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Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells.

Niimi K, Murakumo Y, Watanabe N, Kato T, Mii S, Enomoto A, Asai M, Asai N, Yamamoto E, Kajiyama H, Shibata K, Kikkawa F, Takahashi M - Cancer Sci. (2014)

Bottom Line: Enhanced immunoreactivity to REV7 was associated with poor prognosis represented by reduced progression-free survival in advanced stage (stage II-IV) EOC as assessed using Kaplan-Meier curves and log-rank tests.Knockdown of REV7 in CCC cells decreased cell proliferation without affecting cell cycle distribution.In a nude mouse tumor xenograft model, inoculated REV7-knockdown tumors showed significantly reduced tumor volumes after cisplatin treatment compared with those of the control group.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

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Suppression of REV7 enhances cisplatin (CDDP) sensitivity in vivo. (a) Growth of inoculated tumors in nude mice with and without systemic CDDP treatment. REV7-knockdown (shREV7) or control (shCont) ovarian clear cell carcinoma TOV-21G cells (1 × 107) were used in this analysis. The means ± SDs of tumor volume are shown. *P < 0.05; **P < 0.01. (b) Macroscopic images of transplanted tumors excised at day 32. (c) Reduction of tumor volume by CDDP treatment. Tumor volumes of the CDDP-treated group relative to the mean tumor volume of the PBS-treated group were calculated, and the means ± SDs of relative tumor volumes are shown. *P < 0.05. (d) Immunohistochemical analysis of excised tumors for REV7, cleaved caspase-3, and phospho-H2AX. Excised tumor tissues at day 32 were immunohistochemically stained with anti-REV7 (upper panels), anti-cleaved caspase-3 (middle panels), and anti-phospho-H2AX (lower panels) antibodies. Scale bar = 50 μm. (e, f) Quantitative assessment of cleaved caspase-3-positive cells (e) and phospho-H2AX-positive cells (f) in shREV7 and shCont tumors. Cells were counted under high power fields (HPF). The data obtained from five separate fields are shown as means ± SDs. **P < 0.01.
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fig05: Suppression of REV7 enhances cisplatin (CDDP) sensitivity in vivo. (a) Growth of inoculated tumors in nude mice with and without systemic CDDP treatment. REV7-knockdown (shREV7) or control (shCont) ovarian clear cell carcinoma TOV-21G cells (1 × 107) were used in this analysis. The means ± SDs of tumor volume are shown. *P < 0.05; **P < 0.01. (b) Macroscopic images of transplanted tumors excised at day 32. (c) Reduction of tumor volume by CDDP treatment. Tumor volumes of the CDDP-treated group relative to the mean tumor volume of the PBS-treated group were calculated, and the means ± SDs of relative tumor volumes are shown. *P < 0.05. (d) Immunohistochemical analysis of excised tumors for REV7, cleaved caspase-3, and phospho-H2AX. Excised tumor tissues at day 32 were immunohistochemically stained with anti-REV7 (upper panels), anti-cleaved caspase-3 (middle panels), and anti-phospho-H2AX (lower panels) antibodies. Scale bar = 50 μm. (e, f) Quantitative assessment of cleaved caspase-3-positive cells (e) and phospho-H2AX-positive cells (f) in shREV7 and shCont tumors. Cells were counted under high power fields (HPF). The data obtained from five separate fields are shown as means ± SDs. **P < 0.01.

Mentions: To test whether REV7-depleted tumors are sensitive to systemic therapy of DNA damaging agents, a mouse-tumor model was established using shCont and shREV7 TOV-21G cells, and the effect of systemic CDDP treatment was assessed. We found that REV7-depleted tumors grew more slowly than control tumors, and CDDP treatment further drastically suppressed growth of REV7-depleted tumors (Fig.5a,b). Tumor volumes of control and REV7-depleted tumors at day 32 were reduced to 39.7 ± 8.9% and 15.3 ± 10.2% by CDDP treatment, respectively (P < 0.05) (Fig.5c). Immunohistochemical analyses of the tumor graft tissues at day 32 revealed that shREV7-TOV-21G-derived tumors showed low level expression of REV7 compared with shCont-TOV-21G-derived tumors (Fig.5d, Fig. S5) and the REV7-depleted tumors contained more cleaved caspase-3-positive cells and phospho-H2AX-positive cells than control tumors (P < 0.01) (Fig.5d–f). These results indicate that REV7 depletion confers enhanced sensitivity to CDDP treatment in CCC cells in vivo.


Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells.

Niimi K, Murakumo Y, Watanabe N, Kato T, Mii S, Enomoto A, Asai M, Asai N, Yamamoto E, Kajiyama H, Shibata K, Kikkawa F, Takahashi M - Cancer Sci. (2014)

Suppression of REV7 enhances cisplatin (CDDP) sensitivity in vivo. (a) Growth of inoculated tumors in nude mice with and without systemic CDDP treatment. REV7-knockdown (shREV7) or control (shCont) ovarian clear cell carcinoma TOV-21G cells (1 × 107) were used in this analysis. The means ± SDs of tumor volume are shown. *P < 0.05; **P < 0.01. (b) Macroscopic images of transplanted tumors excised at day 32. (c) Reduction of tumor volume by CDDP treatment. Tumor volumes of the CDDP-treated group relative to the mean tumor volume of the PBS-treated group were calculated, and the means ± SDs of relative tumor volumes are shown. *P < 0.05. (d) Immunohistochemical analysis of excised tumors for REV7, cleaved caspase-3, and phospho-H2AX. Excised tumor tissues at day 32 were immunohistochemically stained with anti-REV7 (upper panels), anti-cleaved caspase-3 (middle panels), and anti-phospho-H2AX (lower panels) antibodies. Scale bar = 50 μm. (e, f) Quantitative assessment of cleaved caspase-3-positive cells (e) and phospho-H2AX-positive cells (f) in shREV7 and shCont tumors. Cells were counted under high power fields (HPF). The data obtained from five separate fields are shown as means ± SDs. **P < 0.01.
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fig05: Suppression of REV7 enhances cisplatin (CDDP) sensitivity in vivo. (a) Growth of inoculated tumors in nude mice with and without systemic CDDP treatment. REV7-knockdown (shREV7) or control (shCont) ovarian clear cell carcinoma TOV-21G cells (1 × 107) were used in this analysis. The means ± SDs of tumor volume are shown. *P < 0.05; **P < 0.01. (b) Macroscopic images of transplanted tumors excised at day 32. (c) Reduction of tumor volume by CDDP treatment. Tumor volumes of the CDDP-treated group relative to the mean tumor volume of the PBS-treated group were calculated, and the means ± SDs of relative tumor volumes are shown. *P < 0.05. (d) Immunohistochemical analysis of excised tumors for REV7, cleaved caspase-3, and phospho-H2AX. Excised tumor tissues at day 32 were immunohistochemically stained with anti-REV7 (upper panels), anti-cleaved caspase-3 (middle panels), and anti-phospho-H2AX (lower panels) antibodies. Scale bar = 50 μm. (e, f) Quantitative assessment of cleaved caspase-3-positive cells (e) and phospho-H2AX-positive cells (f) in shREV7 and shCont tumors. Cells were counted under high power fields (HPF). The data obtained from five separate fields are shown as means ± SDs. **P < 0.01.
Mentions: To test whether REV7-depleted tumors are sensitive to systemic therapy of DNA damaging agents, a mouse-tumor model was established using shCont and shREV7 TOV-21G cells, and the effect of systemic CDDP treatment was assessed. We found that REV7-depleted tumors grew more slowly than control tumors, and CDDP treatment further drastically suppressed growth of REV7-depleted tumors (Fig.5a,b). Tumor volumes of control and REV7-depleted tumors at day 32 were reduced to 39.7 ± 8.9% and 15.3 ± 10.2% by CDDP treatment, respectively (P < 0.05) (Fig.5c). Immunohistochemical analyses of the tumor graft tissues at day 32 revealed that shREV7-TOV-21G-derived tumors showed low level expression of REV7 compared with shCont-TOV-21G-derived tumors (Fig.5d, Fig. S5) and the REV7-depleted tumors contained more cleaved caspase-3-positive cells and phospho-H2AX-positive cells than control tumors (P < 0.01) (Fig.5d–f). These results indicate that REV7 depletion confers enhanced sensitivity to CDDP treatment in CCC cells in vivo.

Bottom Line: Enhanced immunoreactivity to REV7 was associated with poor prognosis represented by reduced progression-free survival in advanced stage (stage II-IV) EOC as assessed using Kaplan-Meier curves and log-rank tests.Knockdown of REV7 in CCC cells decreased cell proliferation without affecting cell cycle distribution.In a nude mouse tumor xenograft model, inoculated REV7-knockdown tumors showed significantly reduced tumor volumes after cisplatin treatment compared with those of the control group.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Show MeSH
Related in: MedlinePlus