Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma

Frontiers in Oncology

Oncology

Santiago Avila-Rios¹  Maribel Soto-Nava¹  Jose S. Lopez-Gonzalez²  Miriam Galicia-Velasco²  Dolores Aguilar-Cazares²  Mario Perez-Medina³  Rodolfo Chavez-Dominguez⁴  Jesus J. Benito-Lopez⁴  Lorenzo Islas-Vazquez⁵  Alfonso Mendez-Tenorio⁶ 

[1] Centro de Investigacion en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Ciudad de Mexico, Mexico;Departamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, Mexico;Departamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, Mexico;Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico;Departamento de Enfermedades Cronico-Degenerativas, Laboratorio de Cancer Pulmonar, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Ciudad de Mexico, Mexico;Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico;Departamento de Inmunologia y Unidad de Investigacion, Instituto de Oftalmologia “Conde de Valenciana”, Ciudad de Mexico, Mexico;Laboratorio de Biotecnologia y Bioinformatica Genomica, Departamento de Bioquimica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico;

关键词: lung cancer;    non-small cell lung carcinoma;    lung adenocarcinoma;    cisplatin;    chemotherapy resistance;    intrinsic resistance;    drug-tolerant persister cells;    SOCS1;   

DOI  :  10.3389/fonc.2023.1208403

 received in 2023-04-19, accepted in 2023-09-22,  发布年份 2023

来源: Frontiers

【 摘 要 】

Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.

【 授权许可】

Unknown   
Copyright © 2023 Chavez-Dominguez, Aguilar-Cazares, Perez-Medina, Avila-Rios, Soto-Nava, Mendez-Tenorio, Islas-Vazquez, Benito-Lopez, Galicia-Velasco and Lopez-Gonzalez