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. 2016 Oct;5(10):2678-2687.
doi: 10.1002/cam4.788. Epub 2016 Sep 20.

Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma

Jiang Chen  1 , Yaojun Yu  1 , Tong Ji  1   2 , Rui Ma  3 , Mingming Chen  1 , Gaofeng Li  2 , Feibo Li  4 , Qiong Ding  4 , Qingsong Kang  4 , Diyu Huang  1 , Xiao Liang  1 , Hui Lin  1 , Xiujun Cai  5
Affiliations

Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma

Jiang Chen et al. Cancer Med. 2016 Oct.

Abstract

In this paper, variation tendency of phosphorylated Nrf2, as the activated form of native Nrf2, was studied in 107 primary hepatocellular carcinoma (HCC) specimens treated by curative hepatectomy. Moreover, the coexpression of oxidative stress markers Keap1 and pNrf2, and their association with pathological features were also evaluated based on those specimens. The results showed that preserved cytoplasmic Keap1 expression of cancer cells was observed in 59 HCCs, while reduced Keap1 expression was determined in remaining 48 ones. With regarding to nuclear pNrf2 expression, 75 HCCs were defined as high and the other 32 ones as low. There was a significant association between Keap1 and pNrf2 expression in HCCs. Higher pNrf2 expression was observed, at a more substantial proportion, in those specimens with reduced Keap1 expression, compared to those with preserved Keap1 expression. The subset with higher pNrf2 and reduced Keap1 expression was defined as pNrf2+ Keap1- . According to the analysis of prognosis, this subset was significantly associated with poor 5-year overall survival and worse disease-free survival in HCCs, indicating that pNrf2 and Keap1 were two-functional biomolecules, not only the oxidative stress markers but also biomarkers for prognosis of HCCs.

Keywords: Hepatocellular carcinoma; Keap1; Oxidative stress; phosphorylated Nrf2 (pNrf2); prognosis.

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Figures

Figure 1
Figure 1
Classification of Keap1 and pNrf2 immunoreactivity in human hepatocellular carcinoma (HCC) tissue. Representative immunohistochemical staining of (P1, P5) strong, (P2, P6) moderate, (P3, P7) weak, and (P4, P8) none Keap1 (A) and pNrf2 (B) immunoreactivity in human HCC tissue.
Figure 2
Figure 2
Correlation of Keap1 and pNrf2 expression in human hepatocellular carcinoma (HCC) tissues. (A) typical staining of high nuclear pNrf2 expression in tumor compare to paratumor, so does total Nrf2. (B) typical staining of reduced keap1 expression in tumor compare to paratumor. (C) Overexpression of Keap1 in HCC was correlated with low level of pNrf2, and vice versa. (D) Percentage of subtype HCC according to expression of pNrf2 and Keap1. PT: Paratumor, Adjacent noncancer.
Figure 3
Figure 3
Oxidative stress markers expression in HCC patients. The mRNA levels of Keap1 and Nrf2(A), NQO1, AKR1B10 and GCLM(B) were assessed by qPCR in tumor(n = 14) and paratumor(n = 14). The expression of total protein Nrf2, pNrf2 and Keap1 were assessed by Western blot in tumor(n = 14) and paratumor(n = 14) (C). The expressions of pNrf2 and Keap1 (D) between tumor and paratumor were Compared(n = 14). The data were presented as *P < 0.05, **P < 0.01. PT, paratumor; T, tumor; P, patient. HCC, hepatocellular carcinoma.
Figure 4
Figure 4
Prognostic significance of pNrf2 and Keap1 expression in 107 patients with HCC after curative resection. Cumulative overall survival (OS) time and disease‐free survival (DFS) time were calculated by Kaplan–Meier method and analyzed by log‐rank test. (A) Regarding the OS rate, significant difference was found between the group with high pNrf2 expression (n = 75) and the group with low pNrf2 expression (n = 32) (P = 0.0177). (B) Regarding the DFS rate, the group with high pNrf2 expression (n = 75) had a significantly poorer prognosis compared with the group with low pNrf2 expression (n = 32) (P = 0.0096). (C) Cumulative OS was not different between Keap1 reduced (n = 48) and preserved (n = 59) group (P = 0.0821). (D) Cumulative DFS was not different between Keap1 reduced (n = 48) and preserved (n = 59) group (P = 0.1422). (E) Cumulative OS was significant different between Keap1 reduced plus high pNrf2 expression (n = 40) and others (n = 67) group (P = 0.0252). (F) Cumulative DFS was significant different between Keap1 reduced plus high pNrf2 expression (n = 40) and preserved (n = 67) group (P = 0.0031). The data were presented as *P < 0.05, **P < 0.01.
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