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Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer

Larsson, Anna H. LU ; Lehn, Sophie LU ; Wangefjord, Sakarias LU ; Karnevi, Emelie LU ; Kuteeva, Eugenia; Sundström, Magnus; Nodin, Björn LU ; Uhlén, Mathias; Eberhard, Jakob LU and Birgisson, Helgi, et al. (2016) In Journal of Translational Medicine 14(1).
Abstract

Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo. Methods: EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot... (More)

Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo. Methods: EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines. Results: High expression of PODXL was significantly associated with high EGFR expression (p <0.001) in all three cohorts, and with BRAF mutation (p <0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p <0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27-2.46), cohort 2 (HR 1.58; 95 % CI 1.05-2.38) and cohort 3 (HR 1.83; 95 % CI 1.19-2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18-3.28 and HR 3.56; 95 % CI 1.75-7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines. Conclusions: The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.

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published
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keywords
BRAF, Colorectal cancer, EGFR, Podocalyxin-like, Prognosis
in
Journal of Translational Medicine
volume
14
issue
1
publisher
BioMed Central
external identifiers
  • Scopus:84968875309
ISSN
1479-5876
DOI
10.1186/s12967-016-0882-0
language
English
LU publication?
yes
id
094ac751-07cb-4757-8d19-da39241919c0
date added to LUP
2016-06-28 16:45:57
date last changed
2016-10-24 11:21:03
@misc{094ac751-07cb-4757-8d19-da39241919c0,
  abstract     = {<p>Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo. Methods: EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines. Results: High expression of PODXL was significantly associated with high EGFR expression (p &lt;0.001) in all three cohorts, and with BRAF mutation (p &lt;0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p &lt;0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27-2.46), cohort 2 (HR 1.58; 95 % CI 1.05-2.38) and cohort 3 (HR 1.83; 95 % CI 1.19-2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18-3.28 and HR 3.56; 95 % CI 1.75-7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines. Conclusions: The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.</p>},
  author       = {Larsson, Anna H. and Lehn, Sophie and Wangefjord, Sakarias and Karnevi, Emelie and Kuteeva, Eugenia and Sundström, Magnus and Nodin, Björn and Uhlén, Mathias and Eberhard, Jakob and Birgisson, Helgi and Jirström, Karin},
  issn         = {1479-5876},
  keyword      = {BRAF,Colorectal cancer,EGFR,Podocalyxin-like,Prognosis},
  language     = {eng},
  month        = {05},
  number       = {1},
  publisher    = {ARRAY(0x9143e40)},
  series       = {Journal of Translational Medicine},
  title        = {Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer},
  url          = {http://dx.doi.org/10.1186/s12967-016-0882-0},
  volume       = {14},
  year         = {2016},
}