Alternative splicing of estrogen receptor alpha in hepatocellular carcinoma

Zhang, Jian; Ren, Jianwei; Wei, Jiamin; Chong, Charing Ching‐Ning; Yang, Dongjie; He, Yulong; Chen, George G.; Lai, Paul Bo San

doi:10.1186/s12885-016-2928-3

Cited by 24 publications

(27 citation statements)

References 28 publications

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“…Toran-Allerand et al reported that 17α-E2 signals through a novel receptor in the brain, which they termed ER-X [29,57]. Although our findings appear to dispute this notion, several reports have shown that ERα exists and functions as multiple alternatively-spliced variants [58][59][60][61][62]. Therefore, we speculate that ER-X may have been a truncated, alternatively-spliced, form of ERα.…”

Section: Discussioncontrasting

confidence: 58%

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Mann

Hadad

Nelson-Holte

et al. 2020

Preprint

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Aging is the greatest risk factor for most chronic diseases. Metabolic dysfunction underlies several chronic diseases, which are further exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging processes, although compliance issues remain paramount due to adverse effects on quality of life.17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanism by which 17α-E2 elicits benefits remain unknown, which has led speculation that an uncharacterized receptor is involved. Herein, we show that 17α-estradiol and 17β-estradiol elicit similar genomic binding and transcriptional activation of ERα and that the ablation of ERα in male mice completely attenuates the beneficial effects of 17α-estradiol. Our findings also suggest that 17α-E2 acts primarily through the liver and/or hypothalamus to elicit benefits, and that 17α-E2 also improves metabolic parameters in male rats. Collectively, these data suggest ERα is a relevant drug target for mitigating chronic diseases in male mammals. KEYWORDS17α-estradiol, aging, estrogen receptor, hypothalamus, liver, metabolism, obesity Aging is the leading risk factor for most chronic diseases, many of which are associated with declines in metabolic homeostasis [1]. Metabolic detriments associated with advancing age are further exacerbated by obesity [2,3], which has risen substantially in the older population (> 65 years) over the past several decades [4,5]. Moreover, obesity in mid-life has been shown to accelerate aging mechanisms and induce phenotypes more commonly observed in older mammals [6][7][8][9][10][11][12]. These observations have led many to postulate that obesity may represent a mild progeria syndrome [13][14][15][16][17]. Although it is well established that dietary interventions, including calorie restriction, can reverse obesity-related metabolic sequelae, many of these strategies are not well tolerated in older patients due to concomitant comorbidities [2,18]. Compliance issues across all age groups also remain a paramount hurdle due to calorie restriction adversely affecting mood, thermoregulation, and musculoskeletal mass [19]. These adverse health outcomes demonstrate the need for pharmacological approaches aimed at curtailing metabolic perturbations associated with obesity and aging.17α-estradiol (17α-E2) is one of the more recently studied compounds to demonstrate efficacy for beneficially modulating obesity-and age-related health outcomes. The NIA Interventions Testing Program (ITP) found that long-term administration of 17α-E2 extends median lifespan of male mice in a dose-dependent manner [20,21]. Our group has been exploring potential mechanisms by which 17α-E2 may improve healthspan and extend lifespan in a sex-specific manner. We have found that 17α-E2 administration reduces food intake and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects [22][23...

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Section: Discussioncontrasting

confidence: 58%

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Mann

Hadad

Nelson-Holte

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…The RNA processing machinery is frequently dysregulated and markedly different expression of spliced isoforms is found in a high proportion of cancer cells . Many studies have demonstrated that spliced variants exhibit different biological functions and contribute to carcinogenesis . In this study, we observed that MTA1dE4 was highly expressed in hepatoma cell lines and HCC tissues, but not in normal liver cells.…”

Section: Discussionmentioning

confidence: 58%

Expression of Metastatic Tumor Antigen 1 Splice Variant Correlates With Early Recurrence and Aggressive Features of Hepatitis B Virus–Associated Hepatocellular Carcinoma

Kao

et al. 2019

Hepatology

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Overexpression of metastatic tumor antigen 1 (MTA1) was correlated with poor prognosis of hepatitis B virus (HBV)‐associated hepatocellular carcinoma (HBV‐HCC). The aim of this study was to examine the clinical significance of the expression of MTA1 and its exon 4‐excluded form (MTA1dE4), the most abundant spliced variant of MTA1, in patients receiving curative resection for HBV‐HCC. We collected 102 patients with HBV‐HCC and received curative resection retrospectively and examined the expressions level of total MTA1/MTA1dE4 in their paired nontumor and tumor liver tissues by using RT‐qPCR. The association between MTA1/MTA1dE4 expression and various tumor features as well as tumor recurrence was analyzed. During the median follow‐up period of 4 years, 25 patients (24.5%) showed early recurrence (within 12 months postresection) and 42 (54.5%) showed late recurrence. In Kaplan‐Meier analysis, MTA1dE4 overexpression in tumor, but not MTA1, was associated with early recurrence (P = 0.0365), but not late recurrence. In multivariate analysis, only alpha‐fetoprotein (AFP) ≥200 ng/mL (P = 0.006) and large tumor size (P = 0.027) were correlated with early recurrence. In the subgroup of patients with AFP <200 ng/mL, high MTA1dE4, but not total MTA1, expression could help predict early recurrence (P = 0.0195). In vitro, wound healing and invasion assays were performed in HCC cells, and MTA1dE4 was found to exhibit a higher ability in promoting migration and invasion of hepatoma cells than full‐length MTA1. Conclusion: MTA1dE4 expression is correlated with more aggressive tumor characteristics and might serve as a more sensitive marker for early recurrence of HBV‐HCC, especially for low‐AFP patients.

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“…Previous study demonstrated that both ERα and ERβ were overexpressed in a proportion of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) [ 70 ]. However, another study shows that the expression of ERα and ERβ were lower in HCC tissues than in normal liver tissues [ 71 ]. The expression of ERα was lower in HCC with portal vein tumor thrombus (PVTT) than those without PVTT, suggesting that ERα-positive HCC is less aggressive [ 72 ].…”

Section: Expression Of Er In Human Tumorsmentioning

confidence: 99%

Mechanisms for estrogen receptor expression in human cancer

et al. 2018

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Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling and brain functions. However, estrogen also promotes mammary, ovarian and endometrial tumorigenesis. Estrogen antagonists and drugs that reduce estrogen biosynthesis have become highly successful therapeutic agents for breast cancer patients. The effects of estrogen are largely mediated by estrogen receptor (ER) α and ERβ, which are members of the nuclear receptor superfamily of transcription factors. The mechanisms underlying the aberrant expression of ER in breast cancer and other types of human tumors are complex, involving considerable alternative splicing of ERα and ERβ, transcription factors, epigenetic and post-transcriptional regulation of ER expression. Elucidation of mechanisms for ER expression may not only help understand cancer progression and evolution, but also shed light on overcoming endocrine therapy resistance. Herein, we review the complex mechanisms for regulating ER expression in human cancer.

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Alternative splicing of estrogen receptor alpha in hepatocellular carcinoma

Cited by 24 publications

References 28 publications

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Expression of Metastatic Tumor Antigen 1 Splice Variant Correlates With Early Recurrence and Aggressive Features of Hepatitis B Virus–Associated Hepatocellular Carcinoma

Mechanisms for estrogen receptor expression in human cancer

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