Zhang Yuting, Xia Pei, Zhang Wenhui, Yan Min, Xiong Xiujuan, Yu Weiwei, Song Enlin
Department of Pathology, Basic Medical College of Nanchang University, Nanchang 330006, China.
Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Hum Pathol. 2017 Jul;65:113-122. doi: 10.1016/j.humpath.2017.04.021. Epub 2017 May 13.
Net1, a guanine nucleotide exchange factor, is implicated in cancer cell invasion through activation of RhoA. However, there is still no report on the association between Net1 and cancer angiogenesis. The current study was designed to explore the role of Net1 in the angiogenesis of cervical squamous cell carcinoma (CSCC) and further observe the effects of Net1 short interfering RNA (siRNA) on the tumor growth. Net1 was overexpressed in CSCC samples (n=80), correlated with the cancer microvessel density (r=0.223, P=.026), and related to aggressive clinical behaviors, including depth of cervical wall invasion (P=.041), parametrial involvement (P=.037), lymph node metastasis (P=.021), and vascular invasion (P=.018). Human umbilical vein endothelial cells treated with supernatant of SiHa cells with Net1 siRNA showed significantly decreased proliferation (0.75±0.038 versus 1.0±0.015, P<.001), migration (39.3±6.5 versus 66.0±10.1, P=.019), and tube formation (13.5±3.05 versus 21.7±2.89, P=.030) compared with those human umbilical vein endothelial cells treated with normal SiHa cells supernatant. Net1 siRNA of SiHa decreased VEGF expression level (0.60±0.026 versus 0.78±0.031, P=.02). Furthermore, Net1 siRNA significantly reduced tumor growth (P=.037) and microvessel density (5.8±0.43 versus 3.4±0.55, P=.012) and decreased the expression level of VEGF (0.31±0.002 versus 0.39±0.004, P<.001) in CSCC. In conclusion, Net1 promotes the angiogenesis of CSCC, and siRNA targeting Net1 can effectively reduce the angiogenesis and thus inhibit the tumor growth of CSCC in vivo.
鸟嘌呤核苷酸交换因子Net1通过激活RhoA参与癌细胞侵袭。然而，关于Net1与癌症血管生成之间的关联尚无报道。本研究旨在探讨Net1在宫颈鳞状细胞癌（CSCC）血管生成中的作用，并进一步观察Net1小干扰RNA（siRNA）对肿瘤生长的影响。Net1在CSCC样本（n = 80）中过表达，与癌组织微血管密度相关（r = 0.223，P = 0.026），并与侵袭性临床行为有关，包括宫颈壁浸润深度（P = 0.041）、宫旁组织受累（P = 0.037）、淋巴结转移（P = 0.021）和血管侵犯（P = 0.018）。与用正常SiHa细胞上清液处理的人脐静脉内皮细胞相比，用Net1 siRNA处理的SiHa细胞上清液处理的人脐静脉内皮细胞显示增殖显著降低（0.75±0.038对1.0±0.015，P<0.001）、迁移能力降低（39.3±6.5对66.0±10.1，P = 0.019）和成管能力降低（13.5±3.05对21.7±2.89，P = 0.030）。SiHa细胞的Net1 siRNA降低了VEGF表达水平（0.60±0.026对0.78±0.031，P = 0.02）。此外，Net1 siRNA显著抑制了CSCC的肿瘤生长（P = 0.037）和微血管密度（5.8±0.43对3.4±0.55，P = 0.012），并降低了VEGF的表达水平（0.31±0.002对0.39±0.004，P<0.001）。总之，Net1促进CSCC的血管生成，靶向Net1的siRNA可有效减少血管生成，从而在体内抑制CSCC的肿瘤生长。
