Laboratory for Cancer Medicine, University of Western Australia Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Western Australia 6000, Australia.
Br J Cancer. 2013 Aug 20;109(4):1023-30. doi: 10.1038/bjc.2013.431. Epub 2013 Jul 30.
The purpose of this study was to evaluate the expression of Notch-induced transcription factors (NTFs) HEY1, HES1 and SOX9 in colorectal cancer (CRC) patients to determine their clinicopathologic and prognostic significance.
Levels of HEY1, HES1 and SOX9 protein were measured by immunohistochemistry in a nonmalignant and malignant tissue microarray of 441 CRC patients, and the findings correlated with pathologic, molecular and clinical variables.
The NTFs HEY1, HES1 and SOX9 were overexpressed in tumours relative to colonic mucosa (OR=3.44, P<0.0001; OR=7.40, P<0.0001; OR=4.08 P<0.0001, respectively). HEY1 overexpression was a negative prognostic factor for all CRC patients (HR=1.29, P=0.023) and strongly correlated with perineural and vascular invasion and lymph node (LN) metastasis. In 5-fluorouracil (5-FU)-treated patients, the tumour overexpression of SOX9 correlated with markedly poorer survival (HR=8.72, P=0.034), but had no predictive effect in untreated patients (HR=0.70, P=0.29). When HEY1, HES1 and SOX9 expression were combined to predict survival with chemotherapy, in treated patients there was an additive increase in the risk of death with each NTF overexpressed (HR=2.09, P=0.01), but no prognostic import in the untreated patient group (HR=0.74, P=0.19).
The present study is the first to discover that HEY1 overexpression correlates with poorer outcome in CRC, and NTF expression is predictive of CRC patient survival with 5-FU chemotherapy. If confirmed in future studies, testing of NTF expression has the potential to enter routine pathological practice for the selection of patients to undergo chemotherapy alone or in combination with Notch inhibitors.
本研究旨在评估 Notch 诱导转录因子（NTFs）HEY1、HES1 和 SOX9 在结直肠癌（CRC）患者中的表达，以确定其临床病理和预后意义。
采用免疫组织化学法检测 441 例 CRC 患者非恶性和恶性组织微阵列中 HEY1、HES1 和 SOX9 蛋白水平，并将结果与病理、分子和临床变量相关联。
与结肠黏膜相比，肿瘤中 NTFs HEY1、HES1 和 SOX9 表达上调（OR=3.44，P<0.0001；OR=7.40，P<0.0001；OR=4.08，P<0.0001）。HEY1 过表达是所有 CRC 患者的负预后因素（HR=1.29，P=0.023），与神经周围和血管侵犯及淋巴结（LN）转移强烈相关。在接受 5-氟尿嘧啶（5-FU）治疗的患者中，SOX9 的肿瘤过表达与生存率明显降低相关（HR=8.72，P=0.034），但在未接受治疗的患者中无预测作用（HR=0.70，P=0.29）。当结合化疗时，将 HEY1、HES1 和 SOX9 的表达联合预测生存情况，在接受治疗的患者中，每种 NTF 过表达都会增加死亡风险（HR=2.09，P=0.01），但在未接受治疗的患者组中无预后意义（HR=0.74，P=0.19）。
本研究首次发现 HEY1 过表达与 CRC 患者的不良预后相关，NTF 表达可预测 CRC 患者接受 5-FU 化疗的生存情况。如果在未来的研究中得到证实，检测 NTF 表达有可能成为常规病理实践的一部分，以选择单独接受化疗或联合 Notch 抑制剂治疗的患者。
