p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy

p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statisti...

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Autores principales:	Jörg Kumbrink, Pan Li, Agnes Pók-Udvari, Frederick Klauschen, Thomas Kirchner, Andreas Jung
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	p130Cas BCAR1 EREG colorectal cancer therapy resistance FOLFIRI Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/695e70acc2594d1bafe0acdcd21486e1
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spelling	oai:doaj.org-article:695e70acc2594d1bafe0acdcd21486e12021-11-25T17:55:43Zp130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy10.3390/ijms2222123641422-00671661-6596https://doaj.org/article/695e70acc2594d1bafe0acdcd21486e12021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12364https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statistical analyses of clinical data sets. p130Cas expression was associated with poor survival in the cancer genome atlas (TCGA) data set. Knockdown/reconstitution experiments showed that p130Cas drives migration but, unexpectedly, inhibits proliferation in CRC cells. TCGA data analyses identified the growth factor epiregulin (EREG) as inversely correlated with p130Cas. p130Cas knockdown and simultaneous EREG treatment further enhanced proliferation. RNA interference and EREG treatment experiments suggested that p130Cas/EREG limit each other’s expression/activity. Inverse p130Cas/EREG Spearman correlations were prominent in right-sided and earlier stage CRC. p130Cas was inducible by 5-fluorouracil (5-FU) and FOLFIRI (folinic acid, 5-FU, irinotecan), and p130Cas and EREG were upregulated in distant metastases (GSE121418). Positive p130Cas/EREG correlations were observed in metastases, preferentially in post-treatment samples (especially pulmonary metastases). p130Cas knockdown sensitized CRC cells to FOLFIRI independent of EREG treatment. RNA sequencing and gene ontology analyses revealed that p130Cas is involved in cytochrome P450 drug metabolism and epithelial-mesenchymal transition. p130Cas expression was associated with poor survival in right-sided, stage I/II, MSS (microsatellite stable), or BRAF-mutated CRC. In summary, p130Cas represents a prognostic factor and potential therapeutic target in CRC.Jörg KumbrinkPan LiAgnes Pók-UdvariFrederick KlauschenThomas KirchnerAndreas JungMDPI AGarticlep130CasBCAR1EREGcolorectal cancertherapy resistanceFOLFIRIBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12364, p 12364 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	p130Cas BCAR1 EREG colorectal cancer therapy resistance FOLFIRI Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	p130Cas BCAR1 EREG colorectal cancer therapy resistance FOLFIRI Biology (General) QH301-705.5 Chemistry QD1-999 Jörg Kumbrink Pan Li Agnes Pók-Udvari Frederick Klauschen Thomas Kirchner Andreas Jung p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy
description	p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statistical analyses of clinical data sets. p130Cas expression was associated with poor survival in the cancer genome atlas (TCGA) data set. Knockdown/reconstitution experiments showed that p130Cas drives migration but, unexpectedly, inhibits proliferation in CRC cells. TCGA data analyses identified the growth factor epiregulin (EREG) as inversely correlated with p130Cas. p130Cas knockdown and simultaneous EREG treatment further enhanced proliferation. RNA interference and EREG treatment experiments suggested that p130Cas/EREG limit each other’s expression/activity. Inverse p130Cas/EREG Spearman correlations were prominent in right-sided and earlier stage CRC. p130Cas was inducible by 5-fluorouracil (5-FU) and FOLFIRI (folinic acid, 5-FU, irinotecan), and p130Cas and EREG were upregulated in distant metastases (GSE121418). Positive p130Cas/EREG correlations were observed in metastases, preferentially in post-treatment samples (especially pulmonary metastases). p130Cas knockdown sensitized CRC cells to FOLFIRI independent of EREG treatment. RNA sequencing and gene ontology analyses revealed that p130Cas is involved in cytochrome P450 drug metabolism and epithelial-mesenchymal transition. p130Cas expression was associated with poor survival in right-sided, stage I/II, MSS (microsatellite stable), or BRAF-mutated CRC. In summary, p130Cas represents a prognostic factor and potential therapeutic target in CRC.
format	article
author	Jörg Kumbrink Pan Li Agnes Pók-Udvari Frederick Klauschen Thomas Kirchner Andreas Jung
author_facet	Jörg Kumbrink Pan Li Agnes Pók-Udvari Frederick Klauschen Thomas Kirchner Andreas Jung
author_sort	Jörg Kumbrink
title	p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy
title_short	p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy
title_full	p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy
title_fullStr	p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy
title_full_unstemmed	p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy
title_sort	p130cas is correlated with ereg expression and a prognostic factor depending on colorectal cancer stage and localization reducing folfiri efficacy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/695e70acc2594d1bafe0acdcd21486e1
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p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy

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