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Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer.

ABSTRACT: The acquisition of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is one of the major problems in the pharmacotherapy against non-small cell lung cancers; however, molecular mechanisms remain to be fully elucidated. Here, using a newly-established erlotinib-resistant cell line, PC9/ER, from PC9 lung cancer cells, we demonstrated that the expression of translation-related molecules, including eukaryotic translation initiation factor 3 subunit C (eIF3c), was upregulated in PC9/ER cells by proteome analyses. Immunoblot analyses confirmed that eIF3c protein increased in PC9/ER cells, compared with PC9 cells. Importantly, the knockdown of eIF3c with its siRNAs enhanced the drug sensitivity in PC9/ER cells. Mechanistically, we found that LC3B-II was upregulated in PC9/ER cells, while downregulated by the knockdown of eIF3c. Consistently, the overexpression of eIF3c increased the number of autophagosomes, proposing the causality between eIF3c expression and autophagy. Moreover, chloroquine, an autophagy inhibitor, restored the sensitivity to erlotinib. Finally, immunohistochemical analyses of biopsy samples showed that the frequency of eIF3c-positive cases was higher in the patients with EGFR-TKI resistance than those prior to EGFR-TKI treatment. Moreover, the eIF3c-positive cases exhibited poor prognosis in EGFR-TKI treatment. Collectively, the upregulation of eIF3c could impair the sensitivity to EGFR-TKI as a novel mechanism of the drug resistance.

SUBMITTER: Shintani T

PROVIDER: S-EPMC6331022 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Project description:Liver cancer is one of the major malignancies with the worst prognosis among all solid tumor types. It is therefore ponderable to explore prognostic biomarkers and therapeutic targets for liver cancer. Eukaryotic translation initiation factor 3 subunit B (EIF3B) is closely linked to the transcription initiation of cancer-associated genes. In the present study, EIF3B was indicated to be a potential prognostic biomarker of liver cancer. The mRNA expression level of EIF3B in liver cancer was assessed by analyzing the Cancer Genome Atlas dataset. ?2 and Fisher's exact tests were used to assess the association of EIF3B expression with clinical parameters. Receiver-operating characteristic curve analysis was used for evaluating the diagnostic value of EIF3B. Overall and relapse-free survival were assessed using Kaplan-Meier curves to determine the association between EIF3B expression and survival. Univariate and multivariate Cox regression analysis were performed to identify the factors affecting overall/relapse-free survival. Gene set enrichment analysis (GSEA) was used to identify signaling pathways associated with EIF3B in liver cancer. It was revealed that EIF3B was highly expressed in liver cancer tissues and it had a promising diagnostic ability. Furthermore, the survival analysis indicated that patients with high EIF3B expression generally had shorter overall as well as relapse-free survival. Univariate and multivariate Cox analysis suggested that high EIF3B mRNA expression may serve as an independent biomarker for the prognostication of patients with liver cancer. GSEA suggested that MYC-V1 (HALLMARK_MYC_TARGETS_V1 geneset; P=0.009), MYC-V2 (HALLMARK_MYC_TARGETS_V2 geneset; P=0.004) and DNA repair pathways (HALLMARK_DNA_REPAIR geneset; P<0.001) were differentially enriched in high EIF3B expression and low EIF3B expression groups. In conclusion, high EIF3B expression was indicated to be an independent prognostic biomarker for patients with liver cancer.

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Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer.

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