Immunohistochemical negative expression of ezrin predicts poor prognosis in clear cell renal cell carcinoma

doi:10.1016/j.urolonc.2019.09.011

Urologic Oncology: Seminars and Original Investigations

Volume 38, Issue 3, March 2020, Pages 75.e1-75.e7

https://doi.org/10.1016/j.urolonc.2019.09.011 Get rights and content

Highlights

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Ezrin and moesin are proteins that link actin cytoskeleton to cell membrane.
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These proteins are important in cell adhesion, migration, and growth.
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Absence of ezrin is related with poor survival rates in kidney cancer.
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Ezrin may be considered as a biomarker in renal cell carcinoma.

Abstract

Purpose

To analyze the immunohistochemical expression of ezrin and moesin in clear cell renal cell carcinoma (ccRCC). These proteins, as part of the ezrin-radixin-moesin complex link the cell membrane to the actin cytoskeleton, affecting such processes as cell adhesion, cell survival, cell motility, and signal transduction. Our aim was to examine the impact of their expression on clinical outcomes and survival rates.

Patients and methods

Five hundred seventy-five consecutive patients who had been treated surgically for ccRCC in a single center between 1985 and 2016 were selected. A single pathologist reviewed all cases to perform a uniform reclassification and determined the most representative tumor areas for construction of a tissue microarray.

Results

Of all ccRCC specimens, 106 (18.3%) were negative for ezrin, and 469 (81.7%) had positive ezrin expression; 16 (2.8%) were negative and 559 (97.2%) were positive for moesin, respectively. Ezrin expression was associated with pT stage (P < 0.001), clinical stage (P = 0.012), synchronic metastasis (P < 0.001), incidental tumors (P = 0.007), and International Society of Urological Pathology histological grade (P = 0.025). There was a correlation between moesin expression and clinical stage (P = 0.027), pT stage (P = 0.025), and pN stage (P = 0.007). Ezrin expression significantly influenced tumor-related deaths. By multivariate analysis, negative ezrin expression was an independent risk factor for disease-specific survival (HR 1.89; 95% CI 1.11–3.20).

Conclusions

Negativity for ezrin in ccRCC patients significantly impacts survival rates. We encourage further prospective studies to analyze ezrin analysis to evaluate its significance in the prognosis of ccRCC.

Introduction

Renal cell carcinoma (RCC) accounts for 2.2% of all adult malignancies worldwide, and its incidence has increased in recent years. Four hundred thousand new cases are estimated in 2018, and 175.000 deaths are expected due to kidney cancer globally [1]. Improvements in diagnostic methods have raised the incidence of small renal masses (SRMs) [2]. These tumors can be treated by surgery, ablative procedures, and even active surveillance [2]. In this context, aggressive RCCs must be distinguished from indolent RCCs, and biomarkers could provide greater accuracy in the decision-making process. In localized RCC, guidelines consider surgery as the main treatment, and there is no consensus with regard to adjuvant therapy [3,4].

Several biomarkers are being examined for RCC [5,6], 1 of which is the ezrin-radixin-moesin complex. These closely related 80-kDa proteins—notably, ezrin and moesin—are key signaling molecules that mediate many processes, such as cell adhesion, cell survival, cell motility, and signal transduction [7,8]. High expression of ezrin and moesin correlates with worse survival rates in several tumors [9], such as head and neck [10], stomach, and colorectal cancers [11]. Due to the relevance of their functions, the clinical impact of their expression, and their association with length of survival, ezrin and moesin are potential prognostic factors in kidney cancer.

The aim of this study was to examine the expression of ezrin and moesin in RCCs and determine their prognostic value with regard to survival rates.

Section snippets

Patients

Five hundred seventy-five cases that involved radical or partial nephrectomy for clear cell renal cell carcinoma (ccRCC) between 1985 and 2016 were selected from the medical records of our institution. Their clinical data were obtained from medical charts in the hospital archives. Patients were evaluated quarterly in the first 2 years and every 6 months thereafter. A single pathologist (MAMM) reviewed all cases to effect uniform reclassification and selected the most representative tumor areas

Results

A total of 284 patients had radical nephrectomy, and 291 patients were treated with nephron-sparing surgeries. Their ages ranged from 21 to 85 years old, with an average age of 55.1 years. The mean postoperative follow-up period was 43.1 months. There was metastatic disease at initial clinical presentation in 73 (12.7%); 386 (67.1%) patients presented with T1 stage disease. The entire cohort mean tumor size was 7.2 cm. At the end of the study, 95 patients died; most of them, 84 (14.6%)

Discussion

The number of tumors that are diagnosed in the early stages is rising due to the increasing use of imaging procedures—particularly ultrasonography and computed tomography [2]. SRM constitutes a significant percentage of tumors that are diagnosed incidentally [12]. Approximately 70% to 80% of such lesions are low-grade and early-stage RCC, which are believed to lack the potential for aggressive behavior, such as tumor progression and metastasis [2]. Percutaneous renal biopsies have expanded

Conflicts of interest

None

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Cited by (2)

Ezrin gone rogue in cancer progression and metastasis: An enticing therapeutic target
2022, Biochimica et Biophysica Acta - Reviews on Cancer
Citation Excerpt :
A recent study has shown that Ezrin inhibits proliferation, anchorage-independent growth and migration while promoting differentiation of neuroblastoma cells by interacting with a tumor suppressor CHL1 (close homolog of L1) [129]. Interestingly, it is reported that higher Ezrin expression is correlated with better patient's survival in Ewing sarcoma [85], urothelial bladder cancer [114–116], ccRCC [139], invasive ductal carcinoma of the pancreas [137], ovarian cancer [131], colorectal adenocarcinoma (CRA) [128] and nodal peripheral T-cell lymphomas [101]. Thus, Ezrin plays a suppressive role in growth, motility and invasion of some cancer types.
Cancer metastasis is the primary cause of morbidity and mortality in cancer as it remains the most complicated, devastating, and enigmatic aspect of cancer. Several decades of extensive research have identified several key players closely associated with metastasis. Among these players, cytoskeletal linker Ezrin (the founding member of the ERM (Ezrin-Radixin-Moesin) family) was identified as a critical promoter of metastasis in pediatric cancers in the early 21st century. Ezrin was discovered 40 years ago as a aminor component of intestinal epithelial microvillus core protein, which is enriched in actin-containing cell surface structures. It controls gastric acid secretion and plays diverse physiological roles including maintaining cell polarity, regulating cell adhesion, cell motility and morphogenesis. Extensive research for more than two decades evinces that Ezrin is frequently dysregulated in several human cancers. Overexpression, altered subcellular localization and/or aberrant activation of Ezrin are closely associated with higher metastatic incidence and patient mortality, thereby justifying Ezrin as a valuable prognostic biomarker in cancer. Ezrin plays multifaceted role in multiple aspects of cancer, with its significant contribution in the complex metastatic cascade, through reorganizing the cytoskeleton and deregulating various cellular signaling pathways. Current preclinical studies using genetic and/or pharmacological approaches reveal that inactivation of Ezrin results in significant inhibition of Ezrin-mediated tumor growth and metastasis as well as increase in the sensitivity of cancer cells to various chemotherapeutic drugs. In this review, we discuss the recent advances illuminating the molecular mechanisms responsible for Ezrin dysregulation in cancer and its pleiotropic role in cancer progression and metastasis. We also highlight its potential as a prognostic biomarker and therapeutic target in various cancers. More importantly, we put forward some potential questions, which we strongly believe, will stimulate both basic and translational research to better understand Ezrin-mediated malignancy, ultimately leading to the development of Ezrin-targeted cancer therapy for the betterment of human life.
Could Moesin Be a New Marker for Indicating Progression in Endometrial Cancer?
2022, Cancer Management and Research

: Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

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Laboratory-Kidney cancerImmunohistochemical negative expression of ezrin predicts poor prognosis in clear cell renal cell carcinoma

Highlights

Abstract

Purpose

Patients and methods

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Conflicts of interest

Lancet (London, England)

Urol Oncol Semin Orig Investig

Curr Opin Cell Biol

J Urol

J Urol

Int J Biochem Cell Biol

Curr Opin Cell Biol

J Gastrointest Surg

J Exp Clin Cancer Res

Eur Urol

Gynecol Oncol

Cancer Cell

Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

CA Cancer J Clin

Active surveillance for small renal masses

Rev Urol

Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy

N Engl J Med

Laboratory-Kidney cancer
Immunohistochemical negative expression of ezrin predicts poor prognosis in clear cell renal cell carcinoma