Lin Ching-Yih, Lee Ying-En, Tian Yu-Feng, Sun Ding-Ping, Sheu Ming-Jen, Lin Chen-Yi, Li Chien-Feng, Lee Sung-Wei, Lin Li-Ching, Chang I-Wei, Wang Chieh-Tien, He Hong-Lin
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan.
Department of Leisure, Recreation, and Tourism Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
J Cancer. 2017 Apr 9;8(6):1089-1096. doi: 10.7150/jca.17471. eCollection 2017.
Numerous transmembrane receptor tyrosine kinase pathways have been found to play an important role in tumor progression in some cancers. This study was aimed to evaluate the clinical impact of Eph receptor A4 (EphA4) in patients with rectal cancer treated with neoadjuvant concurrent chemoradiotherapy (CCRT) combined with mesorectal excision, with special emphasis on tumor regression. Analysis of the publicly available expression profiling dataset of rectal cancer disclosed that was the top-ranking, significantly upregulated, transmembrane receptor tyrosine kinase pathway-associated gene in the non-responders to CCRT, compared with the responders. Immunohistochemical study was conducted to assess the EphA4 expression in pre-treatment biopsy specimens from 172 rectal cancer patients without distant metastasis. The relationships between EphA4 expression and various clinicopathological factors or survival were statistically analyzed. EphA4 expression was significantly associated with vascular invasion (=0.015), post-treatment depth of tumor invasion (=0.006), pre-treatment and post-treatment lymph node metastasis (=0.004 and =0.011, respectively). More importantly, high EphA4 expression was significantly predictive for lesser degree of tumor regression after CCRT (=0.031). At univariate analysis, high EphA4 expression was a negative prognosticator for disease-specific survival (=0.0009) and metastasis-free survival (=0.0001). At multivariate analysis, high expression of EphA4 still served as an independent adverse prognostic factor for disease-specific survival (HR, 2.528; 95% CI, 1.131-5.651; =0.024) and metastasis-free survival (HR, 3.908; 95% CI, 1.590-9.601; =0.003). High expression of EphA4 predicted lesser degree of tumor regression after CCRT and served as an independent negative prognostic factor in patients with rectal cancer.
已发现众多跨膜受体酪氨酸激酶通路在某些癌症的肿瘤进展中发挥重要作用。本研究旨在评估Eph受体A4（EphA4）在接受新辅助同步放化疗（CCRT）联合直肠系膜切除术治疗的直肠癌患者中的临床影响，特别关注肿瘤退缩情况。对公开可得的直肠癌表达谱数据集分析显示，与反应者相比，EphA4是CCRT无反应者中排名最靠前、显著上调的跨膜受体酪氨酸激酶通路相关基因。进行免疫组织化学研究以评估172例无远处转移的直肠癌患者治疗前活检标本中EphA4的表达情况。对EphA4表达与各种临床病理因素或生存率之间的关系进行了统计学分析。EphA4表达与血管侵犯显著相关（P = 0.015）、治疗后肿瘤侵犯深度显著相关（P = 0.006）、治疗前和治疗后淋巴结转移显著相关（分别为P = 0.004和P = 0.011）。更重要的是，EphA4高表达显著预示CCRT后肿瘤退缩程度较小（P = 0.031）。单因素分析时，EphA4高表达是疾病特异性生存（P = 0.0009）和无转移生存（P = 0.0001）的不良预后因素。多因素分析时，EphA4高表达仍然是疾病特异性生存（HR，2.528；95%CI，1.131 - 5.651；P = 0.024）和无转移生存（HR，3.908；95%CI，1.590 - 9.601；P = 0.003）的独立不良预后因素。EphA4高表达预示CCRT后肿瘤退缩程度较小，并在直肠癌患者中作为独立的不良预后因素。
