Correlation of Nrf2, HO-1, and MRP3 in Gallbladder Cancer and Their Relationships to Clinicopathologic Features and Survival

Wang, Jiansheng; Zhang, Mingxin; Zhang, Lingmin; Cai, Hui; Zhou, Suna; Jia, Zhang; Wang, Yang

doi:10.1016/j.jss.2010.05.058

Cited by 62 publications

(68 citation statements)

References 24 publications

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“…Previous studies have demonstrated that patients with NRF2 expression in their carcinoma cells generally had worse prognosis in lung (Solis et al 2010, Inoue et al 2012, gallbladder (Wang et al 2010), and ovarian (Konstantinopoulos et al 2011) carcinomas, which is consistent with the results of the present study. NRF2 activation conferred resistance to chemotherapeutic drugs, including 5-fluorouracil, cisplatin, and paclitaxel, which are frequently used in breast carcinoma, in several carcinoma cells (Shibata et al 2008, Lister et al 2011), and Loignon et al (2009 reported that Cullin 3 ubiquitin E3 ligase (CUL3)-silenced MCF7 cells had increased NRF2 protein levels and exhibited high resistance to both doxorubicin and paclitaxel.…”

Section: Discussionsupporting

confidence: 93%

“…In the present study, nuclear NRF2 immunoreactivity was detected in 44% of the carcinoma cases, while it was positive in 2% of non-neoplastic breast tissues adjacent to the carcinoma and 4% of BBD tissues. Previous studies have demonstrated that NRF2 immunoreactivity is frequently detected in various human malignancies, such as breast (Loignon et al 2009, Karihtala et al 2011, Hartikainen et al 2012, lung (Inoue et al 2012), gastric (Wang et al 2011), pancreatic (Hong et al 2010), intrahepatic cholangiocellular (Wakai et al 2011), gallbladder (Wang et al 2010), endometrial (Chen et al 2010), and ovarian (Konstantinopoulos et al 2011) carcinomas, and its rate of immunopositivity ranged between 26 and 76% in these studies. The results of the immunohistochemical studies carried out in the present study also indicated a significant association between NRF2 status and immunoreactivity of NQO1, which is known to be an NRF2-induced cytoprotective gene (Lewis et al 2012), and subsequent in vitro studies revealed that both MCF7 and SK-BR-3 cells transfected with NRF2 siRNA had decreased NQO1 expression at both mRNA and protein levels.…”

Section: Discussionmentioning

confidence: 73%

“…Moreover, recent data also indicate that p62/SQSTM1 plays an important role in the accumulation of NRF2 in carcinoma cells (Komatsu et al 2010, Inami et al 2011). An association between NRF2 accumulation and adverse clinical outcome of patients has been reported in lung (Solis et al 2010, Inoue et al 2012, gallbladder (Wang et al 2010), and ovarian (Konstantinopoulos et al 2011) carcinomas. These findings indicate that NRF2 is possibly involved in the growth and/or progression of these carcinomas.…”

Section: Introductionmentioning

confidence: 94%

See 2 more Smart Citations

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

Onodera¹,

Motohashi²,

Takagi³

et al. 2013

Endocrine-Related Cancer

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Nuclear factor erythroid 2-related factor 2 (NRF2 (NFE2L2)) is an important transcriptional activator involved in the cellular defense mechanisms against electrophilic and oxidative stress. Recent studies have demonstrated that the expression of NRF2 protein is upregulated in several human malignancies and is associated with worse prognosis in these patients. However, the pathological and clinical significance of NRF2 has remained largely unknown in breast cancer patients. Therefore, in this study, we immunolocalized NRF2 in 106 breast carcinoma cases. NRF2 immunoreactivity was mainly detected in the nucleus of the breast carcinoma cells and it was positive in 44% of the cases. NRF2 status was significantly associated with histological grade, Ki-67 labeling index, p62 immunoreactivity, and NAD(P) H:quinone oxidoreductase 1 (NQO1) immunoreactivity, and the results of multivariate analyses revealed that NRF2 status was an independent adverse prognostic factor for both recurrence and disease-free survival of the patients. Subsequent in vitro studies demonstrated that the expression of NRF2 significantly increased the proliferation activity of MCF7 and SK-BR-3 breast carcinoma cells. These results indicate that nuclear NRF2 protein plays important roles in the proliferation and/or progression of breast carcinoma, and nuclear NRF2 immunoreactivity is therefore considered a potent prognostic factor in breast cancer patients.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

Onodera¹,

Motohashi²,

Takagi³

et al. 2013

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…NRF2 participates in multiple physiological processes, such as phase II drug metabolism and oxidative stress, and is negatively regulated by KEAP1. Aberrant NRF2 expression is found in various cancer types (1,(5)(6)(7)(8)(9) and the dysregulation of NRF2 affects cellular growth and response to therapy. Wang et al reported that overexpression of NRF2 in gallbladder adenocarcinoma was correlated with tumor differentiation, staging and metastasis (1).…”

Section: Discussionmentioning

confidence: 99%

NRF2 is overexpressed in ovarian epithelial carcinoma and is regulated by gonadotrophin and sex-steroid hormones

et al. 2012

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Abstract. Aberrant nuclear factor-erythroid 2 (NRF2) expression correlates with tumor development. We investigated NRF2 expression in ovarian epithelial carcinoma (OEC), aiming to identify associations with clinicopathological factors, hormones and induced reactive oxygen species (ROS). Immunohistochemical staining for NRF2 expression was performed on 10 benign cystadenomas, 4 boderline tumors and 64 OECs. Western blotting was used to determine the effects of hormones on NRF2 expression in OEC. NRF2 protein was found to be overexpressed in OEC. Gonadotrophins and estrogen induced ROS production in OEC; these hormones also enhanced NRF2 expression. Therefore, aberrant expression may be induced by hormones through ROS signaling. Increased NRF2 expression may be a molecular event in OEC carcinogenesis.

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“…ABCC3 is almost exclusively expressed on the basolateral membrane of polarized epithelial cells, and tissue distribution in humans is primarily confined to the adrenal glands, kidney, liver, small intestine, colon, pancreas, and bladder (Borst et al, 2007;Klaassen and Aleksunes, 2010). ABCC3 is also highly expressed in several forms of cancer, including non-small-cell lung carcinoma, gallbladder cancer, and hepatocellular carcinoma (Nies et al, 2001;Young et al, 2001;Wang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Identification of a Functional Antioxidant Response Element within the Eighth Intron of the HumanABCC3Gene

et al. 2014

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The ATP-binding cassette (ABC) family of transporters, including ABCC3, is a large family of efflux pumps that plays a pivotal role in the elimination of xenobiotics from the body. ABCC3 has been reported to be induced during hepatic stress conditions and through the progression of some forms of cancer. Several lines of evidence have implicated the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this induction. However, although rodent models have been investigated, a functional antioxidant response element (ARE) in the human ABCC3 gene has not been identified. The purpose of this study was to identify and characterize the ARE(s) responsible for mediating the Nrf2-dependent induction of the human ABCC3 gene. A high-throughput chromatin immunoprecipitation-sequencing analysis performed in A549 cells revealed a specific interaction between Nrf2 and the eighth intron of the human ABCC3 gene rather than the more prototypical flanking region of the gene. Subsequent in silico analysis of the intron identified two putative ARE elements that contained the core consensus ARE sequence commonly found in several Nrf2-responsive genes. Functional characterization of these two AREs using luciferase-reporter constructs with ARE mutant constructs revealed that one of these putative AREs is functionally active. Finally, DNA pull-down assays confirmed specific binding of these intronic AREs by Nrf2 in vitro. Our findings identify a functional Nrf2 response element within the eighth intron of the ABCC3 gene, which may provide mechanistic insight into the induction of ABCC3 during antioxidant response stimuli.

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Correlation of Nrf2, HO-1, and MRP3 in Gallbladder Cancer and Their Relationships to Clinicopathologic Features and Survival

Cited by 62 publications

References 24 publications

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

NRF2 is overexpressed in ovarian epithelial carcinoma and is regulated by gonadotrophin and sex-steroid hormones

Identification of a Functional Antioxidant Response Element within the Eighth Intron of the HumanABCC3Gene

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