Effect of Tie-2-siRNA Expression Vector on Human Hepatoma Transplanted Subcutaneously in Nude Mice_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

DENG Wei ¹ , LIANG Lijian ²

Department of Hepatobiliary, The First Affiliated Hospital， Guangxi College of Chinese Medicine， Nanning 530023， China;

Corresponding author：

Keywords：

Tie-2-small interference RNA; Liver cancer; Gene therapy

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Objective 　To explore the effect of Tie-2 small interference RNA (siRNA) treatment in human hepatoma transplanted subcutaneously in nude mice.
Methods 　Tumor cells were implanted in the hind flank of male nude mice of 6 weeks. Tumor-bearing mice were divided into two groups （gene therapy group and control group） and injected intra-tumorally with Tie-2-siRNA/Lipofectamine and saline/Lipofectamine respectively. The tumor volume and weight, serum AFP and microvessel density (MVD) and the histological change of the tumor were tested after gene therapy.
Results 　The growth inhibitory rates in gene therapy group were 26.94%， 53.01% and 68.91% on day 4， 7 and 10 after gene therapy respectively. The tumor volumes of gene therapy group (118.47, 111.57 and 104.59 mm3) were smaller than those of the control group (162.17, 237.46 and 336.41 mm3) respectively (P＜0.01), and the weight of tumor in gene therapy group was lighter than that of the control group 〔(0.89±0.09) g vs (1.24±0.03), P＜0.01〕. The AFP value in gene therapy group was obviously lower than that of the control group 〔(107.66±24.13) ng/ml vs (266.08±50.96) ng/ml, P＜0.01〕. There was significant diference of MVD between the gene therapy group (34.63±4.07) and the control group (81.01±9.44) with the method of immunohistochemitry (P＜0.01). Histopathology in the control group showed that the tumor volumes were bigger, and a high atypic of tumor cells were seen. The main pathological changes in tumor tissue of gene therapy group were necrosis, there were massive necrosis. The apoptosis cells were seen in the both of necrosis and non-necrosis areas in only 2 mice of gene therapy group.
Conclusion 　Tie-2-siRNA inhibits the tumor growth and tumor angiogenesis， and is a possible new approach for liver neoplasm gene therapy.

Citation： DENG Wei,LIANG Lijian. Effect of Tie-2-siRNA Expression Vector on Human Hepatoma Transplanted Subcutaneously in Nude Mice. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2007, 14(5): 543-546. doi: Copy

1.	Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation [Ｊ]. Nature, 1995; 376(6535)∶70.
2.	Peters KG, Coogan A, Berry D, et al. Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis [Ｊ]. Br J Cancer, 1998; 77(1)∶51.
3.	Siemeister G, Schirner M, Weindel K, et al. Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway [Ｊ]. Cancer Res， 1999; 59(13)∶3185.
4.	Wassenegger M. Gene silencing [Ｊ]. Int Rev Cytol， 2002; 219∶61.
5.	Osieka R, Houchens DP, Goldin A, et al. Chemotherapy of human colon cancer xenograft in athymic nude mice [Ｊ]. Cancer, 1977; 40(5 Suppl)∶2640.
6.	Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis [Ｊ]. Science, 1997; 277(5322)∶55.
7.	Chin KF, Greenman J, Reusch P, et al. Vascular endothelial growth factor and soluble Tie-2 receptor in colorectal cancer: associations with disease recurrence [Ｊ]. Eur J Surg Oncol, 2003; 29(6)∶497.
8.	Quartarone E, Alonci A, Allegra A, et al. Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies [Ｊ]. Eur J Haematol, 2006; 77(6)∶480.
9.	Homer JJ, Greenman J, Drevs J, et al. Soluble Tie-2 receptor levels independently predict locoregional recurrence in head and neck squamous cell carcinoma [Ｊ]. Head Neck, 2002; 24(8)∶773.
10.	邓伟, 梁力建. 血管生成素和VEGF在人肝细胞癌血管生成作用机制的研究 [Ｊ]. 中国普通外科杂志, 2005; 14(6)∶343.
11.	Niu Q, Perruzzi C, Voskas D, et al. Inhibition of Tie-2 signaling induces endothelial cell apoptosis, decreases Akt signaling, and induces endothelial cell expression of the endogenous anti-angiogenic molecule, thrombospondin-1 [Ｊ]. Cancer Biol Ther, 2004; 3(4)∶402.
12.	Hodous BL, Geuns-Meyer SD, Hughes PE, et al. Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor [Ｊ]. J Med Chem, 2007; 50(4)∶611.
13.	Luo Y, Wen YJ, Ding ZY, et al. Immunotherapy of tumors with protein vaccine based on chicken homologous Tie-2 [Ｊ]. Clin Cancer Res, 2006; 12(6)∶1813.
14.	Popkov M, Jendreyko N, McGavern DB, et al. Targeting tu-mor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody [Ｊ]. Cancer Res, 2005; 65(3)∶972.
15.	Miyazaki Y, Tang J, Maeda Y, et al. Orally active 4-amino-5-diarylurea-furo (2,3-d) pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2 [Ｊ]. Bioorg Med Chem Lett, 2007; 17(6)∶1773.
16.	Sun HC, Tang ZY, Li XM, et al. Microvessel density of hepatocellular carcinoma: its relationship with prognosis [Ｊ]. J Cancer Res Clin Oncol, 1999; 125(7)∶419.

1. 　Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation [Ｊ]. Nature, 1995; 376(6535)∶70.
2. 　Peters KG, Coogan A, Berry D, et al. Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis [Ｊ]. Br J Cancer, 1998; 77(1)∶51.
3. 　Siemeister G, Schirner M, Weindel K, et al. Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway [Ｊ]. Cancer Res， 1999; 59(13)∶3185.
4. 　Wassenegger M. Gene silencing [Ｊ]. Int Rev Cytol， 2002; 219∶61.
5. 　Osieka R, Houchens DP, Goldin A, et al. Chemotherapy of human colon cancer xenograft in athymic nude mice [Ｊ]. Cancer, 1977; 40(5 Suppl)∶2640.
6. 　Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis [Ｊ]. Science, 1997; 277(5322)∶55.
7. 　Chin KF, Greenman J, Reusch P, et al. Vascular endothelial growth factor and soluble Tie-2 receptor in colorectal cancer: associations with disease recurrence [Ｊ]. Eur J Surg Oncol, 2003; 29(6)∶497.
8. 　Quartarone E, Alonci A, Allegra A, et al. Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies [Ｊ]. Eur J Haematol, 2006; 77(6)∶480.
9. 　Homer JJ, Greenman J, Drevs J, et al. Soluble Tie-2 receptor levels independently predict locoregional recurrence in head and neck squamous cell carcinoma [Ｊ]. Head Neck, 2002; 24(8)∶773.
10. 　邓伟, 梁力建. 血管生成素和VEGF在人肝细胞癌血管生成作用机制的研究 [Ｊ]. 中国普通外科杂志, 2005; 14(6)∶343.
11. 　Niu Q, Perruzzi C, Voskas D, et al. Inhibition of Tie-2 signaling induces endothelial cell apoptosis, decreases Akt signaling, and induces endothelial cell expression of the endogenous anti-angiogenic molecule, thrombospondin-1 [Ｊ]. Cancer Biol Ther, 2004; 3(4)∶402.
12. 　Hodous BL, Geuns-Meyer SD, Hughes PE, et al. Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor [Ｊ]. J Med Chem, 2007; 50(4)∶611.
13. 　Luo Y, Wen YJ, Ding ZY, et al. Immunotherapy of tumors with protein vaccine based on chicken homologous Tie-2 [Ｊ]. Clin Cancer Res, 2006; 12(6)∶1813.
14. 　Popkov M, Jendreyko N, McGavern DB, et al. Targeting tu-mor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody [Ｊ]. Cancer Res, 2005; 65(3)∶972.
15. 　Miyazaki Y, Tang J, Maeda Y, et al. Orally active 4-amino-5-diarylurea-furo (2,3-d) pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2 [Ｊ]. Bioorg Med Chem Lett, 2007; 17(6)∶1773.
16. 　Sun HC, Tang ZY, Li XM, et al. Microvessel density of hepatocellular carcinoma: its relationship with prognosis [Ｊ]. J Cancer Res Clin Oncol, 1999; 125(7)∶419.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect of Tie-2-siRNA Expression Vector on Human Hepatoma Transplanted Subcutaneously in Nude Mice

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