Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance

Raghunath, Azhwar; Sundarraj, Kiruthika; Arfuso, Frank; Sethi, Gautam

doi:10.3390/cancers10120481

Cited by 153 publications

(106 citation statements)

References 176 publications

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“…From a biosynthetic point of view, the monomeric lignin precursors (6)(7)(8)(9)(10)(11), coumarins (17)(18)(19), and the condensation of lignin with coumarins-coumarinolignans (20)(21)(22)(23)(24)(25) were successively isolated from this plant. Therefore, we regarded Compounds 2 and 3 as natural plant constituents.…”

Section: Structure Elucidation Of Excoecoumarin a (2) And Excoecoumarmentioning

confidence: 99%

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Chemical Constituents with GNMT-Promoter-Enhancing and NRF2-Reduction Activities from Taiwan Agarwood Excoecaria formosana

Cheng

Yen

et al. 2020

Molecules

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Hepatocellular carcinoma (HCC) is considered to be a silent killer, and was the fourth leading global cause of cancer deaths in 2018. For now, sorafenib is the only approved drug for advanced HCC treatment. The introduction of additional chemopreventive agents and/or adjuvant therapies may be helpful for the treatment of HCC. After screening 3000 methanolic extracts from the Formosan plant extract bank, Excoecaria formosana showed glycine N-methyltransferase (GNMT)-promoter-enhancing and nuclear factor erythroid 2-related factor 2 (NRF2)-suppressing activities. Further, the investigation of the whole plant of E. formosana led to the isolation of a new steroid, 7α-hydroperoxysitosterol-3-O-β-d-(6-O-palmitoyl)glucopyranoside (1); two new coumarinolignans, excoecoumarin A (2) and excoecoumarin B (3); a new diterpene, excoeterpenol A (4); and 40 known compounds (5–44). Among them, Compounds 38 and 40–44 at a 100 μM concentration showed a 2.97 ± 0.27-, 3.17 ± 1.03-, 2.73 ± 0.23-, 2.63 ± 0.14-, 6.57 ± 0.13-, and 2.62 ± 0.05-fold increase in GNMT promoter activity, respectively. In addition, Compounds 40 and 43 could reduce NRF2 activity, a transcription factor associated with drug resistance, in Huh7 cells with relative activity of 33.1 ± 0.2% and 45.2 ± 2.5%. These results provided the basis for the utilization of Taiwan agarwood for the development of anti-HCC agents.

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Section: Structure Elucidation Of Excoecoumarin a (2) And Excoecoumarmentioning

confidence: 99%

“…The EtOAc-soluble fraction (100 g) was subjected to column chromatography (silica gel; column size: 10 cm × 80 cm; n-hexane/EtOAc 100:1 to 100% acetone, then finally washed with 100% methanol) to yield 12 subfractions (Fr. [1][2][3][4][5][6][7][8][9][10][11][12]. Fr.…”

Section: Extraction and Isolationmentioning

confidence: 99%

Chemical Constituents with GNMT-Promoter-Enhancing and NRF2-Reduction Activities from Taiwan Agarwood Excoecaria formosana

Cheng

Yen

et al. 2020

Molecules

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“…FoxM1 regulates expression of the antioxidant response transcription factor Nrf2 (29,30). Nrf2 promotes cell survival and proliferation in response to oxidative stress conditions, often an environment inherent in HCC development (23). Nrf2 activation is tightly linked to CAR activation, likely through CAR-mediated induction of oxidative stress (31).…”

Section: The Foxm1 and Nrf2 Pathways Are Activated In Atx + Tc Tissuesmentioning

confidence: 99%

“…Strong β-catenin activation is a hallmark of these tumors. The FoxM1 and Nrf2 transcription factor pathways, which promote HCC progression and are linked to poor prognosis in human HCC (23,24), were also upregulated in the CAR/HBx tumors. Interestingly, while 8-week-old ATX mice have mildly increased β-catenin target expression compared to wildtypes, acute CAR activation appears to suppress β-catenin activation.…”

mentioning

confidence: 97%

Constitutive Androstane Receptor and Hepatitis B Virus X Protein Cooperatively Induce β-catenin-Activated Liver Tumors

Scott

Liu

Klatt

et al. 2020

Preprint

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Background and Aims: The xenobiotic nuclear receptor Constitutive Androstane Receptor (CAR) is essential for xenobiotic tumor promotion in mouse models. In these models, β-catenin is genetically activated in approximately 80% of tumors. Chronic Hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), and β-catenin activation is also frequently activated in HBV-associated HCCs. The goal of this research was to determine whether activation of CAR in a mouse model of chronic HBV infection would result in tumor formation and whether these tumors would display increased β-catenin activation. Approach and Results: We treated transgenic mice expressing the HBV X protein (HBx) in hepatocytes with a single dose of the potent CAR agonist TCPOBOP. After 10 months, these mice developed large liver tumors that are characterized by β-catenin nuclear localization and upregulation of β-catenin targets. The β-catenin regulator FoxM1 and the oxidative stress master regulator Nrf2, both of which are CAR gene targets, were also overactivated in tumors. The CAR/HBx tumors share a conserved gene signature with HBV-related human hepatocellular carcinoma. Conclusions: Activation of CAR in the presence of HBx results in tumors with strong β-catenin activation. The mouse model we have described reflects the gene expression patterns seen in human HBV-associated HCC and presents an attractive basis for future studies.

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“…Finally, we determined the levels of two transcription factors, whose role in liver cancer is becoming more and more relevant, namely nuclear factor erythroid 2 like 2 (NFE2L2/NRF2) and heat shock factor transcription factor 1 (HSF1) in TAZS89A/∆N90-β-catenin and YAPS127A/∆N90-β-catenin tumors [30][31][32]. Levels of NRF2, its regulator Kelch like ECH associated protein 1 (Keap1), and those of its target NAD(P)H quinone dehydrogenase 1 (Nqo1), were upregulated in both mouse models, without statistical differences between the two cohorts, when compared with wild-type mice ( Supplementary Figure 8).…”

Section: Commonalities and Differences Between Tazs89a/∆n90-β-cateninmentioning

confidence: 99%

The Hippo effector TAZ cooperates with oncogenic β-catenin in experimental and human hepatoblastoma development

Tao

Zhang

et al. 2019

Preprint

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Backgrounds: Hepatoblastoma (HB) is the most common pediatric liver tumor. Though Wnt/β-catenin and Hippo cascades are implicated in HB development, there is no study on the crosstalk of β-catenin and Hippo downstream effector TAZ in HB. Methods: The expression of TAZ and of β-catenin in human HB specimens was assessed by immunohistochemistry (IHC). The functional interplay between TAZ and β-catenin was tested through delivering either an activated form of TAZ (TAZS89A) alone or co-delivering TAZS89A and an activated form of β-catenin (∆N90-β-catenin) to mouse liver using sleeping beauty transposase via hydrodynamic tail vein injection (SBT-HTVI). In addition, the role of transcriptional enhanced associate domain (TEAD) factors, canonical Notch cascade, Yap, and the tumor modifier heat shock transcription factor 1 (HSF1) along TAZ/β-catenin-driven HB development was studied in vivo and vitro. Results: Activation of TAZ often co-occurred with that of β-catenin in clinical specimens. While overexpression of TAZS89A alone was unable to promote liver tumorigenesis, the concomitant overexpression of TAZ and ∆N90-β-catenin induced the development of HB lesions exhibiting both epithelial and mesenchymal features. Mechanistically, HB development driven by TAZ/β-catenin required TAZ interaction with TEAD factors. Furthermore, TAZ/β-catenin overexpression induced HB development in conditional Yes-associated protein knockout (Yap KO) mice, indicating that Yap activation is dispensable in this model. Activation of the Notch signaling was observed in TAZ/β-catenin mouse lesions, consistent with that reported in human HBs. Blocking of the canonical Notch cascade using the dominant negative form of RBP-J (dnRBP-J) did not inhibit TAZ/β-catenin dependent HB formation in mice, although suppressed the mesenchymal differentiation. Similarly, upregulation of HSF1 was detected in TAZ/β-catenin lesions, but its inactivation did not affect HB development. In human HB cell lines, silencing of TAZ resulted in decreased cell growth, which was reduced more substantially when TAZ knockdown was associated with suppression of either β-catenin or YAP gene. Conclusions: Overall, our study identifies TAZ as a critical oncogene in HB development and progression. Yap, Notch, and HSF1 are dispensable for TAZ/β-catenin induced HB development in mice.

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Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance

Cited by 153 publications

References 176 publications

Chemical Constituents with GNMT-Promoter-Enhancing and NRF2-Reduction Activities from Taiwan Agarwood Excoecaria formosana

Chemical Constituents with GNMT-Promoter-Enhancing and NRF2-Reduction Activities from Taiwan Agarwood Excoecaria formosana

Constitutive Androstane Receptor and Hepatitis B Virus X Protein Cooperatively Induce β-catenin-Activated Liver Tumors

The Hippo effector TAZ cooperates with oncogenic β-catenin in experimental and human hepatoblastoma development

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