High cytoplasmic HuR expression is associated with advanced pT stage, high grade and increased microvessel density in urothelial bladder carcinoma

Fus, Łukasz; Pihowicz, Paweł; Koperski, Łukasz; Marczewska, Janina; Górnicka, Barbara

doi:10.1016/j.anndiagpath.2017.12.002

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…MVD is used to assess tumor vasculature using an antibody that identifies endothelial cells. Increased MVD has been correlated with adverse pathological factors and poor outcomes in patients with bladder cancer [21,47].…”

Section: Discussionmentioning

confidence: 99%

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Expression of GLUT4 and FAP in urothelial bladder carcinoma: correlation with angiogenesis and clinicopathological characteristics

El-Azeem

Ali

El-Shorbagy

2022

J Egypt Natl Canc Inst

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Background Urothelial carcinoma (UC) is the most common type of bladder cancer. Glucose transporter 4 (GLUT4) is one of glucose transporter proteins’ family which facilitates glucose transport inside the cells. It was found to be overexpressed in several malignant tumors. Cancer-associated fibroblasts (CAFs) are heterogeneous stromal cells located adjacent to cancer cells and are considered one of the most important tumor stromal cells. They have been associated with enhancing tumor growth and invasion. GLUT4 expression in malignant epithelial cells and fibroblast activation protein (FAP) expression in CAFs of UC in relation to angiogenesis and clinicopathological characteristics are studied in this work. Materials and methods The study was carried out on 72 paraffin blocks of UC (27 radical cystectomies and 45 transurethral resections). Immunohistochemical staining was performed with GLUT4, FAP, and CD34 antibodies. Expression of GLUT4 and FAP was classified according to the staining intensities and percentages into low and high groups. CD34-stained microvessels’ mean count in five microscopic fields (×200) was taken as the microvessel density (MVD). Results GLUT4 overexpression was detected in 32 UC. It was significantly associated with high-grade tumors, advanced primary tumor (pT) stage, lymphovascular invasion (LVI), and regional lymph node invasion. High FAP expression was appreciated in 27 UC and was significantly linked to LVI and advanced TNM staging. Intratumor MVD significantly increased in UC with muscle invasion, LVI, and regional lymph node and/or distant metastasis. A significant positive correlation between GLUT4, FAP expression, and MVD was found. Conclusion GLUT4 and FAP expression was significantly associated with increased intratumor MVD and adverse clinicopathological factors.

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Section: Discussionmentioning

confidence: 99%

“…Stained microvessels were counted in five microscopic fields (×200), and the mean number was considered as the microvessel density (MVD). Large vessels with thick muscular walls were excluded from counting [21].…”

Section: Determination Of Microblood Vessel Density (Mvd)mentioning

confidence: 99%

Expression of GLUT4 and FAP in urothelial bladder carcinoma: correlation with angiogenesis and clinicopathological characteristics

El-Azeem

Ali

El-Shorbagy

2022

J Egypt Natl Canc Inst

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“…As stated previously, HuR in normal tissues is primarily localized to the nucleus where it can function in splicing (Akaike et al, ; Izquierdo, ; H. Zhu, Zhou, Hasman, & Lou, ) and alternative polyadenylation (Izquierdo, ; H. Zhu et al, ). However, HuR's regulation of target stability in the cytoplasm is thought to be central to its protumorigenic function (Fus, Pihowicz, Koperski, Marczewska, & Gornicka, ; Gallouzi et al, ; Gauchotte et al, ; Guo et al, ; Hostetter et al, ; Lim et al, ; Melling et al, ; Miyata et al, ; Nowotarski & Shantz, ; Tatarian et al, ; Toyota et al, ; D. Wang et al, ; Z. Zhu et al, ). As HuR cytoplasmic localization is commonly observed in cancer, inhibiting the translocation of HuR from the nucleus to the cytoplasm can be thought of as tantamount to inhibiting HuR's ability to promote tumor progression.…”

Section: Tools For Targeting Hurmentioning

confidence: 99%

“…Zhu et al, 2007). However, HuR's regulation of target stability in the cytoplasm is thought to be central to its protumorigenic function (Fus, Pihowicz, Koperski, Marczewska, & Gornicka, 2018;Gallouzi et al, 2000;Gauchotte et al, 2017;Guo et al, 2016;Hostetter et al, 2008;Lim et al, 2009;Melling et al, 2016;Miyata et al, 2013;Nowotarski & Shantz, 2010;Tatarian et al, 2018;Toyota et al, 2018;D. Wang et al, 2014;Z.…”

Section: Inhibiting Hur Translocationmentioning

confidence: 99%

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

et al. 2020

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Altered gene expression is a characteristic feature of many disease states such as tumorigenesis, and in most cancers, it facilitates cancer cell survival and adaptation. Alterations in global gene expression are strongly impacted by post‐transcriptional gene regulation. The RNA binding protein (RBP) HuR (ELAVL1) is an established regulator of post‐transcriptional gene regulation and is overexpressed in most human cancers. In many cancerous settings, HuR is not only overexpressed, but it is “overactive” as denoted by increased subcellular localization within the cytoplasm. This dysregulation of HuR expression and cytoplasmic localization allows HuR to stabilize and increase the translation of various prosurvival messenger RNA (mRNAs) involved in the pathogenesis of numerous cancers and various diseases. Based on almost 20 years of work, HuR is now recognized as a therapeutic target. Herein, we will review the role HuR plays in the pathophysiology of different diseases and ongoing therapeutic strategies to target HuR. We will focus on three ongoing‐targeted strategies: (1) inhibiting HuR's translocation from the nucleus to the cytoplasm; (2) inhibiting the ability of HuR to bind target RNA; and (3) silencing HuR expression levels. In an oncologic setting, HuR has been demonstrated to be critical for a cancer cell's ability to survive a variety of cancer relevant stressors (including drugs and elements of the tumor microenvironment) and targeting this protein has been shown to sensitize cancer cells further to insult. We strongly believe that targeting HuR could be a powerful therapeutic target to treat different diseases, particularly cancer, in the near future. This article is categorized under: RNA in Disease and Development > RNA in Disease NRA Turnover and Surveillance > Regulation of RNA Stability Translation > Translation Regulation

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“…mRNA turnover by ribonucleoproteins, HuR is one of the best-studied regulators of cytoplasmic mRNA fate (21), and evidence supports its interaction with the 3'-untranslated region of E-cadherin mRNA and regulation of E-cadherin translation (25). In BC, HuR appears to regulate the expression of many urinary tumors-associated molecules (26), and a significant association between positive cytoplasmic HuR signal and high tumor grade, pT stage and micro-vessel density has been reported in BC (27). Differences found between E-cadherin expression levels in both cell lines and between mRNA and protein levels found may be, at least in part, related to the expression of HuR in the murine cell model and modulation of E-cadherin mRNA and protein stability.…”

Section: Expression Of E-cadherin and Emt-related Markers In Mb49 Andmentioning

confidence: 96%

Ephrin-B1 Is a Novel Biomarker of Bladder Cancer Aggressiveness. Studies in Murine Models and in Human Samples

et al. 2020

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Bladder cancer (BC) is the ninth most common cancer worldwide, but molecular changes are still under study. During tumor progression, Epithelial cadherin (E-cadherin) expression is altered and β-catenin may be translocated to the nucleus, where it acts as co-transcription factor of tumor invasion associated genes. This investigation further characterizes E-cadherin and β-catenin associated changes in BC, by combining bioinformatics, an experimental murine cell model (MB49/MB49-I) and human BC samples. In in silico studies, a DisGeNET (gene-disease associations database) analysis identified CDH1 (E-cadherin gene) as one with highest score among 130 BC related-genes. COSMIC mutation analysis revealed CDH1 low mutations rates. Compared to MB49 control BC cells, MB49-I invasive cells showed decreased E-cadherin expression, E-to P-cadherin switch, higher β-catenin nuclear signal and lower cytoplasmic p-Ser33-β-catenin signal, higher Ephrin-B1 ligand and EphB2 receptor expression, higher Phospho-Stat3 and Urokinase-type Plasminogen Activator (UPA), and UPA receptor expression. MB49-I cells transfected with Ephrin-B1 siRNA showed lower migratory and invasive capacity than control cells (scramble siRNA). By immunohistochemistry, orthotopic MB49-I tumors had lower E-cadherin, increased nuclear β-catenin, lower pSer33-β-catenin cytoplasmic signal, and higher Ephrin-B1 expression than MB49 tumors. Similar changes were found in human BC tumors, and 83% of infiltrating tumors depicted a high Ephrin-B1 stain. An association between higher Ephrin-B1 expression and higher stage and tumor grade was found. No association was found between abnormal E-cadherin signal, Ephrin-B1 expression or clinical-pathological parameter. This study thoroughly analyzed E-cadherin and associated changes in BC, and reports Ephrin-B1 as a new marker of tumor aggressiveness.

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High cytoplasmic HuR expression is associated with advanced pT stage, high grade and increased microvessel density in urothelial bladder carcinoma

Cited by 6 publications

References 26 publications

Expression of GLUT4 and FAP in urothelial bladder carcinoma: correlation with angiogenesis and clinicopathological characteristics

Expression of GLUT4 and FAP in urothelial bladder carcinoma: correlation with angiogenesis and clinicopathological characteristics

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

Ephrin-B1 Is a Novel Biomarker of Bladder Cancer Aggressiveness. Studies in Murine Models and in Human Samples

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