Department of Medical Research, Chi Mei Hospital Chiali, 606, Shin-Hwa Road, Chiali District, Tainan 722, Taiwan.
Mol Cancer Res. 2012 Jun;10(6):750-9. doi: 10.1158/1541-7786.MCR-11-0598-T. Epub 2012 Apr 27.
Although gastric cancer is one of the most common malignancies worldwide, little is known on the molecular process of its development and progression. This study investigates the involvement of guanine nucleotide exchange factor Vav3 in tumor progression and in the prognosis of human gastric cancer. The two patient cohorts in this study consisted of 167 gastric cancer cases from 1997 through 2001, documenting pathologic and clinical factors, as well as the clinical outcomes. Immunohistochemistry, reverse transcription PCR, immunoblotting, and immunofluorescence were used to examine Vav3 expression in tumor and nontumor pairs of gastric tissues and gastric cell lines. Small hairpin RNA (shRNA) technology was used to study the effects of Vav3 knockdown on the growth and spread of gastric cancer cells. Finally, xenograph proliferation was used to study the tumor growth. Overexpression of Vav3 was associated with the depth of invasion (P = 0.0004), nodal status (P = 0.0260), distant metastasis (P = 0.0003), stage (P = 0.0002), and vascular invasion (P = 0.0286); and correlated with poor disease-free survival (P < 0.0001). Multivariate Cox regression analysis shows that overexpression of Vav3 is an independent prognostic marker for gastric cancer (P = 0.033). Disrupting the expression of Vav3 using shRNA technology inhibited gastric cancer cell growth, spread, and xenograph proliferation. This study suggests that overexpression of Vav3 can be a useful marker for predicting the outcome of patients with gastric cancer and that Vav3 targeting can represent a potential modality for treating gastric cancer.
尽管胃癌是全球最常见的恶性肿瘤之一，但对于其发展和进展的分子过程知之甚少。本研究探讨了鸟嘌呤核苷酸交换因子 Vav3 在肿瘤进展和人类胃癌预后中的作用。本研究的两个患者队列包括 1997 年至 2001 年间的 167 例胃癌病例，记录了病理和临床因素以及临床结果。免疫组织化学、逆转录 PCR、免疫印迹和免疫荧光用于检测肿瘤和非肿瘤配对胃组织和胃细胞系中 Vav3 的表达。小发夹 RNA (shRNA) 技术用于研究 Vav3 敲低对胃癌细胞生长和扩散的影响。最后，异种移植增殖用于研究肿瘤生长。Vav3 的过表达与浸润深度（P = 0.0004）、淋巴结状态（P = 0.0260）、远处转移（P = 0.0003）、分期（P = 0.0002）和血管侵犯（P = 0.0286）相关；与无病生存不良相关（P < 0.0001）。多变量 Cox 回归分析显示，Vav3 的过表达是胃癌的独立预后标志物（P = 0.033）。使用 shRNA 技术破坏 Vav3 的表达抑制了胃癌细胞的生长、扩散和异种移植增殖。本研究表明，Vav3 的过表达可以作为预测胃癌患者预后的有用标志物，Vav3 靶向可能代表治疗胃癌的一种潜在方式。
