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γ-H2AX promotes hepatocellular carcinoma angiogenesis via EGFR/HIF-1α/VEGF pathways under hypoxic condition.

Xiao H, Tong R, Ding C, Lv Z, Du C, Peng C, Cheng S, Xie H, Zhou L, Wu J, Zheng S - Oncotarget (2015)

Bottom Line: Using mRNA microarray analysis, we found that H2AX decreased under hypoxic conditions.Combined γ-H2AX, HIF-1α and EGFR has better prognostic value for HCC after LT.This study suggests that γ-H2AX is associated with angiogenesis of HCC and γ-H2AX or a combination of γ-H2AX/EGFR/HIF-1α is a novel marker in the prognosis of HCC after LT and a potential therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most deadly cancers. Using mRNA microarray analysis, we found that H2AX decreased under hypoxic conditions. Hypoxia is an important physiological and pathological stress that induces H2AX phosphorylation (γ-H2AX), but the regulatory mechanism of γ-H2AX remains elusive in the progress of HCC. We report here that increased γ-H2AX expression in HCC is associated with tumor size, vascular invasion, TNM stage and reduced survival rate after liver transplantation (LT). γ-H2AX knockdown was able to effectively inhibit VEGF expression in vitro and tumorigenicity and angiogenesis of HCC in vivo. The mechanism of γ-H2AX on the angiogenic activity of HCC might go through EGFR/HIF-1α/VEGF pathways under hypoxic conditions. Combined γ-H2AX, HIF-1α and EGFR has better prognostic value for HCC after LT. This study suggests that γ-H2AX is associated with angiogenesis of HCC and γ-H2AX or a combination of γ-H2AX/EGFR/HIF-1α is a novel marker in the prognosis of HCC after LT and a potential therapeutic target.

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Increased levels of γ-H2AX indicate worsening prognosis and recurrence/metastasis of HCC(A) Protein levels of γ-H2AX were determined in 57 samples of HCC, 37 samples of peritumoral tissues and 17 samples of normal tissues samples. (B) Protein levels of γ-H2AX in tumor tissues of patients with post-LT HCC recurrence (n = 24) in comparison to patients with no-recurrence (n = 33). The unit of scale (y-axis of the (A) and (B)) presents the staining density. (C) The tumor-free and over-all survival rates of 57 patients with HCC post LT were compared between the low-γ-H2AX and high-γ-H2AX groups. (D) HCC samples in a tissue microarray were immunostained with a monoclonal anti-γ-H2AX antibody. Representative low-γ-H2AX (L) and high-γ-H2AX expression (H) samples are also shown (×200). (E) ROC curve of γ-H2AX level was used to predict tumor recurrence and non-recurrence after liver transplant.
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Figure 2: Increased levels of γ-H2AX indicate worsening prognosis and recurrence/metastasis of HCC(A) Protein levels of γ-H2AX were determined in 57 samples of HCC, 37 samples of peritumoral tissues and 17 samples of normal tissues samples. (B) Protein levels of γ-H2AX in tumor tissues of patients with post-LT HCC recurrence (n = 24) in comparison to patients with no-recurrence (n = 33). The unit of scale (y-axis of the (A) and (B)) presents the staining density. (C) The tumor-free and over-all survival rates of 57 patients with HCC post LT were compared between the low-γ-H2AX and high-γ-H2AX groups. (D) HCC samples in a tissue microarray were immunostained with a monoclonal anti-γ-H2AX antibody. Representative low-γ-H2AX (L) and high-γ-H2AX expression (H) samples are also shown (×200). (E) ROC curve of γ-H2AX level was used to predict tumor recurrence and non-recurrence after liver transplant.

Mentions: In this study, the levels of γ-H2AX in 57 samples of HCC, 37 samples of peritumoral tissue and 17 samples of normal tissue were examined by immunohistochemistry. The results showed that γ-H2AX levels (Fig. 2A) were higher in tumor tissues of patients than peritumoral tissues (p = 0.001) and normal tissues (p = 0.001). And the results showed that γ-H2AX levels were higher in tumor tissues of patients with post-LT HCC recurrence (n = 24) in comparison to patients with no-recurrence (n = 33) (p < 0.001) (Fig. 2B). To investigate the clinicopathologic features of γ-H2AX in HCC and to determine whether γ-H2AX expression in HCC was associated with tumor-free survival and overall post-transplanted survival, all 57 patients with HCC after LT were divided into two groups: the high-expression group (n = 36) and low-expression group (n = 21). The results showed that tumor size, vascular invasion and TNM stage showed significant differences (p < 0.05) (Table 1). Kaplan–Meier analysis revealed that HCC tissues with high expression of γ-H2AX had either worse overall survival (p = 0.002) or shorter tumor-free survival (p < 0.001) (Fig. 2C, D). The 1, 3 and 5 year overall survival rates among patients with high-γ-H2AX were 63.9%, 41.7% and 25.5%, respectively, whereas the rates in the patients with low-γ-H2AX were 90.5%, 71.4% and 59.6 %. Moreover, the 1, 3 and 5 years tumor-free survival after LT were much worse for high-γ-H2AX than low-γ-H2AX expression group (Table 2). ROC curve of γ-H2AX level was used to predict tumor recurrence and non-recurrence after LT. When considering a cutoff point of 0.79, sensitivity and specificity were 79.6% and50.6 % respectively with an AUC value of 0.79 (Fig. 2E). Thus, γ-H2AX is a valuable predicting factor for recurrence and survival in patients with HCC after LT.


γ-H2AX promotes hepatocellular carcinoma angiogenesis via EGFR/HIF-1α/VEGF pathways under hypoxic condition.

Xiao H, Tong R, Ding C, Lv Z, Du C, Peng C, Cheng S, Xie H, Zhou L, Wu J, Zheng S - Oncotarget (2015)

Increased levels of γ-H2AX indicate worsening prognosis and recurrence/metastasis of HCC(A) Protein levels of γ-H2AX were determined in 57 samples of HCC, 37 samples of peritumoral tissues and 17 samples of normal tissues samples. (B) Protein levels of γ-H2AX in tumor tissues of patients with post-LT HCC recurrence (n = 24) in comparison to patients with no-recurrence (n = 33). The unit of scale (y-axis of the (A) and (B)) presents the staining density. (C) The tumor-free and over-all survival rates of 57 patients with HCC post LT were compared between the low-γ-H2AX and high-γ-H2AX groups. (D) HCC samples in a tissue microarray were immunostained with a monoclonal anti-γ-H2AX antibody. Representative low-γ-H2AX (L) and high-γ-H2AX expression (H) samples are also shown (×200). (E) ROC curve of γ-H2AX level was used to predict tumor recurrence and non-recurrence after liver transplant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385844&req=5

Figure 2: Increased levels of γ-H2AX indicate worsening prognosis and recurrence/metastasis of HCC(A) Protein levels of γ-H2AX were determined in 57 samples of HCC, 37 samples of peritumoral tissues and 17 samples of normal tissues samples. (B) Protein levels of γ-H2AX in tumor tissues of patients with post-LT HCC recurrence (n = 24) in comparison to patients with no-recurrence (n = 33). The unit of scale (y-axis of the (A) and (B)) presents the staining density. (C) The tumor-free and over-all survival rates of 57 patients with HCC post LT were compared between the low-γ-H2AX and high-γ-H2AX groups. (D) HCC samples in a tissue microarray were immunostained with a monoclonal anti-γ-H2AX antibody. Representative low-γ-H2AX (L) and high-γ-H2AX expression (H) samples are also shown (×200). (E) ROC curve of γ-H2AX level was used to predict tumor recurrence and non-recurrence after liver transplant.
Mentions: In this study, the levels of γ-H2AX in 57 samples of HCC, 37 samples of peritumoral tissue and 17 samples of normal tissue were examined by immunohistochemistry. The results showed that γ-H2AX levels (Fig. 2A) were higher in tumor tissues of patients than peritumoral tissues (p = 0.001) and normal tissues (p = 0.001). And the results showed that γ-H2AX levels were higher in tumor tissues of patients with post-LT HCC recurrence (n = 24) in comparison to patients with no-recurrence (n = 33) (p < 0.001) (Fig. 2B). To investigate the clinicopathologic features of γ-H2AX in HCC and to determine whether γ-H2AX expression in HCC was associated with tumor-free survival and overall post-transplanted survival, all 57 patients with HCC after LT were divided into two groups: the high-expression group (n = 36) and low-expression group (n = 21). The results showed that tumor size, vascular invasion and TNM stage showed significant differences (p < 0.05) (Table 1). Kaplan–Meier analysis revealed that HCC tissues with high expression of γ-H2AX had either worse overall survival (p = 0.002) or shorter tumor-free survival (p < 0.001) (Fig. 2C, D). The 1, 3 and 5 year overall survival rates among patients with high-γ-H2AX were 63.9%, 41.7% and 25.5%, respectively, whereas the rates in the patients with low-γ-H2AX were 90.5%, 71.4% and 59.6 %. Moreover, the 1, 3 and 5 years tumor-free survival after LT were much worse for high-γ-H2AX than low-γ-H2AX expression group (Table 2). ROC curve of γ-H2AX level was used to predict tumor recurrence and non-recurrence after LT. When considering a cutoff point of 0.79, sensitivity and specificity were 79.6% and50.6 % respectively with an AUC value of 0.79 (Fig. 2E). Thus, γ-H2AX is a valuable predicting factor for recurrence and survival in patients with HCC after LT.

Bottom Line: Using mRNA microarray analysis, we found that H2AX decreased under hypoxic conditions.Combined γ-H2AX, HIF-1α and EGFR has better prognostic value for HCC after LT.This study suggests that γ-H2AX is associated with angiogenesis of HCC and γ-H2AX or a combination of γ-H2AX/EGFR/HIF-1α is a novel marker in the prognosis of HCC after LT and a potential therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most deadly cancers. Using mRNA microarray analysis, we found that H2AX decreased under hypoxic conditions. Hypoxia is an important physiological and pathological stress that induces H2AX phosphorylation (γ-H2AX), but the regulatory mechanism of γ-H2AX remains elusive in the progress of HCC. We report here that increased γ-H2AX expression in HCC is associated with tumor size, vascular invasion, TNM stage and reduced survival rate after liver transplantation (LT). γ-H2AX knockdown was able to effectively inhibit VEGF expression in vitro and tumorigenicity and angiogenesis of HCC in vivo. The mechanism of γ-H2AX on the angiogenic activity of HCC might go through EGFR/HIF-1α/VEGF pathways under hypoxic conditions. Combined γ-H2AX, HIF-1α and EGFR has better prognostic value for HCC after LT. This study suggests that γ-H2AX is associated with angiogenesis of HCC and γ-H2AX or a combination of γ-H2AX/EGFR/HIF-1α is a novel marker in the prognosis of HCC after LT and a potential therapeutic target.

Show MeSH
Related in: MedlinePlus