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Downregulation of developmentally regulated endothelial cell locus-1 inhibits the growth of colon cancer.

Zou X, Qiao H, Jiang X, Dong X, Jiang H, Sun X - J. Biomed. Sci. (2008)

Bottom Line: Gene transfection of Del1-shRNA downregulated expression of Del1 in LS-174T cells in vivo and in vitro, but did not alter the proliferative or survival properties of cells in vitro.Both Del1-shRNA and VEGF-shRNA gene therapies exhibited anti-tumor activities and they also showed a synergistic effect in suppressing growth of colon tumors by anti-angiogenesis and anti-proliferation.Although further investigation to clarify the mechanisms explaining the role of Del1 in tumor growth, and the interaction between VEGF and Del1, is required, the results indicate that downregulation of Del1 presents a potent therapeutic strategy to combat colon cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Hepatosplenic Surgery Center, Department of General Surgery, The First Clinical College of Harbin Medical University, Harbin 150001, PR China. zouxiaolongbs@163.com

ABSTRACT
Developmentally regulated endothelial cell locus-1 (Del1) is an embryonic angiogenic factor expressed in early embryonic endothelial cells, but recently has been found to be expressed in some forms of cancers including colon and breast cancers, and melanoma, and human cancer cell lines. Overexpression of Del1 accelerates tumor growth by enhancing vascular formation, implying Del1 may be a potential target for anti-angiogenic cancer therapy. The study aims to investigate whether downregulation of Del1 could inhibit the growth of tumors established in nude Balb/c mice by subcutaneous implantation of human LS-174T colon cancer cells. The shRNA expression vectors targeting human Del1, and vascular endothelial growth factor (VEGF) were constructed. Gene transfection of Del1-shRNA downregulated expression of Del1 in LS-174T cells in vivo and in vitro, but did not alter the proliferative or survival properties of cells in vitro. Gene transfection of VEGF-shRNA downregulated expression of both VEGF and Del1 in LS-174T cells in vivo and in vitro. Both Del1-shRNA and VEGF-shRNA gene therapies exhibited anti-tumor activities and they also showed a synergistic effect in suppressing growth of colon tumors by anti-angiogenesis and anti-proliferation. Although further investigation to clarify the mechanisms explaining the role of Del1 in tumor growth, and the interaction between VEGF and Del1, is required, the results indicate that downregulation of Del1 presents a potent therapeutic strategy to combat colon cancer.

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shRNA gene therapy inhibits tumor cell proliferation in situ. Illustrated are representative tumor sections prepared 3 weeks after treatment from mice receiving either control vector (A), Del1-shRNA (B), VEGF-shRNA (C), or a combination of Del1-shRNA plus VEGF-shRNA plasmids (D). Tumor sections were stained with anti-Ki-67 Ab to detect proliferative cells. (E) The Ki-67 positive cells were counted to calculate the proliferation index. A significant difference in proliferation index between tumors treated with Del1-shRNA or VEGF-shRNA compared with control is denoted by "*", and a highly significant difference between Del1-shRNA + VEGF-shRNA versus control by "**", and a significant difference between the combinational therapy and Del1-shRNA or VEGF-shRNA monotherapies by "‡".
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Figure 5: shRNA gene therapy inhibits tumor cell proliferation in situ. Illustrated are representative tumor sections prepared 3 weeks after treatment from mice receiving either control vector (A), Del1-shRNA (B), VEGF-shRNA (C), or a combination of Del1-shRNA plus VEGF-shRNA plasmids (D). Tumor sections were stained with anti-Ki-67 Ab to detect proliferative cells. (E) The Ki-67 positive cells were counted to calculate the proliferation index. A significant difference in proliferation index between tumors treated with Del1-shRNA or VEGF-shRNA compared with control is denoted by "*", and a highly significant difference between Del1-shRNA + VEGF-shRNA versus control by "**", and a significant difference between the combinational therapy and Del1-shRNA or VEGF-shRNA monotherapies by "‡".

Mentions: We next investigated whether shRNA gene therapy could inhibit cell proliferation in LS-174T tumors in situ. The tumor sections from above were stained with an anti-Ki-67 Ab. There were fewer Ki-67 positive cells in tumors treated with Del1-shRNA (Figure 5B) or VEGF-shRNA (Figure 5C) plasmids, compared with control vector-treated tumors (Figure 5A); and there were even fewer Ki-67 positive cells in tumors treated by the combinational therapy with Del1-shRNA + VEGF-shRNA plasmids (Figure 5D), compared with tumors treated by the monotherapies. Ki-67 positive cells in sections were counted to record proliferation index. Gene transfer of Del1-shRNA resulted in a significant 31% (P < 0.05) reduction in proliferation index compared with control, and VEGF-shRNA therapy also reduced proliferation index by 42% compared with control (P < 0.01). Furthermore, the combinational therapy with Del1-shRNA + VEGF-shRNA plasmids highly significantly reduced the proliferation index by 71%, compared with mock treatment (P < 0.001) (Figure 5E).


Downregulation of developmentally regulated endothelial cell locus-1 inhibits the growth of colon cancer.

Zou X, Qiao H, Jiang X, Dong X, Jiang H, Sun X - J. Biomed. Sci. (2008)

shRNA gene therapy inhibits tumor cell proliferation in situ. Illustrated are representative tumor sections prepared 3 weeks after treatment from mice receiving either control vector (A), Del1-shRNA (B), VEGF-shRNA (C), or a combination of Del1-shRNA plus VEGF-shRNA plasmids (D). Tumor sections were stained with anti-Ki-67 Ab to detect proliferative cells. (E) The Ki-67 positive cells were counted to calculate the proliferation index. A significant difference in proliferation index between tumors treated with Del1-shRNA or VEGF-shRNA compared with control is denoted by "*", and a highly significant difference between Del1-shRNA + VEGF-shRNA versus control by "**", and a significant difference between the combinational therapy and Del1-shRNA or VEGF-shRNA monotherapies by "‡".
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2666667&req=5

Figure 5: shRNA gene therapy inhibits tumor cell proliferation in situ. Illustrated are representative tumor sections prepared 3 weeks after treatment from mice receiving either control vector (A), Del1-shRNA (B), VEGF-shRNA (C), or a combination of Del1-shRNA plus VEGF-shRNA plasmids (D). Tumor sections were stained with anti-Ki-67 Ab to detect proliferative cells. (E) The Ki-67 positive cells were counted to calculate the proliferation index. A significant difference in proliferation index between tumors treated with Del1-shRNA or VEGF-shRNA compared with control is denoted by "*", and a highly significant difference between Del1-shRNA + VEGF-shRNA versus control by "**", and a significant difference between the combinational therapy and Del1-shRNA or VEGF-shRNA monotherapies by "‡".
Mentions: We next investigated whether shRNA gene therapy could inhibit cell proliferation in LS-174T tumors in situ. The tumor sections from above were stained with an anti-Ki-67 Ab. There were fewer Ki-67 positive cells in tumors treated with Del1-shRNA (Figure 5B) or VEGF-shRNA (Figure 5C) plasmids, compared with control vector-treated tumors (Figure 5A); and there were even fewer Ki-67 positive cells in tumors treated by the combinational therapy with Del1-shRNA + VEGF-shRNA plasmids (Figure 5D), compared with tumors treated by the monotherapies. Ki-67 positive cells in sections were counted to record proliferation index. Gene transfer of Del1-shRNA resulted in a significant 31% (P < 0.05) reduction in proliferation index compared with control, and VEGF-shRNA therapy also reduced proliferation index by 42% compared with control (P < 0.01). Furthermore, the combinational therapy with Del1-shRNA + VEGF-shRNA plasmids highly significantly reduced the proliferation index by 71%, compared with mock treatment (P < 0.001) (Figure 5E).

Bottom Line: Gene transfection of Del1-shRNA downregulated expression of Del1 in LS-174T cells in vivo and in vitro, but did not alter the proliferative or survival properties of cells in vitro.Both Del1-shRNA and VEGF-shRNA gene therapies exhibited anti-tumor activities and they also showed a synergistic effect in suppressing growth of colon tumors by anti-angiogenesis and anti-proliferation.Although further investigation to clarify the mechanisms explaining the role of Del1 in tumor growth, and the interaction between VEGF and Del1, is required, the results indicate that downregulation of Del1 presents a potent therapeutic strategy to combat colon cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Hepatosplenic Surgery Center, Department of General Surgery, The First Clinical College of Harbin Medical University, Harbin 150001, PR China. zouxiaolongbs@163.com

ABSTRACT
Developmentally regulated endothelial cell locus-1 (Del1) is an embryonic angiogenic factor expressed in early embryonic endothelial cells, but recently has been found to be expressed in some forms of cancers including colon and breast cancers, and melanoma, and human cancer cell lines. Overexpression of Del1 accelerates tumor growth by enhancing vascular formation, implying Del1 may be a potential target for anti-angiogenic cancer therapy. The study aims to investigate whether downregulation of Del1 could inhibit the growth of tumors established in nude Balb/c mice by subcutaneous implantation of human LS-174T colon cancer cells. The shRNA expression vectors targeting human Del1, and vascular endothelial growth factor (VEGF) were constructed. Gene transfection of Del1-shRNA downregulated expression of Del1 in LS-174T cells in vivo and in vitro, but did not alter the proliferative or survival properties of cells in vitro. Gene transfection of VEGF-shRNA downregulated expression of both VEGF and Del1 in LS-174T cells in vivo and in vitro. Both Del1-shRNA and VEGF-shRNA gene therapies exhibited anti-tumor activities and they also showed a synergistic effect in suppressing growth of colon tumors by anti-angiogenesis and anti-proliferation. Although further investigation to clarify the mechanisms explaining the role of Del1 in tumor growth, and the interaction between VEGF and Del1, is required, the results indicate that downregulation of Del1 presents a potent therapeutic strategy to combat colon cancer.

Show MeSH
Related in: MedlinePlus