Estrogen Suppresses Metastasis in Rat Hepatocellular Carcinoma through Decreasing Interleukin-6 and Hepatocyte Growth Factor Expression

Wang, Yongcang; Xu, Ge‐Liang; Jia, Weidong; Han, Sheng-Jin; Ren, Weihua; Wang, Wei; Liu, Wenbin; Zhang, Chuanhai; Chen, Hao

doi:10.1007/s10753-011-9299-3

Cited by 37 publications

(32 citation statements)

References 14 publications

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“…Previous studies reported that estrogen reduces IL-6 production and therefore inhibits carcinogenesis and osteoporosis [41, 49–51]. More importantly, estrogen may have an anti-inflammatory effect due to inhibition of NF-κB activation [52].…”

Section: Discussionmentioning

confidence: 99%

Estrogen decreases tight junction protein ZO-1 expression in human primary gut tissues

Zhou

Zhang

Ding

et al. 2017

Clinical Immunology

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Females have a higher prevalence of most autoimmune diseases; however, the mechanism is unknown. In this study, we examined the expression of tight junction protein zonula occludens 1 (ZO-1) and estrogen receptor (ER)-α/β in human primary gut tissues by immunohistochemistry, immunofluorescence and qPCR. The expression of ZO-1 and ER-β but not ER-α was present in both male and female gut tissues. There was no sex difference in ER-β expression, but ZO-1 expression was decreased in females compared to males. In vitro, estrogen treatment decreased ZO-1 mRNA and protein expression, ZO-1 promoter activity, IL-6 production, and NF-κB activation in human primary gut tissues or the Caco-2 cells, but increased the ER-β expression in Caco-2 cells. Consistently, plasma IL-6 levels in females were reduced relative to males in vivo. Our finding indicates that estrogen may play a role in gut tight junction expression and permeability.

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Section: Discussionmentioning

confidence: 99%

Estrogen decreases tight junction protein ZO-1 expression in human primary gut tissues

Zhou

Zhang

Ding

et al. 2017

Clinical Immunology

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“…The fact that isRNA induces the synthesis of type 1 interferon but not pro-inflammatory cytokines is important for the evaluation of the inducer as a potential adjuvant, since the inflammatory microenvironment contributes to the development of hepatic fibrosis, cirrhosis, carcinogenesis, and eventually tumor metastasis [29,30]. Pro-inflammatory cytokines TNF-α and IL-6 were found to be the main mediators of HCC invasion [31]. Similar results were reported by other groups [26,32-34]; these data show that 6–7 hours after injection into mice of different types of immunostimulatory siRNA with mixed functions complexed with cationic liposomes, a systemic immune response was induced, accompanied by IFN-α, IL (interleukin)-6, and/or IFN-γ production.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy of hepatocellular carcinoma with small double-stranded RNA

et al. 2014

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BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Since HCC has been shown to be immunogenic, immunotherapy is considered a promising therapeutic approach. Small interfering RNAs (siRNAs), depending on their structure and sequence, can trigger the innate immune system, which can potentially enhance the adaptive anticancer immune response in the tumor-bearing subjects. Immunostimulatory properties of nucleic acids can be applied to develop adjuvants for HCC treatment.MethodsThe transplantable HCC G-29 tumor in male CBA/LacSto (CBA) mice was used to study the effects of immunostimulatory RNA on tumor growth. Tumor size, metastases area in different organs of mice and mouse survival rate were analyzed. Furthermore the mouse serum IFN-α levels were measured using ELISA.ResultsIn the present study, we found that a 19-bp RNA duplex (ImmunoStimulattory RNA or isRNA) with 3-nt overhangs at the 3′-ends of specific sequence displays immunostimulatory, antitumor, and antimetastatic activities in mice bearing HCC G-29. Our results demonstrate that isRNA strongly increases the level of interferon-α (IFN-α) by up to 25-fold relative to the level in mice injected with Lipofectamine alone (Mock), and to a lesser extent increases the level of proinflammatory cytokine interleukin-6 (IL-6) (by up to 5.5-fold relative to the Mock level), in mice blood serum. We showed that isRNA reliably (P < 0.05) inhibits primary tumor growth in mice compared to the mock group. Furthermore, injections of isRNA significantly enhanced necrotic processes in the center of the primary tumor, and decreased by twofold the width of the undifferentiated peripheral zone and the number of mitotic cells in this zone. The results showed that isRNA efficiently reduces the area of metastases in the liver, kidneys, and heart of CBA/LacSto mice with HCC.ConclusionsThe obtained results clearly demonstrate immunostimulatory and antimetastatic properties of the isRNAs in mice with HCC. Consequently, this short double-stranded RNA can be considered as a potential adjuvant for the therapy of HCC.

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“…Previous reports showed that ERs are highly expressed in neoplastic liver, while increased ARs are associated with poor HCC prognosis . Recently, physiological doses of estrogen, no matter endogenous or exogenous, are demonstrated to suppress metastasis of HCC through modulation of inflammatory tumor microenvironment by suppression of HGF and IL‐6 production . Estrogen attenuates HCC progression in vitro and in vivo, and this may contribute to the gender differences in HCC behavior.…”

Section: Noncellular Component Involving Hcc Metastasismentioning

confidence: 99%

Tumor microenviroment and hepatocellular carcinoma metastasis

Wang

Chen

2013

J of Gastro and Hepatol

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The cross talk between tumor cells and the surrounding peritumoral stroma has been extensively studied as a dynamic system involving the processes of hepatocarcinogenesis, tumor invasion, and metastasis in recent few decades. Besides hepatocytes, liver tumor microenvironments are generally classified into cellular and noncellular components, including hepatic stellate cells, fibroblasts, immune, endothelial, mesenchymal stem cells, together with growth factors, cytokines, extracellular matrix, hormone as well as viruses et al. The noncellular components manipulate hepatocellular carcinoma invasion and metastasis by facilitating epithelial-mesenchymal transition, increasing proteolytic activity of matrix metalloproteinases, and regulating antitumor immunity, etc. Because the main cause of death in hepatocellular carcinoma patients is tumor progression with metastasis, a better understanding of the interplay between hepatocytes and their environment during tumor metastasis may be helpful for the discovery of novel molecular targets.

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Estrogen Suppresses Metastasis in Rat Hepatocellular Carcinoma through Decreasing Interleukin-6 and Hepatocyte Growth Factor Expression

Cited by 37 publications

References 14 publications

Estrogen decreases tight junction protein ZO-1 expression in human primary gut tissues

Estrogen decreases tight junction protein ZO-1 expression in human primary gut tissues

Immunotherapy of hepatocellular carcinoma with small double-stranded RNA

Tumor microenviroment and hepatocellular carcinoma metastasis

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