Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome

Wei, Qing; Guo, Pengbo; Mu, Kun; Zhang, Ying; Zhao, Wei; Huai, Wanwan; Qiu, Yumin; Li, Tao; Ma, Xiaomin; Liu, Yafei; Chen, Xiaoyan; Han, Lihui

doi:10.1038/labinvest.2015.63

Cited by 115 publications

(91 citation statements)

References 32 publications

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“…The NALP3 gene has an essential role in endometriosis progression because NALP3 −/− mice have a defect in ectopic lesion growth under endometriosis. ERβ involves in upregulation of NALP3 inflammasome in hepatocellular carcinoma cells upon estrogen stimulation even though the interaction of ERβ to NALP3 is not clearly demonstrated (Wei et al, 2015). Here, we revealed that ERβ interacts with inflammasome components and enhances inflammasome activity through the activation of caspase 1 activity.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis

Han

Jung

et al. 2015

Cell

287

286

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Summary Alterations in estrogen-mediated cellular signaling play an essential role in the pathogenesis of endometriosis. In addition to higher estrogen receptor (ER)β levels, enhanced ERβ activity was detected in endometriotic tissues, and the inhibition of enhanced ERβ activity by an ERβ-selective antagonist suppressed mouse ectopic lesion growth. Notably, gain of ERβ function stimulated the progression of endometriosis. As a mechanism to evade endogenous immune surveillance for cell survival, ERβ interacts with cellular apoptotic machinery in the cytoplasm to inhibit TNFα-induced apoptosis. ERβ also interacts with components of the cytoplasmic inflammasome to increase interleukin-1β and thus enhance its cellular adhesion and proliferation properties. Furthermore, this gain of ERβ function enhances epithelial-mesenchymal transition signaling, thereby increasing the invasion activity of endometriotic tissues for establishment of ectopic lesions. Collectively, we reveal how endometrial tissue generated by retrograde menstruation can escape immune surveillance and develop into sustained ectopic lesions via gain of ERβ function.

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Section: Discussionmentioning

confidence: 99%

Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis

Han

Jung

et al. 2015

Cell

287

286

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“…Others have suggested that estrogen may inhibit hepatic tumor growth and progression by acting as a suppressor for alternative activation of tumor-associated macrophages and inhibiting the Jak1-Stat6 signaling pathway 31 . A recent report provided new insight into the protection of estrogen in HCC via the regulation of NLRP3 inflammasome by estrogen through the ER β/ MARK pathway 32 .…”

Section: Discussionmentioning

confidence: 99%

Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma

Hassan

Botrus

Abdel-Wahab

et al. 2017

Clinical Gastroenterology and Hepatology

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Background & Aims Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. We investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC. Methods We performed a case–control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls), from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC. Results The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% CI, 0.32–0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5±0.9 years) vs non-users (mean, 59.2±1.1 years) (P=.001) and the reduced risk of HCC among long-term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20– 0.63). Users of estrogen also had a reduced risk for hepatitis-associated HCC: AOR for users, 4.37 (95% CI, 1.67–11.44) vs AOR for non-users, 17.60 (95% CI, 3.88–79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40–0.77) (P=.01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7–41.3 months) and 24.1 months for non-users (95% CI, 19.02–29.30 months) (P=.008). Conclusion In a case–control study of women with HCC vs female controls at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor.

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“…The proliferation status of cells were detected at different time points, including 0, 12 h, 24 h, 36 h, 48 h, and 72 h. Cell invasion and colony formation assay were performed as described before [26, 27]. …”

Section: Methodsmentioning

confidence: 99%

Loss of AIM2 expression promotes hepatocarcinoma progression through activation of mTOR-S6K1 pathway

et al. 2016

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Absent in melanoma (AIM2) is a member of the interferon-inducible HIN-200 protein family and is recently recognized to play an important dual role in both innate immunity and tumor pathology. However, the role of AIM2 in the development of hepatocellular carcinoma (HCC) remains to be clarified. Here we showed that AIM2 expression was significantly decreased in liver cancer tissues, and loss of its expression was significantly correlated with more advanced tumor progression. Exogenous overexpression of AIM2 in HCC cells suppressed mammalian target of rapamycin (mTOR)-S6K1 pathway and further inhibited proliferation, colony formation and invasion of HCC cells. On the contrary, block of AIM2 in HCC cells induced (mTOR)-S6K1 pathway activation and thus promoted HCC progression. Treatment with mTOR pathway inhibitor rapamycin further verified its contribution to HCC progression in AIM2 absent HCC cells. Thus, these data suggested that AIM2 played a critical role as a tumor suppressor and might serve as a potential therapeutic target for future development of AIM2-based gene therapy for human liver cancer. This study also paves a new avenue to treat AIM2-deficient cancer by suppression of mTOR.

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Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome

Cited by 115 publications

References 32 publications

Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis

Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis

Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma

Loss of AIM2 expression promotes hepatocarcinoma progression through activation of mTOR-S6K1 pathway

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