Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma

Wu, Hua; Yao, Su; Zhang, Shen; Wang, Jing Ru; Guo, Peng; Li, Xiu Ming; Gan, Wen Juan; Mei, Lin; Gao, Tian Ming; Li, Jian Ming

doi:10.1016/j.jhep.2017.01.030

Cited by 32 publications

(31 citation statements)

References 34 publications

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“…From these analyses, a series of appealing candidate genes were identified. Among them we found ERBIN , previously shown to be expressed in hepatocellular carcinoma and to promote tumorigenesis ( 15 ), and FOXA1 , which significantly negatively correlated with ESR1 expression (Pearson Correlation = −0.45; p = 0.014) and is known to regulate ISL1 and PPP1R14C, two other identified estrogen-related genes. Finally, SLC6A8 also attracted our interest based on its significant 2.6-fold overexpression in male lactotroph tumors ( p = 0.00231) and its capacity to be inhibited by estrogens and stimulated by testosterone ( 16 ).…”

Section: Resultsmentioning

confidence: 87%

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

et al. 2018

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Sex-related differences have been reported in various cancers, in particular men with lactotroph tumors have a worse prognosis than women. While the underlying mechanism of this sexual dimorphism remains unclear, it has been suggested that a lower estrogen receptor alpha expression may drive the sex differences observed in aggressive and malignant lactotroph tumors that are resistant to dopamine agonists. Based on this observation, we aimed to explore the molecular importance of the estrogen pathway through a detailed analysis of the transcriptomic profile of lactotroph tumors from 20 men and 10 women. We undertook gene expression analysis of the selected lactotroph tumors following their pathological grading using the five-tiered classification. Chromosomic alterations were further determined in 13 tumors. Functional analysis showed that there were differences between tumors from men and women in gene signatures associated with cell morphology, cell growth, cell proliferation, development, and cell movement. Hundred-forty genes showed an increased or decreased expression with a minimum 2-fold change. A large subset of those genes belonged to the estrogen receptor signaling pathway, therefore confirming the potent role of this pathway in lactotroph tumor sex-associated aggressiveness. Genes belonging to the X chromosome, such as CTAG2, FGF13, and VEGF-D, were identified as appealing candidates with a sex-linked dysregulation in lactotroph tumors. Through our comparative genomic hybridization analyses (CGH), chromosomic gain, in particular chromosome 19p, was found only in tumors from men, while deletion of chromosome 11 was sex-independent, as it was found in most (5/6) of the aggressive and malignant tumors. Comparison of transcriptomic and CGH analysis revealed four genes (CRB3, FAM138F, MATK, and STAP2) located on gained regions of chromosome 19 and upregulated in lactotroph tumors from men. MATK and STAP2 are both implicated in cell growth and are reported to be associated with the estrogen signaling pathway. Our work confirms the proposed involvement of the estrogen signaling pathway in favoring the increased aggressiveness of lactotroph tumors in men. More importantly, we highlight a number of ER-related candidate genes and further identify a series of target molecules with sex-specific expression that could contribute to the aggressive behavior of lactotroph tumors in men.

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Section: Resultsmentioning

confidence: 87%

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

et al. 2018

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“…Conversely, several lines of evidence indicate that oestrogen and its downstream signalling protect against HCC development 36–38. In N-nitrosodiethylamine (DEN)-induced HCC mouse model, it has been shown that ablation of interleukin-6 (IL-6) abolished the gender differences in HCC development, and oestrogen attenuates serum IL-6 levels and IL-6 mRNA levels of Kupffer cell.…”

Section: The Risks Of Liver Cirrhosis and Hccmentioning

confidence: 99%

Alcohol and hepatocellular carcinoma

Matsushita

Takaki

2019

BMJ Open Gastroenterol

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BackgroundAlcohol is classified as a Group 1 carcinogen by the International Agency for Research on Cancer because it induces hepatocellular carcinoma (among other cancers) in humans. An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, and cirrhosis and eventually lead to hepatocellular carcinoma. It has been reported that alcohol abuse increases the relative risk of hepatocellular carcinoma by 3- to 10-fold.Aim and MethodsTo clarify the known mechanisms of alcohol-related carcinogenesis, we searched Pubmed using the terms alcohol and immune mechanism, alcohol and cancer, and immune mechanism and cancer and summarized the articles as a qualitative review.ResultsFrom a clinical perspective, it is well known that alcohol interacts with other factors, such as smoking, viral hepatitis, and diabetes, leading to an increased risk of hepatocellular carcinoma. There are several possible mechanisms through which alcohol may induce liver carcinogenicity, including the mutagenic effects of acetaldehyde and the production of ROS due to the excessive hepatic deposition of iron. Furthermore, it has been reported that alcohol accelerates hepatitis C virus-induced liver tumorigenesis through TLR4 signaling. Despite intense investigations to elucidate the mechanisms, they remain poorly understood.ConclusionThis review summarizes the recent findings of clinical and pathological studies that have investigated the carcinogenic effects of alcohol in the liver.

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“…In our previous study [ 4 ], Erbin interacts with EGFR and promotes tumourigenesis and tumour growth in CRC. Recently, we reported that Erbin interacts with ER-α and helps for Tamoxifen resistance in hepatocellular carcinoma [ 5 ]. Besides these functions, Erbin was suggested involved in Nod2-dependent activation of NF-κB and cytokine secretion by interacting with Nod2 [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Erbin exerts a protective effect against inflammatory bowel disease by suppressing autophagic cell death

Shen

Cai

et al. 2018

Oncotarget

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The pathogenesis and key functional molecules involved in inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) remain unclear. Here, we reported that Erbin, a protein required for the polarity of epithelial cells, is conserved across species and highly expressed in the intestinal mucosa in mice and zebrafish. Pathologically, Erbin expression in the intestinal mucosa was significantly decreased in DSS induced acute colitis mice, IL-10 deficient mice and clinical biopsy specimens from patients with ulcerative colitis. Moreover, Erbin deficient mice are more susceptible to experimental colitis, exhibiting more severe intestinal barrier disruption, with increased histological scores and excessive production of proinflammatory cytokines. Mechanistically, Erbin deficiency or knockdown significantly exacerbated activation of autophagic program and autophagic cell death in vivo and in vitro. And, inhibition of autophagy by Chloroquine attenuates excessive inflammatory response in the DSS-induced colitis mouse model of Erbin deletion. Generally, our study uncovers a crucial role of Erbin in autophagic cell death and IBD, giving rise to a new strategy for IBD therapy by inhibiting excessive activation of autophagy and autophagic cell death.

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Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma

Cited by 32 publications

References 34 publications

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

Alcohol and hepatocellular carcinoma

Erbin exerts a protective effect against inflammatory bowel disease by suppressing autophagic cell death

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