EZH2 in Bladder Cancer, a Promising Therapeutic Target Martínez-Fernández, Mónica; Rubio, Carolina; Segovia, Cristina ...
International Journal of Molecular Sciences,
11/2015, Letnik:
16, Številka:
11
Journal Article, Book Review
Recenzirano
Odprti dostop
Bladder Cancer (BC) represents a current clinical and social challenge. The recent studies aimed to describe the genomic landscape of BC have underscored the relevance of epigenetic alterations in ...the pathogenesis of these tumors. Among the epigenetic alterations, histone modifications occupied a central role not only in cancer, but also in normal organism homeostasis and development. EZH2 (Enhancer of Zeste Homolog 2) belongs to the Polycomb repressive complex 2 as its catalytic subunit, which through the trimethylation of H3 (Histone 3) on K27 (Lysine 27), produces gene silencing. EZH2 is frequently overexpressed in multiple tumor types, including BC, and plays multiple roles besides the well-recognized histone mark generation. In this review, we summarize the present knowledge on the oncogenic roles of EZH2 and its potential use as a therapeutic target, with special emphasis on BC pathogenesis and management.
Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances
. Recent molecular characterization has defined new (epi)genetic drivers and potential targets ...for bladder cancer
. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients
. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten
; Trp53
; Rb1
; Rbl1
) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
Serrated adenocarcinoma (SAC) is a tumor recognized by the WHO as a histological subtype accounting for around 9% of colorectal carcinomas. Compared to conventional carcinomas, SACs are characterized ...by a worse prognosis, weak development of the immune response, an active invasive front and a frequent resistance to targeted therapy due to a high occurrence of KRAS or BRAF mutation. Nonetheless, several high-throughput studies have recently been carried out unveiling the biology of this cancer and identifying potential molecular targets, favoring a future histologically based treatment. This review revises the current evidence, aiming to propose potential molecular targets and specific treatments for this aggressive tumor.
Fascin1 is the key actin-bundling protein involved in cancer invasion and metastasis whose expression is associated with bad prognosis in tumor from different origins.
In the present study, virtual ...screening (VS) was performed for the search of Fascin1 inhibitors and RAL, an FDA-approved inhibitor of human immunodeficiency virus-1 (HIV-1) integrase, was identified as a potential Fascin1 inhibitor. Biophysical techniques including nuclear magnetic resonance (NMR) and differential scanning fluorimetry (DSF) were carried out in order to confirm RAL as a Fascin1 blocker. The effect of RAL on actin-bundling activity Fascin1 was assessed by transmission electron microscopy (TEM), immunofluorescence, migration, and invasion assays on two human colorectal adenocarcinoma cell lines: HCT-116 and DLD-1. In addition, the anti-metastatic potential of RAL was in vivo evaluated by using the zebrafish animal model.
NMR and DSF confirmed in silico predictions and TEM demonstrated the RAL-induced disorganization of the actin structure compared to control conditions. The protrusion of lamellipodia in cancer cell line overexpressing Fascin1 (HCT-116) was abolished in the presence of this drug. By following the addition of RAL, migration of HCT-116 and DLD-1 cell lines was significantly inhibited. Finally, using endogenous and exogenous models of Fascin1 expression, the invasive capacity of colorectal tumor cells was notably impaired in the presence of RAL in vivo assays; without undesirable cytotoxic effects.
The current data show the in vitro and in vivo efficacy of the antiretroviral drug RAL in inhibiting human colorectal cancer cells invasion and metastasis in a Fascin1-dependent manner.
Aims
To estimate the effectiveness of a brief motivational intervention (BMI) in increasing the duration of exclusive breastfeeding in the first 6 months postpartum. A complementary aim was to ...examine a potential mediating role of breastfeeding self‐efficacy in the effectiveness of the BMI.
Background
Breastfeeding is associated with benefits for babies and mothers’ health. Among the pool of techniques used to encourage healthy behaviours, BMI is highlighted based on the principles of motivational interviewing. One of the main components of these interventions is the promotion of self‐efficacy, which, in fact, is a key factor for breastfeeding success.
Design
A multi‐centre randomized controlled clinical trial of parallel groups.
Methods
Women who begin to breastfeed in the first hour after birth will be randomly assigned to the intervention group (receiving a BMI at immediate postpartum plus a telephone booster at the 1st and 3rd month postpartum) or the control group (receiving standard breastfeeding education at the same time). Outcome measures include the following: breastfeeding, breastfeeding self‐efficacy, general self‐efficacy, and postnatal depression. Data will be collected before the intervention and at the 1st, 3rd, and 6th month after birth. The study protocol has been approved by Badajoz Ethics Committee of Clinical Research in October 2017.
Discussion
This study will identify the effectiveness of BMI in improving exclusive breastfeeding rates. The findings will give useful evidence to health professionals about how to support breastfeeding.
Impact
This study will address the low‐exclusive breastfeeding rates, that in our country are far lower than World Health Organization's recommendation.
目的
评估短暂动机干预(BMI)提高产后前6个月纯母乳喂养时间的有效性。
补充目的是检查母乳喂养自我效能在BMI有效性中可能存在的调和作用。
背景
母乳喂养对婴儿和母亲的健康都有好处。在鼓励健康行为的潜在技术中,BMI因为其动机干预的原则而突出。其中一项主要的干预措施是提高自我效能,而这也是母乳喂养成功的关键因素。
设计
平行组多中心随机对照临床试验。
方法
出生后第一个小时开始母乳喂养的妇女将被随机分配到干预组(产后立即接受BMI,产后第一个月和第三个月接受电话辅助)或对照组(同时接受标准母乳喂养教育)。
结果测量包括以下内容:母乳喂养、母乳喂养自我效能、一般自我效能和产后抑郁。在干预前以及出生后1、3和6个月收集数据。2017年10月,巴达赫兹临床研究伦理委员会批准了该研究提案。
讨论
本研究将确定BMI提高纯母乳喂养率的有效性。研究结果将为卫生专业人员提供关于支持母乳喂养的可靠证据。
影响
本研究将解决纯母乳喂养率低的问题,在我国,纯母乳喂养率远低于世界卫生组织的建议喂养率。
To quantify the association between the presence and type of drug detected and trauma recidivism in a cohort of patients admitted due to trauma.
A cohort study was conducted based on data from a ...project where the presence of alcohol and other drugs (cannabis, cocaine, amphetamines, methamphetamines, tricyclic antidepressants, barbiturates, opiates and benzodiazepines) was analysed in 1,187 patients aged 16 to 70 years admitted due to trauma. The patients were followed for a period of between 10 to 52 months until June 2016. For this study, the recurrence of injuries from a sample of 929 patients from this cohort was analysed according to their consumption profile. Survival curves were estimated and adjusted Hazard Rate Ratios (aHRR) and adjusted incidence rate ratios (aIRR) were calculated.
The incidence rate of TR was 10.94 cases per 100 patient-years in the group of patients negative for substances and 27.99 per 100 patient-years in positive patients. The survival curves show very significant differences in cumulative recurrence-free survival between the groups (Log Rank: p<0.001). Both the aHRR and the aIRR estimates show an increased risk of re-injury due to alcohol consumption (aIRR: 2.33 (1.72-3.15), p<0.001), cannabis use (aIRR: 1.87 (1.09-3.20), p = 0.022) and polydrug use (aIRR: 2.34 (1.80-3.04), p<0.001).
The presence of alcohol and/or illicit drugs in these patients doubles the risk of trauma recidivism.
The high rates of tumor recurrence and progression represent a major clinical problem in non-muscle invasive bladder cancer. Previous data showed that EZH2-dependent signaling mediates these ...processes, whereas the frequent alterations of PIK3CA gene (copy gains and mutations) are predictive of reduced recurrence. Here we show, using clinical samples and bladder cancer cell lines, a functional interaction between EZH2- and PIK3CA-dependent signaling pathways. PIK3CA alterations mediated, on the one hand, the increased expression of two miRNAs, miR-101 and miR-138, which posttranscriptionally downregulate EZH2 expression. On the other hand, PIK3CA alterations facilitate the activation of Akt which phosphorylates EZH2 on Ser21, precluding the trimethylation of histone H3 in K27. Remarkably the increased expression of miR101 or miR138 and the expression of Ser21-phosphorylated EZH2 are good prognostic factors regarding non-muscle invasive bladder cancer recurrence and progression. Collectively, this study provides molecular evidences indicating that the gene expression rewiring occurring in primary bladder tumors, associated with increased EZH2 expression and activity and mediating the increased recurrence and progression risk, are prevented by PIK3CA-dependent signaling. This molecular process may have deep implications in the management of bladder cancer patients and in the design of novel molecularly targeted therapeutic approaches.
Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor ...(EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors.
Bladder cancer is a current clinical and social problem. At diagnosis, most patients present with nonmuscle-invasive tumors, characterized by a high recurrence rate, which could progress to ...muscle-invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in bladder cancer is still unclear.
Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed
by experiments with bladder cancer cell lines and peripheral blood monocyte-derived macrophages.
We observed
expression is associated and favored type II macrophage differentiation.
experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from bladder cancer cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL10. Using a series of human bladder cancer patient samples, we also observed increased expression of
in advanced and undifferentiated tumors in close correlation with epithelial-mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced
expression.
These findings suggest that BMP4 secretion by bladder cancer cells provides the M2 signal necessary for a protumoral immune environment. In addition, the repression of
by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth.
.
Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of ...standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP).
Bladder cancer cell lines were tested for
sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its
activity.
Cell lines tested were sensitive to CDK4/6 inhibition, independent on
gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation
and
and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer.
CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for patients with advanced bladder cancer previously classified as unfit for current treatment options.
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