Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer.
Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer.
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DOI：
10.1186/s12967-016-0882-0
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发表时间：
2016-05-10
影响因子：
7.4
通讯作者：
Jirström K
中科院分区：
文献类型：
--
作者：
Larsson AH;Lehn S;Wangefjord S;Karnevi E;Kuteeva E;Sundström M;Nodin B;Uhlén M;Eberhard J;Birgisson H;Jirström K
Podocalyxin-like 1 （PODXL）是一种抗粘附跨膜蛋白，已被证明是结直肠癌（CRC）预后不良的独立因素。编码PODXL的基因位于7号染色体上，该染色体也含有表皮生长因子受体（EGFR）的基因。本研究的目的是在体外和体内研究CRC中PODXL和EGFR表达之间的关系。在三个独立患者队列的肿瘤中分析EGFR表达；队列1 (n = 533)，队列2 （n = 259）和队列3 (n = 310)，先前分析了PODXL的免疫组织化学表达以及KRAS和BRAF突变（队列1和3）。western blot检测6种不同结直肠癌细胞系中EGFR和PODXL的表达水平。在所有三个队列中，PODXL的高表达与EGFR的高表达显著相关（p < 0.001），在队列1和3中与BRAF突变显著相关（p < 0.001）。在队列1中，EGFR高表达与BRAF突变相关（p < 0.001）。高EGFR表达与不良临床病理因素相关，并独立预测队列1 （HR 1.77; 95% CI 1.27-2.46）、队列2 （HR 1.58; 95% CI 1.05-2.38）和队列3 （HR 1.83; 95% CI 1.19-2.81）的5年总生存率（OS）降低。在队列1和队列3中，EGFR和PODXL均高表达的肿瘤患者5年内死亡风险最高（HR 1.97; 95% CI 1.18-3.28; HR 3.56; 95% CI 1.75-7.22）。Western blot分析显示，在所有6个CRC细胞系中，PODXL和EGFR的表达一致。本研究结果表明，EGFR高表达是结直肠癌预后不良的独立因素。此外，最近提出的候选生物标志物PODXL的表达与体内和体外CRC中EGFR的表达以及体内BRAF突变之间存在密切联系。PODXL和EGFR的高表达也可能对生存产生协同不利影响。这些发现表明，在结直肠癌中，PODXL、EGFR和BRAF之间存在潜在的功能联系，它们都起源于7号染色体，这可能与临床环境高度相关，因此值得未来深入研究。本文的在线版本（doi:10.1186/s12967-016-0882-0）包含补充材料，可供授权用户使用。
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. 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. 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. 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. The online version of this article (doi:10.1186/s12967-016-0882-0) contains supplementary material, which is available to authorized users.