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Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma.

Hu W, Lu SX, Li M, Zhang C, Liu LL, Fu J, Jin JT, Luo RZ, Zhang CZ, Yun JP - Oncotarget (2015)

Bottom Line: PKM2 depletion decreased the degradation of Bim.Combination of PKM2 and Bim levels had the best prognostic significance.We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.

ABSTRACT
Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389-2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214-2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

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PKM2 is overexpressed in HCC cell lines and tissues(A) Expression of PKM2 mRNA was detected in 9 HCC cell lines by qRT-PCR. Immortalized liver cell line L-02 was used as control. (B) The relevant expression of PKM2 in HCC cell lines was examined by western blot. (C) PKM2 mRNA level was determined in 58 pairs of fresh primary HCC tissues (P < 0.0001, Wilcoxon matched-paired test) (T, tumorous tissue; N, nontumorous tissue). (D) The expression level of PKM2 protein in 58-paired samples was also examined by western blot. Representative results and the ratio of T/N were shown. Increased expression of PKM2 protein in tumorous tissues was indicated by histogram (P < 0.0001, Wilcoxon matched-paired test). (E) PKM2 expression in 638 HCC tissues was determined by IHC. Representative images of strong/weak staining in HCC tissue and negative staining in the nontumorous tissue were shown. (F) The box plot showed the IHC score of PKM2 in 638 HCC cases. Data are mean ± SEM (**P < 0.0001, Wilcoxon matched-paired test).
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Figure 1: PKM2 is overexpressed in HCC cell lines and tissues(A) Expression of PKM2 mRNA was detected in 9 HCC cell lines by qRT-PCR. Immortalized liver cell line L-02 was used as control. (B) The relevant expression of PKM2 in HCC cell lines was examined by western blot. (C) PKM2 mRNA level was determined in 58 pairs of fresh primary HCC tissues (P < 0.0001, Wilcoxon matched-paired test) (T, tumorous tissue; N, nontumorous tissue). (D) The expression level of PKM2 protein in 58-paired samples was also examined by western blot. Representative results and the ratio of T/N were shown. Increased expression of PKM2 protein in tumorous tissues was indicated by histogram (P < 0.0001, Wilcoxon matched-paired test). (E) PKM2 expression in 638 HCC tissues was determined by IHC. Representative images of strong/weak staining in HCC tissue and negative staining in the nontumorous tissue were shown. (F) The box plot showed the IHC score of PKM2 in 638 HCC cases. Data are mean ± SEM (**P < 0.0001, Wilcoxon matched-paired test).

Mentions: The expression of PKM2 in HCC cells was firstly determined. Results showed that PKM2 expression at both mRNA and protein levels in 9 HCC cells was noticeably up-regulated, compared to the immortalized hepatic cell L-02 (Figure 1A&1B). In HCC fresh samples, PKM2 mRNA was significantly overexpressed in tumorous tissues (Figure 1C). Consistently, the protein level of PKM2 was markedly increased in 54 out of 58 (93.1%) primary HCC cases, compared to the corresponding nontumorous tissues (Figure 1D and Supplementary Figure 1). In a large cohort of 638 HCC patients, results of immunostaining showed that PKM2 expression in HCC tissues was remarkably higher than that in the adjacent normal liver tissues (Figure 1E&1F, P < 0.0001, Wilcoxon matched-paired test).


Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma.

Hu W, Lu SX, Li M, Zhang C, Liu LL, Fu J, Jin JT, Luo RZ, Zhang CZ, Yun JP - Oncotarget (2015)

PKM2 is overexpressed in HCC cell lines and tissues(A) Expression of PKM2 mRNA was detected in 9 HCC cell lines by qRT-PCR. Immortalized liver cell line L-02 was used as control. (B) The relevant expression of PKM2 in HCC cell lines was examined by western blot. (C) PKM2 mRNA level was determined in 58 pairs of fresh primary HCC tissues (P < 0.0001, Wilcoxon matched-paired test) (T, tumorous tissue; N, nontumorous tissue). (D) The expression level of PKM2 protein in 58-paired samples was also examined by western blot. Representative results and the ratio of T/N were shown. Increased expression of PKM2 protein in tumorous tissues was indicated by histogram (P < 0.0001, Wilcoxon matched-paired test). (E) PKM2 expression in 638 HCC tissues was determined by IHC. Representative images of strong/weak staining in HCC tissue and negative staining in the nontumorous tissue were shown. (F) The box plot showed the IHC score of PKM2 in 638 HCC cases. Data are mean ± SEM (**P < 0.0001, Wilcoxon matched-paired test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466635&req=5

Figure 1: PKM2 is overexpressed in HCC cell lines and tissues(A) Expression of PKM2 mRNA was detected in 9 HCC cell lines by qRT-PCR. Immortalized liver cell line L-02 was used as control. (B) The relevant expression of PKM2 in HCC cell lines was examined by western blot. (C) PKM2 mRNA level was determined in 58 pairs of fresh primary HCC tissues (P < 0.0001, Wilcoxon matched-paired test) (T, tumorous tissue; N, nontumorous tissue). (D) The expression level of PKM2 protein in 58-paired samples was also examined by western blot. Representative results and the ratio of T/N were shown. Increased expression of PKM2 protein in tumorous tissues was indicated by histogram (P < 0.0001, Wilcoxon matched-paired test). (E) PKM2 expression in 638 HCC tissues was determined by IHC. Representative images of strong/weak staining in HCC tissue and negative staining in the nontumorous tissue were shown. (F) The box plot showed the IHC score of PKM2 in 638 HCC cases. Data are mean ± SEM (**P < 0.0001, Wilcoxon matched-paired test).
Mentions: The expression of PKM2 in HCC cells was firstly determined. Results showed that PKM2 expression at both mRNA and protein levels in 9 HCC cells was noticeably up-regulated, compared to the immortalized hepatic cell L-02 (Figure 1A&1B). In HCC fresh samples, PKM2 mRNA was significantly overexpressed in tumorous tissues (Figure 1C). Consistently, the protein level of PKM2 was markedly increased in 54 out of 58 (93.1%) primary HCC cases, compared to the corresponding nontumorous tissues (Figure 1D and Supplementary Figure 1). In a large cohort of 638 HCC patients, results of immunostaining showed that PKM2 expression in HCC tissues was remarkably higher than that in the adjacent normal liver tissues (Figure 1E&1F, P < 0.0001, Wilcoxon matched-paired test).

Bottom Line: PKM2 depletion decreased the degradation of Bim.Combination of PKM2 and Bim levels had the best prognostic significance.We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.

ABSTRACT
Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389-2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214-2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

Show MeSH
Related in: MedlinePlus