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Prognostic significance of Cbx4 expression and its beneficial effect for transarterial chemoembolization in hepatocellular carcinoma.

Jiao HK, Xu Y, Li J, Wang W, Mei Z, Long XD, Chen GQ - Cell Death Dis (2015)

Bottom Line: By univariate and multivariate analyses, we show that Cbx4 is an independent prognostic factor of HCC, and both TAE and TACE treatments have no effects on the overall survival in HCC patients with low Cbx4 expression.Moreover, Cbx4 overexpression enhances while Cbx4 silencing antagonizes doxorubicin-induced cell death of HCC cell lines.In conclusion, Cbx4 is an independent prognostic factor for HCC patients, and the patients with high Cbx4 expression should receive postoperative TACE treatment to improve their survival.

View Article: PubMed Central - PubMed

Affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences/Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.

ABSTRACT
Our recent investigations showed that polycomb chromobox 4 (Cbx4) promotes angiogenesis and metastasis of hepatocellular carcinoma (HCC) through its sumoylating action on hypoxia-inducible factor-1α protein. Here, we attempt to identify the prognostic significances of Cbx4 by a retrospective analyses in 727 cases of HCC patients with and without postoperative transarterial chemoembolization (TACE) or transarterial embolization (TAE). Binary logistic regression tests indicated that Cbx4 is correlated with histological grading, tumor-node-metastasis stage, microvessel density, distant metastasis and hematogenous metastasis of HCC. By univariate and multivariate analyses, we show that Cbx4 is an independent prognostic factor of HCC, and both TAE and TACE treatments have no effects on the overall survival in HCC patients with low Cbx4 expression. More intriguingly, TACE prolongs, while TAE shortens, the overall survival of HCC patients with high Cbx4 expression, indicating that Cbx4 is a good biomarker on decision-making to perform postoperative TACE in HCC patients. Moreover, Cbx4 overexpression enhances while Cbx4 silencing antagonizes doxorubicin-induced cell death of HCC cell lines. In conclusion, Cbx4 is an independent prognostic factor for HCC patients, and the patients with high Cbx4 expression should receive postoperative TACE treatment to improve their survival.

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Cbx4 increases the sensitivity of SMMC-7721 and MHCC97L cells to doxorubicin-induced cell death. SMMC-7721 and MHCC97L cells were stably infected with empty or Flag-tagged Cbx4. (a and b) Doxorubicin was added into SMMC-7721, 2 μM (a) and MHCC97L, 3 μM (b) cells for 36 and 48 h, followed by immunoblots for the indicated proteins. (c and d) SMMC-7721 (c) and MHCC97L (d) with or without ectopic Cbx4 expression were respectively treated with and without different concentrations of doxorubicin for 36 h, and cell growth was assessed by CCK-8 assay and IC50 values of doxorubicin were calculated by GraphPad Prism 6 software. (e and f) SMMC-7721 (e) and MHCC97L (f) with or without ectopic Cbx4 expression were treated with 2 μM (e) or 3 μM (f) of doxorubicin for 36 and 48 h, and percentages of TUNEL-positive cells were calculated
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fig4: Cbx4 increases the sensitivity of SMMC-7721 and MHCC97L cells to doxorubicin-induced cell death. SMMC-7721 and MHCC97L cells were stably infected with empty or Flag-tagged Cbx4. (a and b) Doxorubicin was added into SMMC-7721, 2 μM (a) and MHCC97L, 3 μM (b) cells for 36 and 48 h, followed by immunoblots for the indicated proteins. (c and d) SMMC-7721 (c) and MHCC97L (d) with or without ectopic Cbx4 expression were respectively treated with and without different concentrations of doxorubicin for 36 h, and cell growth was assessed by CCK-8 assay and IC50 values of doxorubicin were calculated by GraphPad Prism 6 software. (e and f) SMMC-7721 (e) and MHCC97L (f) with or without ectopic Cbx4 expression were treated with 2 μM (e) or 3 μM (f) of doxorubicin for 36 and 48 h, and percentages of TUNEL-positive cells were calculated

Mentions: Based on the above-mentioned findings that TACE was beneficial while TAE was harmful to HCC patients with tumors of high Cbx4 expression, we hypothesize that Cbx4 can affect the sensitivity of HCC cells to chemotherapeutic drugs. To address this, two HCC cell lines, SMMC-7721 and MHCC97L, were stably infected with retrovirus carrying Flag alone or Flag-tagged Cbx4 (Figures 4a and b), followed by the treatment with increasing concentrations (from 0.1 to 20 μM for SMMC-7721 (Shanghai, China) and from 0.1 to 40 μM for MHCC97L (Shanghai, China)) of doxorubicin, a commonly used drug in TACE intervention. Thirty-six hours later, CCK-8 assay showed that Cbx4 overexpression significantly increased sensitivity of both HCC cell lines to doxorubicin (Figures 4c and d). The half-maximal inhibitory concentrations (IC50) of doxorubicin were 0.629 versus 1.244 μM and 3.414 versus 5.969 μM in Flag-tagged Cbx4 and empty vector-infected SMMC-7721 and MHCC97L cells, respectively. Furthermore, Cbx4 overexpression significantly increased doxorubicin-induced cell death in these two cell lines, as assessed by TUNEL assay (Figures 4e and f) and proteolytic activations of caspases 9 and 3 as well as poly(ADP-ribose)polymerase (PARP) cleavage (Figures 4a and b).


Prognostic significance of Cbx4 expression and its beneficial effect for transarterial chemoembolization in hepatocellular carcinoma.

Jiao HK, Xu Y, Li J, Wang W, Mei Z, Long XD, Chen GQ - Cell Death Dis (2015)

Cbx4 increases the sensitivity of SMMC-7721 and MHCC97L cells to doxorubicin-induced cell death. SMMC-7721 and MHCC97L cells were stably infected with empty or Flag-tagged Cbx4. (a and b) Doxorubicin was added into SMMC-7721, 2 μM (a) and MHCC97L, 3 μM (b) cells for 36 and 48 h, followed by immunoblots for the indicated proteins. (c and d) SMMC-7721 (c) and MHCC97L (d) with or without ectopic Cbx4 expression were respectively treated with and without different concentrations of doxorubicin for 36 h, and cell growth was assessed by CCK-8 assay and IC50 values of doxorubicin were calculated by GraphPad Prism 6 software. (e and f) SMMC-7721 (e) and MHCC97L (f) with or without ectopic Cbx4 expression were treated with 2 μM (e) or 3 μM (f) of doxorubicin for 36 and 48 h, and percentages of TUNEL-positive cells were calculated
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385935&req=5

fig4: Cbx4 increases the sensitivity of SMMC-7721 and MHCC97L cells to doxorubicin-induced cell death. SMMC-7721 and MHCC97L cells were stably infected with empty or Flag-tagged Cbx4. (a and b) Doxorubicin was added into SMMC-7721, 2 μM (a) and MHCC97L, 3 μM (b) cells for 36 and 48 h, followed by immunoblots for the indicated proteins. (c and d) SMMC-7721 (c) and MHCC97L (d) with or without ectopic Cbx4 expression were respectively treated with and without different concentrations of doxorubicin for 36 h, and cell growth was assessed by CCK-8 assay and IC50 values of doxorubicin were calculated by GraphPad Prism 6 software. (e and f) SMMC-7721 (e) and MHCC97L (f) with or without ectopic Cbx4 expression were treated with 2 μM (e) or 3 μM (f) of doxorubicin for 36 and 48 h, and percentages of TUNEL-positive cells were calculated
Mentions: Based on the above-mentioned findings that TACE was beneficial while TAE was harmful to HCC patients with tumors of high Cbx4 expression, we hypothesize that Cbx4 can affect the sensitivity of HCC cells to chemotherapeutic drugs. To address this, two HCC cell lines, SMMC-7721 and MHCC97L, were stably infected with retrovirus carrying Flag alone or Flag-tagged Cbx4 (Figures 4a and b), followed by the treatment with increasing concentrations (from 0.1 to 20 μM for SMMC-7721 (Shanghai, China) and from 0.1 to 40 μM for MHCC97L (Shanghai, China)) of doxorubicin, a commonly used drug in TACE intervention. Thirty-six hours later, CCK-8 assay showed that Cbx4 overexpression significantly increased sensitivity of both HCC cell lines to doxorubicin (Figures 4c and d). The half-maximal inhibitory concentrations (IC50) of doxorubicin were 0.629 versus 1.244 μM and 3.414 versus 5.969 μM in Flag-tagged Cbx4 and empty vector-infected SMMC-7721 and MHCC97L cells, respectively. Furthermore, Cbx4 overexpression significantly increased doxorubicin-induced cell death in these two cell lines, as assessed by TUNEL assay (Figures 4e and f) and proteolytic activations of caspases 9 and 3 as well as poly(ADP-ribose)polymerase (PARP) cleavage (Figures 4a and b).

Bottom Line: By univariate and multivariate analyses, we show that Cbx4 is an independent prognostic factor of HCC, and both TAE and TACE treatments have no effects on the overall survival in HCC patients with low Cbx4 expression.Moreover, Cbx4 overexpression enhances while Cbx4 silencing antagonizes doxorubicin-induced cell death of HCC cell lines.In conclusion, Cbx4 is an independent prognostic factor for HCC patients, and the patients with high Cbx4 expression should receive postoperative TACE treatment to improve their survival.

View Article: PubMed Central - PubMed

Affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences/Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.

ABSTRACT
Our recent investigations showed that polycomb chromobox 4 (Cbx4) promotes angiogenesis and metastasis of hepatocellular carcinoma (HCC) through its sumoylating action on hypoxia-inducible factor-1α protein. Here, we attempt to identify the prognostic significances of Cbx4 by a retrospective analyses in 727 cases of HCC patients with and without postoperative transarterial chemoembolization (TACE) or transarterial embolization (TAE). Binary logistic regression tests indicated that Cbx4 is correlated with histological grading, tumor-node-metastasis stage, microvessel density, distant metastasis and hematogenous metastasis of HCC. By univariate and multivariate analyses, we show that Cbx4 is an independent prognostic factor of HCC, and both TAE and TACE treatments have no effects on the overall survival in HCC patients with low Cbx4 expression. More intriguingly, TACE prolongs, while TAE shortens, the overall survival of HCC patients with high Cbx4 expression, indicating that Cbx4 is a good biomarker on decision-making to perform postoperative TACE in HCC patients. Moreover, Cbx4 overexpression enhances while Cbx4 silencing antagonizes doxorubicin-induced cell death of HCC cell lines. In conclusion, Cbx4 is an independent prognostic factor for HCC patients, and the patients with high Cbx4 expression should receive postoperative TACE treatment to improve their survival.

Show MeSH
Related in: MedlinePlus