Cong Zhuangzhuang, Wu Haiwei, Guo Zhong, Qin Tao, Xu Yang, Jing Hua, Wang Yanqing, Shen Yi
1 Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
2 Department of Cardiothoracic Surgery, Jinling Hospital, School of Medicine, Southern Medical University, Guangzhou, China.
Tumour Biol. 2017 Jun;39(6):1010428317708698. doi: 10.1177/1010428317708698.
C-X-C chemokine receptor 4 and Notch1 have been shown to play oncogenic role individually. This study aimed to determine the combinatorial role of C-X-C chemokine receptor 4 and Notch1 in lung adenocarcinoma. Expression of C-X-C chemokine receptor 4 and Notch1 was detected in resected tumor samples from 185 patients with lung adenocarcinoma at stage I-IIIa by immunohistochemistry. Correlations of their immunoscores with clinicopathological characteristics and disease-specific survival were retrospectively investigated. A three-dimensional capillary-like sprouting model was established to assess the effects of C-X-C chemokine receptor 4 and Notch1 on angiogenesis in vitro. The results revealed that expression of C-X-C chemokine receptor 4 and Notch1 was elevated in lung adenocarcinoma tissues. The high co-expression of C-X-C chemokine receptor 4 and Notch1 was significantly correlated with tumor size, tumor status, nodal status, tumor stage, and lymphovascular invasion, as well as decreased disease-specific survival. Multivariate analysis showed that lymphovascular invasion (hazard ratio: 0.205, 95% confidence interval: 0.086-0.491, p < 0.0001) and co-expression of C-X-C chemokine receptor 4 and Notch1 (hazard ratio: 0.293, 95% confidence interval: 0.168-0.510, p < 0.0001) were independent indicators of poor prognosis in lung adenocarcinoma. Furthermore, Notch1 enhanced the effects of C-X-C chemokine receptor 4 to promote angiogenesis by regulating Flt1 and Flt4 in vitro. In conclusion, co-expression of C-X-C chemokine receptor 4 and Notch1 is associated with tumor progression and lymphovascular invasion and is an independent indicator of poor survival in lung adenocarcinoma. In lung adenocarcinoma patients with high C-X-C chemokine receptor 4 and Notch1 expression, simultaneous inhibition of both factors might be an effective treatment strategy.
C-X-C趋化因子受体4和Notch1已被证明各自发挥致癌作用。本研究旨在确定C-X-C趋化因子受体4和Notch1在肺腺癌中的联合作用。通过免疫组织化学检测了185例I-IIIa期肺腺癌患者切除的肿瘤样本中C-X-C趋化因子受体4和Notch1的表达。回顾性研究了它们的免疫评分与临床病理特征及疾病特异性生存的相关性。建立了三维毛细血管样芽生模型以评估C-X-C趋化因子受体4和Notch1对体外血管生成的影响。结果显示，肺腺癌组织中C-X-C趋化因子受体4和Notch1的表达升高。C-X-C趋化因子受体4和Notch1的高共表达与肿瘤大小、肿瘤状态、淋巴结状态、肿瘤分期和淋巴管侵犯显著相关，且疾病特异性生存降低。多变量分析表明，淋巴管侵犯（风险比：0.205，95%置信区间：0.086-0.491，p<0.0001）和C-X-C趋化因子受体4与Notch1的共表达（风险比：0.293，95%置信区间：0.168-0.510，p<0.0001）是肺腺癌预后不良的独立指标。此外，Notch1通过在体外调节Flt1和Flt4增强了C-X-C趋化因子受体4促进血管生成的作用。总之，C-X-C趋化因子受体4和Notch1的共表达与肿瘤进展和淋巴管侵犯相关，是肺腺癌生存不良的独立指标。在C-X-C趋化因子受体4和Notch1表达高的肺腺癌患者中，同时抑制这两种因子可能是一种有效的治疗策略。
