Dataset Information

Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma.

ABSTRACT:

Background

Identification of potential novel targets for reversing resistance to Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) holds great promise for the treatment of relapsed lung adenocarcinoma (LUAD). In the present study, we aim to investigate the role of methyltransferase-like 7B (METTL7B) in inducing EGFR-TKIs resistance in LUAD and whether it could be a therapeutic target for reversing the resistance.

Methods

METTL7B-overexpressed LUAD cell lines, gefitinib and osimertinib-resistant Cell-Derived tumor Xenograft (CDX) and Patient-Derived tumor Xenograft (PDX) mouse models were employed to evaluate the role of METTL7B in TKIs resistance. Ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was used to identify the metabolites regulated by METTL7B. Methylated RNA immunoprecipitation (MeRIP)-qPCR analysis was performed to measure the N⁶-methyladenosine (m⁶A) status of mRNA of METTL7B targeted genes. Gold nanocluster-assisted delivery of siRNA targeting METTL7B (GNC-siMETTL7B) was applied to evaluate the effect of METTL7B in TKIs resistance.

Results

Increased expression of METTL7B was found in TKIs-resistant LUAD cells and overexpression of METTL7B in LUAD cells induced TKIs resistance both in vitro and in vivo. Activated ROS-metabolism was identified in METTL7B-overexpressed LUAD cells, accompanied with upregulated protein level of GPX4, HMOX1 and SOD1 and their enzymatic activities. Globally elevated m⁶A levels were found in METTL7B-overexpressed LUAD cells, which was reduced by knock-down of METTL7B. METTL7B induced m⁶A modification of GPX4, HMOX1 and SOD1 mRNA. Knock-down of METTL7B by siRNA re-sensitized LUAD cells to gefitinib and osimertinib both in vitro and in vivo.

Conclusions

This study uncovered a new critical link in METTL7B, glutathione metabolism and drug resistance. Our findings demonstrated that METTL7B inhibitors could be used for reversing TKIs resistance in LUAD patients.

SUBMITTER: Song H

PROVIDER: S-EPMC8830004 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma.

Song Huibin H Liu Dongcheng D Wang Lingwei L Liu Kaisheng K Chen Chen C Wang Le L Ren Yi Y Ju Bing B Zhong Fuhua F Jiang Xingyu X Wang Guangsuo G Chen Zhe-Sheng ZS Zou Chang C

Molecular cancer 20220210 1

<h4>Background</h4>Identification of potential novel targets for reversing resistance to Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) holds great promise for the treatment of relapsed lung adenocarcinoma (LUAD). In the present study, we aim to investigate the role of methyltransferase-like 7B (METTL7B) in inducing EGFR-TKIs resistance in LUAD and whether it could be a therapeutic target for reversing the resistance.<h4>Methods</h4>METTL7B-overexpressed LUAD cell ...[more]

PMID: 35144642

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Project description:BACKGROUND:Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are beneficial to lung adenocarcinoma patients with sensitive EGFR mutations, resistance to these inhibitors induces a cancer stem cell (CSC) phenotype. Here, we clarify the function and molecular mechanism of shisa3 as a suppressor that can reverse EGFR-TKI resistance and inhibit CSC properties. METHODS:The suppresser genes involved in EGFR-TKI resistance were identified and validated by transcriptome sequencing, quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Biological function analyses, cell half maximal inhibitory concentration (IC50), self-renewal, and migration and invasion capacities, were detected by CCK8, sphere formation and Transwell assays. Tumorigenesis and therapeutic effects were investigated in nonobese diabetic/severe combined immunodeficiency (nod-scid) mice. The underlying mechanisms were explored by Western blot and immunoprecipitation analyses. RESULTS:We found that low expression of shisa3 was related to EGFR-TKI resistance in lung adenocarcinoma patients. Ectopic overexpression of shisa3 inhibited CSC properties and the cell cycle in the lung adenocarcinoma cells resistant to gefitinib/osimertinib. In contrast, suppression of shisa3 promoted CSC phenotypes and the cell cycle in the cells sensitive to EGFR-TKIs. For TKI-resistant PC9/ER tumors in nod-scid mice, overexpressed shisa3 had a significant inhibitory effect. In addition, we verified that shisa3 inhibited EGFR-TKI resistance by interacting with FGFR1/3 to regulate AKT/mTOR signaling. Furthermore, combinational administration of inhibitors of FGFR/AKT/mTOR and cell cycle signaling could overcome EGFR-TKI resistance associated with shisa3-mediated CSC capacities in vivo. CONCLUSION:Taken together, shisa3 was identified as a brake to EGFR-TKI resistance and CSC characteristics, probably through the FGFR/AKT/mTOR and cell cycle pathways, indicating that shisa3 and concomitant inhibition of its regulated signaling may be a promising therapeutic strategy for reversing EGFR-TKI resistance.

Project description:BackgroundLung adenocarcinoma (LUAD) is still one of the major causes of cancer-related mortality across the globe. Therefore, there is a dire need to identify early specific and sensitive biomarkers or drug targets of LUAD for developing improved diagnosis and clinical management. We aimed to investigate the role of methyltransferase-like 7B (METTL7B) on LUAD tumor development and progression in this study.MethodsMETTL7B's expression was confirmed in two independent clinical cohort samples, including LUAD tissues microarray (TMA) via immunohistochemistry (IHC) and serum samples via enzyme-linked immunosorbent assay (ELISA). The correlation between METTL7B expression with clinicopathological features and overall survival rate in LUAD patients was then further analyzed. Meanwhile, the messenger ribonucleic acid (mRNA) and protein levels of METTL7B were verified in cell lines and in vitro experiments, including cell proliferation assay, and migration. Invasion assays were conducted to explore the effects of METTL7B on LUAD by silencing the protein expression.ResultsMETTL7B was remarkably overexpressed in clinical LUAD tumor tissues and serum compared to the normal control group and in LUAD cell lines. The expression level of METTL7B was significantly correlated with tumor size, advanced tumor node and metastases (TNM) stages, and lymph node metastasis. The Kaplan-Meier survival curves proved that high METTL7B expression was significantly associated with a reduced survival rate in LUAD patients (P<0.05), and univariate analysis showed that high METTL7B expression was significantly associated with poor overall survival [hazard ratio (HR) =2.220, 95% confidence interval (CI): 1.211-4.086; P=0.010]. In vitro assays showed that METTL7B overexpression augmented cell proliferation, migration, and the invasion in LUAD.ConclusionsMETTL7B was overexpressed in LUAD and significantly associated with the poor progression, showing that METTL7B may serve as a potential novel biomarker for the diagnosis and prognosis of LUAD. Moreover, METTL7B plays a role in promoting tumor proliferation, migration, and invasion in LUAD.

Dataset Information

Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma.

Background

Methods

Results

Conclusions

Publications

Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma.

Similar Datasets

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