Association of BIM Deletion Polymorphism and BIM-γ RNA Expression in NSCLC with EGFR Mutation

Isobe, Kazutoshi; Kakimoto, Atsushi; Mikami, Tetsuo; Kaburaki, Kyohei; Kobayashi, Hiroshi; Yoshizawa, Takahiro; Makino, Takashi; Otsuka, Hajime; Sano, Go; Sugino, Keishi; Sakamoto, Susumu; Takai, Yujiro; Tochigi, Naobumi; Iyoda, Akira; Homma, Sakae

doi:10.21873/cgp.20010

Cited by 10 publications

(6 citation statements)

References 36 publications

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“…The EGFR is an important factor involved in the progression of NSCLC. 30 , 31 EGFR affects numerous systems involved in oncogenesis. 32 It has been proposed as an attractive and promising target for anti-cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer

et al. 2017

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Lung cancer is the major form of cancer resulting in cancer-related mortality around the world. MicroRNAs are endogenous small non-coding single-stranded RNAs, which can engage in the regulation of gene expression. In this study, miR-18a-5p significantly upregulated in non-small cell lung cancer (NSCLC) tissues and NSCLC cell lines, suggesting an oncogenic function in lung cancer. Additionally, miR-18a-5p can promote carcinogenesis by directly targeting interferon regulatory factor 2 (IRF2). Further experiments indicated that IRF2 can increase cell apoptosis, inhibit cell proliferation and migration ability. Our study demonstrates that miR-18a-5p promotes autophagy in NSCLC. Collectively, these results indicate that miR-18a-5p can not only promote NSCLC by suppressing IRF2, but also will be a promising target in the near future.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer

et al. 2017

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“…A longer progressionfree survival (PFS) was reported in NSCLC patients with such mutations who were treated with an EGFR-TKI as a first-line therapy compared with those receiving platinum-based chemotherapy (7)(8)(9)(10)(11). The expression of PD-L1, BCL2L11 (BIM), p53 upregulated modular of apoptosis (PUMA), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor A (VEGFA), EGFR and mesenchymal-epithelial transition (MET) were reported to be prognostic factors for patients with EGFR mutations receiving EGFR-TKI therapy (12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

PD-L1 mRNA expression in EGFR-mutant lung adenocarcinoma

et al. 2018

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Molecular mechanisms of programmed death-ligand 1 (PD-L1) mRNA expression and roles of apoptosis and biomarkers are poorly understood in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients. Thirty-three patients with recurrent postoperative EGFR-mutant lung adenocarcinoma (exon 19 deletion in 16, L858R in 15, G719C in 2 patients) treated with gefitinib were studied. PD-L1 mRNA expression of formalin-fixed paraffin-embedded paratumoral and intratumoral tissues was quantified by PCR. Correlations of PD-L1 mRNA expression with BIM, p53 upregulated modular of apoptosis (PUMA), human epidermal growth factor receptor 2 (HER2), mesenchymal-epithelial transition (MET), EGFR, and vascular endothelial growth factor A (VEGFA) were determined. Eleven of the 33 patients (33.3%) and 14/33 patients (42.4%) expressed intratumoral and paratumoral PD-L1 mRNA, respectively. Patients with intratumoral PD-L1 mRNA expression had significantly higher BIM and lower VEGFA expression compared with paratumoral PD-L1 mRNA patients (P=0.049, P=0.009). PD-L1 mRNA expression was not associated with the expression of PUMA, HER2, EGFR and MET but was positively correlated with BIM expression (r=0.41, P=0.017) and inversely correlated with VEGFA expression (r=-0.33, P=0.043). Patients with intratumoral PD-L1 mRNA expression had significantly shorter median progression-free survival (PFS) after gefitinib therapy compared with no PD-L1 expression (255 vs. 732 days, respectively; P=0.032). Thus, PD-L1 mRNA expression in EGFR-mutant lung adenocarcinoma was associated with BIM and VEGFA mRNA expression and with shorter PFS after gefitinib therapy.

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“…Imatinib, a tyrosine kinase inhibitor of BCR-ABL in CML, can also bind to the BH3 domain of the Bcl-2 family member BIM (also known as BCL2L11), promoting its pro-apoptotic function (Kuroda et al, 2006). AS resulting in the skipping of exon 4 promotes the BIM-γ isoform, which lacks the BH3 domain and therefore mediates resistance to Imatinib (Isobe et al, 2016). Given the prominent role of cell death dysregulation in cancer, further exploration into how AS may drive carcinogenesis and therapeutic resistance in the newly discovered pathways, such as ferroptosis, may provide important insights into novel mechanisms that may offer therapeutically targetable options.…”

Section: Splicing As a Therapeutic Vulnerability In Cancer As-related Therapeutic Efficacy And Patient Prognosismentioning

confidence: 99%

Alternative RNA splicing in tumour heterogeneity, plasticity and therapy

Pöhl

Myant

2022

Disease Models &Amp; Mechanisms

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Alternative splicing is a process by which a single gene is able to encode multiple different protein isoforms. It is regulated by the inclusion or exclusion of introns and exons that are joined in different patterns prior to protein translation, thus enabling transcriptomic and proteomic diversity. It is now widely accepted that alternative splicing is dysregulated across nearly all cancer types. This widespread dysregulation means that nearly all cellular processes are affected – these include processes synonymous with the hallmarks of cancer – evasion of apoptosis, tissue invasion and metastasis, altered cellular metabolism, genome instability and drug resistance. Emerging evidence indicates that the dysregulation of alternative splicing also promotes a permissive environment for increased tumour heterogeneity and cellular plasticity. These are fundamental regulators of a patient's response to therapy. In this Review, we introduce the mechanisms of alternative splicing and the role of aberrant splicing in cancer, with particular focus on newfound evidence of alternative splicing promoting tumour heterogeneity, cellular plasticity and altered metabolism. We discuss recent in vivo models generated to study alternative splicing and the importance of these for understanding complex tumourigenic processes. Finally, we review the effects of alternative splicing on immune evasion, cell death and genome instability, and how targeting these might enhance therapeutic efficacy.

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Association of BIM Deletion Polymorphism and BIM-γ RNA Expression in NSCLC with EGFR Mutation

Cited by 10 publications

References 36 publications

MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer

MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer

PD-L1 mRNA expression in EGFR-mutant lung adenocarcinoma

Alternative RNA splicing in tumour heterogeneity, plasticity and therapy

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