerized tools dsRNA adenosine deaminase gene repression in vivo innovation mRNA Precursor malignant breast neoplasm malignant stomach neoplasm member mouse model mutant negative affect next generation sequencing novel novel therapeutics objective response rate patient response posttranscriptional response therapy development tool transcriptome transcriptome sequencing tumor progression

Adenosine Apoptosis Asian population Bioinformatics Biological Cancer Biology Cancer Etiology Cancer Patient Cancer cell line Cancerous Cell Line Cells Cessation of life Chemoresistance Circulation Code Coupled DNA Sequence Alteration DRADA2b protein Dedications Disease Disease Progression Drug resistance Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event Extracellular Signal Regulated Kinases Future Gefitinib Genes Genetic Transcription Glioblastoma Human Genome Inosine MAPK3 gene MET gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Messenger RNA MicroRNAs Modernization Modification Molecular Molecular Target Mutate Mutation Names Non-Small-Cell Lung Carcinoma Nucleotides Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Positioning Attribute Post-Transcriptional RNA Processing Protein Family RNA RNA Editing RNA Primary Transcript Receptor Protein-Tyrosine Kinases Regulation Reporting Repression Research Personnel Resistance Resistance development Role Signal Repression Signal Transduction Somatic Mutation Structure Structure of parenchyma of lung Technology Testing Therapeutic Uses Tissues Transfection Tyrosine Kinase Inhibitor Untranslated RNA cancer drug resistance combat computerized tools dsRNA adenosine deaminase gene repression in vivo innovation mRNA Precursor malignant breast neoplasm malignant stomach neoplasm member mouse model mutant negative affect next generation sequencing novel novel therapeutics objective response rate patient response posttranscriptional response therapy development tool transcriptome transcriptome sequencing tumor progression

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项目摘要

PROJECT SUMMARY Lung cancer is the primary cause of cancer-related deaths in the U.S. Despite encouraging progress in creating new therapeutics, most lung cancer patients develop resistance and succumb to metastatic disease. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that is frequently mutated in lung cancer (10-50%). Several EGFR inhibitors have been developed to mitigate the transformative effects of mutant EGFR. For example, gefitinib and osimertinib are tyrosine kinase inhibitors (TKIs) used for treating EGFR- mutated non-small cell lung cancer (NSCLC). Unfortunately, despite the initial responsiveness of patients to these drugs, a rapidly acquired resistance occurs mainly because of new genetic alterations, including amplification of the hepatocyte growth factor receptor (MET). Adenosine to Inosine (A-to-I) RNA editing represents 90% of all the RNA editing events in the cell and regulates mRNA sequence, function, degradation, and structure. RNA editing has been observed in both coding and non- coding genes, including miRs. Furthermore, coding RNA editing dysregulation has been recently associated with cancerous phenotype and drug resistance, including against TKIs. Recent high throughput interrogation of the human genome has allowed for the identification of miR editing deregulation in cancer. However, the biological impact of edited non-coding RNAs (i.e., miRs) in lung cancer progression and drug resistance remains largely unknown. We preliminarily identified a reduction of A-to-I editing in position 5 of miR-411-5p in the tissues of lung cancer patients. We determined that ed.miR-411-5p negatively affects the ERK1/2 pathway, directly targets MET, and alters TKI drug resistance in NSCLC cell lines. Furthermore, it is reported that MET transcriptionally regulates the expression of miR-222. We have also found that the miR-222 targets ADAR2, a member of the ADAR proteins family, responsible for pre-mRNA and non-coding RNA A-to-I editing. ADAR2 also induces A-to-I editing in miRs, including miR-411-5p. We found that ADAR2 is downregulated in lung cancer tissues and TKI resistant tissue and cell lines and anticorrelates with miR-222 expression. We hypothesize that miR editing dysregulation contributes to the pathobiology of lung cancer. Therefore, we aim to globally evaluate the impact that ed.miR-411-5p has on NSCLC progression and TKI resistance. Then, we also intend to investigate by RNA seq. if the ed.miR-411-5p induces ADAR2 expression and activity through MET, ERK1/2, and miR-222 signaling repression with the scope of uncovering new post-transcriptional mechanisms that regulate lung cancer progression and drug resistance.

项目摘要肺癌是美国与癌症相关死亡的主要原因，尽管令人鼓舞新的治疗剂，大多数肺癌患者会产生抗药性并屈服于转移性疾病。这表皮生长因子受体（EGFR）是一种受体酪氨酸激酶（RTK），经常在肺中突变癌症（10-50％）。已经开发了几种EGFR抑制剂来减轻突变体的变化作用 egfr。例如，吉非替尼和osimertinib是用于治疗EGFR-的酪氨酸激酶抑制剂（TKIS）突变的非小细胞肺癌（NSCLC）。不幸的是，尽管患者对这些药物，迅速获得的抗药性主要是由于新的遗传改变，包括肝细胞生长因子受体的扩增（MET）。腺苷对插入（A-TO-I）RNA编辑代表细胞中所有RNA编辑事件的90％，并调节 mRNA序列，功能，降解和结构。在编码和非 - 编码基因，包括miR。此外，编码RNA编辑失调最近与癌性表型和耐药性，包括针对TKI。最近对人类基因组的高吞吐量询问允许识别miR编辑在癌症中放松管制。但是，编辑的非编码RNA（即miR）在肺癌中的生物学影响进展和耐药性在很大程度上仍然未知。我们初步确定了在肺癌组织中miR-411-5p的位置5的A到I编辑的降低患者。我们确定ED.MIR-411-5P对ERK1/2途径产生负面影响，直接针对MET，并且改变NSCLC细胞系中的TKI耐药性。此外，据报道MET在转录中调节 miR-222的表达。我们还发现，miR-222靶向ADAR的成员Adar2 蛋白质家族，负责前MRNA和非编码RNA A-to-I编辑。 ADAR2还诱导A到I编辑在mir中，包括mir-411-5p。我们发现ADAR2在肺癌组织和TKI抗性中被下调组织和细胞系以及具有miR-222表达的反交流。我们假设MIR编辑失调有助于肺癌病理生物学。因此，我们的目标在全球范围内评估ED.MIR-411-5P对NSCLC进展和TKI抗性的影响。然后，我们还打算通过RNA SEQ进行调查。如果ED.MIR-411-5P通过 MET，ERK1/2和miR-222信号抑制，涉及新的转录后范围调节肺癌进展和耐药性的机制。