KFU. Card publication. NEDD9 Restrains dsDNA Damage Response during Non-Small Cell Lung Cancer (NSCLC) Progression

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FEDERAL UNIVERSITY

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NEDD9 RESTRAINS DSDNA DAMAGE RESPONSE DURING NON-SMALL CELL LUNG CANCER (NSCLC) PROGRESSION

Form of presentation

Articles in international journals and collections

Year of publication

2022

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Authors, employees of KFU

Deneka Aleksandr Yaroslavovich, author

Tikhomirova Mariya Vladimirovna, author

Topchu Yuliya Alekseevna, author

Other authors

Barmin Vitaliy , author

Ratner Ekaterina Yurevna, author

Sabirov Alnksey , author

Authors, postgraduates KFU

Mazitova Aleksandra Maratovna, postgraduate kfu

Bibliographic description in the original language

Tikhomirova M. NEDD9 restrains dsDNA damage eesponse during non-small cell lung cancer (NSCLC) progression / M. Tikhomirova, I. Topchu, A. Mazitova, V. Barmin, E. Ratner, A. Sabirov, Z. Abramova, A. Y. Deneka // Cancers (Basel).- 2022.- V.14, N.10,-:2517 doi: 10.3390/cancers14102517

Annotation

DNA damaging modalities are the backbone of treatments for non-small cell lung cancer (NSCLC). Alterations in DNA damage response (DDR) in tumor cells commonly contribute to emerging resistance to platinating agents, other targeted therapies, and radiation. The goal of this study is to identify the previously unreported role of NEDD9 scaffolding protein in controlling DDR processes and sensitivity to DNA damaging therapies. Using a siRNA-mediated approach to deplete NEDD9 in a group of human and murine KRAS/TP53-mutant NSCLC cell lines, coupled with a set of cell viability and clonogenic assays, flow cytometry analysis, and Western blotting, we evaluated the effects of NEDD9 silencing on cellular proliferation, DDR and epithelial-to-mesenchymal transition (EMT) signaling, cell cycle, and sensitivity to cisplatin and UV irradiation. Using publicly available NSCLC datasets (TCGA) and an independent cohort of primary NSCLC tumors, subsequent in silico and immunohistochemical (IHC) analyses were performed to assess relevant changes in NEDD9 RNA and protein expression across different stages of NSCLC. The results of our study demonstrate that NEDD9 depletion is associated with the increased tumorigenic capacity of NSCLC cells. These phenotypes were accompanied by significantly upregulated ATM-CHK2 signaling, shifting towards a more mesenchymal phenotype in NEDD9 depleted cells and elevated sensitivity to UV-irradiation. IHC analyses revealed an association between reduced NEDD9 protein expression and a decrease in overall (OS) and progression-free survival (PFS) of the NSCLC patients. These data, for the first time, identified NEDD9 as a negative regulator of ATM kinase activity and related DDR signaling in numerous KRAS/TP53 mutated NSCLC, with its effects on the regulation of DDR-dependent EMT signaling, sensitivity to DNA damaging modalities in tumor cells, and the survival of the patients.

Keywords

HEF1, DNA damage response,CHK2, ERCC4, non-small cell lung cancer, overall survival

The name of the journal

Cancers

URL

https://pubmed.ncbi.nlm.nih.gov/35626121/

Please use this ID to quote from or refer to the card

https://repository.kpfu.ru/eng/?p_id=267293&p_lang=2

Resource files

File name	Size (MB)	Format
Statya_M_Tikhomirovoj_cancers.pdf	3,07	pdf	show / download

Full metadata record

Field DC	Value	Language
dc.contributor.author	Deneka Aleksandr Yaroslavovich	ru_RU
dc.contributor.author	Tikhomirova Mariya Vladimirovna	ru_RU
dc.contributor.author	Topchu Yuliya Alekseevna	ru_RU
dc.contributor.author	Barmin Vitaliy	ru_RU
dc.contributor.author	Ratner Ekaterina Yurevna	ru_RU
dc.contributor.author	Sabirov Alnksey	ru_RU
dc.contributor.author	Mazitova Aleksandra Maratovna	ru_RU
dc.date.accessioned	2022-01-01T00:00:00Z	ru_RU
dc.date.available	2022-01-01T00:00:00Z	ru_RU
dc.date.issued	2022	ru_RU
dc.identifier.citation	Tikhomirova M. NEDD9 restrains dsDNA damage eesponse during non-small cell lung cancer (NSCLC) progression / M. Tikhomirova, I. Topchu, A. Mazitova, V. Barmin, E. Ratner, A. Sabirov, Z. Abramova, A. Y. Deneka // Cancers (Basel).- 2022.- V.14, N.10,-:2517 doi: 10.3390/cancers14102517	ru_RU
dc.identifier.uri	https://repository.kpfu.ru/eng/?p_id=267293&p_lang=2	ru_RU
dc.description.abstract	Cancers	ru_RU
dc.description.abstract	DNA damaging modalities are the backbone of treatments for non-small cell lung cancer (NSCLC). Alterations in DNA damage response (DDR) in tumor cells commonly contribute to emerging resistance to platinating agents, other targeted therapies, and radiation. The goal of this study is to identify the previously unreported role of NEDD9 scaffolding protein in controlling DDR processes and sensitivity to DNA damaging therapies. Using a siRNA-mediated approach to deplete NEDD9 in a group of human and murine KRAS/TP53-mutant NSCLC cell lines, coupled with a set of cell viability and clonogenic assays, flow cytometry analysis, and Western blotting, we evaluated the effects of NEDD9 silencing on cellular proliferation, DDR and epithelial-to-mesenchymal transition (EMT) signaling, cell cycle, and sensitivity to cisplatin and UV irradiation. Using publicly available NSCLC datasets (TCGA) and an independent cohort of primary NSCLC tumors, subsequent in silico and immunohistochemical (IHC) analyses were performed to assess relevant changes in NEDD9 RNA and protein expression across different stages of NSCLC. The results of our study demonstrate that NEDD9 depletion is associated with the increased tumorigenic capacity of NSCLC cells. These phenotypes were accompanied by significantly upregulated ATM-CHK2 signaling, shifting towards a more mesenchymal phenotype in NEDD9 depleted cells and elevated sensitivity to UV-irradiation. IHC analyses revealed an association between reduced NEDD9 protein expression and a decrease in overall (OS) and progression-free survival (PFS) of the NSCLC patients. These data, for the first time, identified NEDD9 as a negative regulator of ATM kinase activity and related DDR signaling in numerous KRAS/TP53 mutated NSCLC, with its effects on the regulation of DDR-dependent EMT signaling, sensitivity to DNA damaging modalities in tumor cells, and the survival of the patients.	ru_RU
dc.language.iso	ru	ru_RU
dc.subject	HEF1	ru_RU
dc.subject	DNA damage response	ru_RU
dc.subject	CHK2	ru_RU
dc.subject	ERCC4	ru_RU
dc.subject	non-small cell lung cancer	ru_RU
dc.subject	overall survival	ru_RU
dc.title	NEDD9 Restrains dsDNA Damage Response during Non-Small Cell Lung Cancer (NSCLC) Progression	ru_RU
dc.type	Articles in international journals and collections	ru_RU