Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.

Radiation therapy plays a major role in the treatment of lung cancer patients. However, cancer cells develop resistance to radiation. Tumor radioresistance is a complex multifactorial mechanism which may be dependent on DNA damage and repair, hypoxic conditions inside tumor microenvironment, and the...

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Autores principales:	Dominic Leiser, Santanu Samanta, John Eley, Josh Strauss, Michael Creed, Tami Kingsbury, Paul N Staats, Binny Bhandary, Minjie Chen, Tijana Dukic, Sanjit Roy, Javed Mahmood, Zeljko Vujaskovic, Hem D Shukla
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/83210a4592d247b58d2161d0d8a8c51a
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spelling	oai:doaj.org-article:83210a4592d247b58d2161d0d8a8c51a2021-12-02T20:07:38ZRole of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.1932-620310.1371/journal.pone.0258951https://doaj.org/article/83210a4592d247b58d2161d0d8a8c51a2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0258951https://doaj.org/toc/1932-6203Radiation therapy plays a major role in the treatment of lung cancer patients. However, cancer cells develop resistance to radiation. Tumor radioresistance is a complex multifactorial mechanism which may be dependent on DNA damage and repair, hypoxic conditions inside tumor microenvironment, and the clonal selection of radioresistant cells from the heterogeneous tumor site, and it is a major cause of treatment failure in non-small cell lung cancer (NSCLC). In the present investigation caveolin-1 (CAV-1) has been observed to be highly expressed in radiation resistant A549 lung cancer cells. CRISPR-Cas9 knockout of CAV-1 reverted the cells to a radio sensitive phenotype. In addition, CAV-1 overexpression in parental A549 cells, led to radiation resistance. Further, gene expression analysis of A549 parental, radiation resistant, and caveolin-1 overexpressed cells, exhibited overexpression of DNA repair genes RAD51B, RAD18, SOX2 cancer stem cell marker, MMPs, mucins and cytoskeleton proteins in resistant and caveolin-1 over expressed A549 cells, as compared to parental A549 cells. Bioinformatic analysis shows upregulation of BRCA1, Nuclear Excision DNA repair, TGFB and JAK/STAT signaling pathways in radioresistant and caveolin-1 overexpressed cells, which may functionally mediate radiation resistance. Immunohistochemistry data demonstrated heterogeneous expression of CAV-1 gene in human lung cancer tissues, which was analogous to its enhanced expression in human lung cancer cell line model and mouse orthotopic xenograft lung cancer model. Also, TCGA PanCancer clinical studies have demonstrated amplification, deletions and missense mutation in CAV-1 gene in lung cancer patients, and that CAV-1 alteration has been linked to poor prognosis, and poor survival in lung cancer patients. Interestingly, we have also optimized ELISA assay to measure caveolin-1 protein in the blood of A549 radiation resistant human xenograft preclinical mouse model and discovered higher level of caveolin-1 (950 pg/ml) in tumor bearing animals treated with radiation, as compared to xenograft with radiosensitive lung cancer cells (450 pg/ml). Thus, we conclude that caveolin-1 is involved in radio-resistance and contributes to tumor aggression, and it has potential to be used as prognostic biomarker for radiation treatment response, and tumor progression for precision medicine in lung cancer patients.Dominic LeiserSantanu SamantaJohn EleyJosh StraussMichael CreedTami KingsburyPaul N StaatsBinny BhandaryMinjie ChenTijana DukicSanjit RoyJaved MahmoodZeljko VujaskovicHem D ShuklaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0258951 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dominic Leiser Santanu Samanta John Eley Josh Strauss Michael Creed Tami Kingsbury Paul N Staats Binny Bhandary Minjie Chen Tijana Dukic Sanjit Roy Javed Mahmood Zeljko Vujaskovic Hem D Shukla Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.
description	Radiation therapy plays a major role in the treatment of lung cancer patients. However, cancer cells develop resistance to radiation. Tumor radioresistance is a complex multifactorial mechanism which may be dependent on DNA damage and repair, hypoxic conditions inside tumor microenvironment, and the clonal selection of radioresistant cells from the heterogeneous tumor site, and it is a major cause of treatment failure in non-small cell lung cancer (NSCLC). In the present investigation caveolin-1 (CAV-1) has been observed to be highly expressed in radiation resistant A549 lung cancer cells. CRISPR-Cas9 knockout of CAV-1 reverted the cells to a radio sensitive phenotype. In addition, CAV-1 overexpression in parental A549 cells, led to radiation resistance. Further, gene expression analysis of A549 parental, radiation resistant, and caveolin-1 overexpressed cells, exhibited overexpression of DNA repair genes RAD51B, RAD18, SOX2 cancer stem cell marker, MMPs, mucins and cytoskeleton proteins in resistant and caveolin-1 over expressed A549 cells, as compared to parental A549 cells. Bioinformatic analysis shows upregulation of BRCA1, Nuclear Excision DNA repair, TGFB and JAK/STAT signaling pathways in radioresistant and caveolin-1 overexpressed cells, which may functionally mediate radiation resistance. Immunohistochemistry data demonstrated heterogeneous expression of CAV-1 gene in human lung cancer tissues, which was analogous to its enhanced expression in human lung cancer cell line model and mouse orthotopic xenograft lung cancer model. Also, TCGA PanCancer clinical studies have demonstrated amplification, deletions and missense mutation in CAV-1 gene in lung cancer patients, and that CAV-1 alteration has been linked to poor prognosis, and poor survival in lung cancer patients. Interestingly, we have also optimized ELISA assay to measure caveolin-1 protein in the blood of A549 radiation resistant human xenograft preclinical mouse model and discovered higher level of caveolin-1 (950 pg/ml) in tumor bearing animals treated with radiation, as compared to xenograft with radiosensitive lung cancer cells (450 pg/ml). Thus, we conclude that caveolin-1 is involved in radio-resistance and contributes to tumor aggression, and it has potential to be used as prognostic biomarker for radiation treatment response, and tumor progression for precision medicine in lung cancer patients.
format	article
author	Dominic Leiser Santanu Samanta John Eley Josh Strauss Michael Creed Tami Kingsbury Paul N Staats Binny Bhandary Minjie Chen Tijana Dukic Sanjit Roy Javed Mahmood Zeljko Vujaskovic Hem D Shukla
author_facet	Dominic Leiser Santanu Samanta John Eley Josh Strauss Michael Creed Tami Kingsbury Paul N Staats Binny Bhandary Minjie Chen Tijana Dukic Sanjit Roy Javed Mahmood Zeljko Vujaskovic Hem D Shukla
author_sort	Dominic Leiser
title	Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.
title_short	Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.
title_full	Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.
title_fullStr	Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.
title_full_unstemmed	Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.
title_sort	role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/83210a4592d247b58d2161d0d8a8c51a
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Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer.

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