High Levels of Ezrin Expressed by Human Pancreatic Adenocarcinoma Cell Lines with High Metastatic Potential

Akisawa, Naoaki; Nishimori, Isao; Iwamura, Takeshi; Onishi, Saburo; Hollingsworth, Michael A.

doi:10.1006/bbrc.1999.0653

Cited by 131 publications

(94 citation statements)

References 19 publications

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“…Although several authors have speculated that the ERM proteins may play a role in cancer (Tsukita et al, 1994), data concerning their expression in tumors are rather limited (Akisawa et al, 1999;Ichikawa et al, 1998). Interestingly, the neurofibromatosis 2 (NF2) tumor suppressor gene encodes a protein (merlin or schwannomin) structurally related to the ERM family of proteins (Rouleau et al, 1993;Trofatter et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…The ERM proteins bind to actin filaments at their carboxy-terminal domain (Algrain et al, 1993;Henry et al, 1995;Turunen et al, 1994), and to several integral membrane proteins, such as CD43, CD44, and ICAM-1, -2, and -3, and so on, at their aminoterminal domains (Heiska et al, 1998;Mangeat et al, 1999;Yonemura et al, 1998). The ERM proteins are involved in a variety of cellular functions, such as cell adhesion, migration, and the organization of cell surface structures (Bretscher et al, 1997;Mangeat et al, 1999;Martin et al, 1995;Sato et al, 1991Sato et al, , 1992.Although several authors have speculated that the ERM proteins may play a role in cancer (Tsukita et al, 1994), data concerning their expression in tumors are rather limited (Akisawa et al, 1999;Ichikawa et al, 1998). Interestingly, the neurofibromatosis 2 (NF2) tumor suppressor gene encodes a protein (merlin or schwannomin) structurally related to the ERM family of proteins (Rouleau et al, 1993;Trofatter et al, 1993).…”

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Altered Expression of the ERM Proteins in Lung Adenocarcinoma

Tokunou

Niki²,

Saitoh

et al. 2000

Laboratory Investigation

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SUMMARY:Radixin is a member of the ERM (ezrin/radixin/moesin) protein family that is proposed to function as a membrane-cytoskeletal linker. Using differential display analysis, we have identified radixin as a gene down-regulated in primary lung adenocarcinoma. Real-time quantitative reverse transcription polymerase chain reaction confirmed that radixin mRNA was decreased, both in 10 early-stage bronchioloalveolar carcinomas and in 16 invasive lung adenocarcinomas, by 69% (p ϭ 0.0002) and 82% (p Ͻ 0.0001), respectively, compared with 9 nontumor lung tissues. Similarly, moesin and ezrin mRNA levels were reduced in lung adenocarcinoma. Immunohistochemistry confirmed that cancer cells expressed very little radixin and moesin, whereas non-neoplastic alveolar and bronchiolar epithelial cells, and endothelial cells, including those within the tumor stroma, were consistently positive for these two proteins. Ezrin was localized in the apical surface of non-neoplastic bronchiolar and alveolar epithelial cells and, in contrast to radixin and moesin, the majority of tumor cells retained expression of ezrin. Localization of ezrin was altered in a significant proportion of tumor cells: whereas tumor cells forming lumina displayed membranous staining on the apical side, tumor cells with disorganized structures were either negative or diffusely positive for ezrin in the cytoplasm. Furthermore, a fraction of tumor cells invading the stroma in a scattered manner were strongly positive for ezrin. In conclusion, expression of radixin and moesin is down-regulated in lung adenocarcinoma, including early-stage bronchioloalveolar carcinoma. An intriguing implication of this finding is that these two genes may function as tumor suppressors in lung adenocarcinoma oncogenesis. Although structurally related to radixin and moesin, ezrin may have a distinct function in tumor-cell invasion. (Lab Invest 2000, 80:1643-1650.O f the various malignant tumors, lung cancer is the most common cause of cancer death worldwide. However the biological behavior of lung cancer is not fully characterized, and the outcome of surgical treatment remains unsatisfactory. Identification of genes that are involved in tumorigenesis and in the progression of lung cancer will be required to formulate more effective therapies. One approach to the identification of such genes is to use differential display analysis (Bauer et al, 1993;Liang et al, , 1993Sager et al, 1993;Yoshikawa et al, 1998).Radixin is a member of the ERM (ezrin/radixin/ moesin) family of proteins (Mangeat et al, 1999;Sato et al, 1992), which was first isolated as a constituent of adherence junctions in rat liver (Tsukita and Hieda, 1989). Ezrin was first purified as a component of intestinal microvilli that is tyrosine-phosphorylated by epidermal growth factor receptor (EGFR; Bretscher, 1989), and moesin was originally identified as a heparin-binding protein (Lankes and Furthmayr, 1991). The amino-terminal half of the ERM protein is about 85% homologous, whereas homology in the carboxy-terminal hal...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Altered Expression of the ERM Proteins in Lung Adenocarcinoma

Tokunou

Niki²,

Saitoh

et al. 2000

Laboratory Investigation

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“…1,2 In human tumors, ezrin deregulation or impaired functionality is related to poor prognosis. [3][4][5][6][7][8][9] Ezrin belongs to the MERM family of cytoskeleton-associated proteins 10 and functions as a linker between the actin cortical cytoskeleton and various membrane-bound molecules 11,12 through its C-terminal and N-terminal domains, respectively.ERM proteins are implicated in a wide variety of important cellular processes. 10,13-18 Notably, ezrin is primarily involved in both cell-to-cell adhesion and cell adhesion to the ECM through association with ICAMs, CD44, E-cadherin and b-catenin.…”

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Pleiotropic function of ezrin in human metastatic melanomas

Federici

Brambilla

Lozupone

et al. 2009

Intl Journal of Cancer

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The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors. ' UICCKey words: CD44; merlin; Lamp-1; phagocytic vacuole; organelle acidity The molecular events governing progression from a primary tumor to an invasive, malignant tumor remain poorly defined despite intense scientific endeavor mostly due to molecular biology and biochemical data collected from non human models. 1 The metastatic phenomenon is characterized by a cascade of events that assumes the existence of very harmful cells within the primitive tumor mass. These cells must acquire the ability to breach underlying basement membrane, migrate through interstitial stroma, gain access to and migrate through blood or lymphatic vessels, attach, enter, survive and proliferate within metastatic organs.Mounting evidence suggesting that ezrin contributes to tumor metastasis promotion, arose mainly from experiments employing syngeneic implantation models correlated to gene expression profiling performed on pediatric tumors. 1,2 In human tumors, ezrin deregulation or impaired functionality is related to poor prognosis. [3][4][5][6][7][8][9] Ezrin belongs to the MERM family of cytoskeleton-associated proteins 10 and functions as a linker between the actin cortical cytoskeleton and various membrane-bound molecules 11,12 through its C-terminal and N-terminal domains, respectively.ERM proteins are implicated in a wide variety of important cellular processes. 10,13-18 Notably, ezrin is primarily involved in both cell-to-cell adhesion and cell adhesion to the ECM through association with ICAMs, CD44, E-cadherin and b-catenin. 12,19 To this family belongs also the tumor suppressor merlin (NF-2, schwannomin), whose loss is r...

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“…3 Recent studies suggest a metastasis-promoting role for ezrin in several tumor entities by facilitating tumor cell motility. These include pancreatic carcinoma, 4 breast carcinoma, 5 ovarian carcinoma, 6,7 melanoma, 8 and osteosarcoma. 9 Furthermore, inhibition of ezrin by antisense oligonucleotides blocked invasiveness of endometrial adenocarcinoma cell lines.…”

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Ezrin expression is related to poor prognosis in FIGO stage I endometrioid carcinomas

et al. 2006

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As a cortical cytoskeletal protein, ezrin adapts the cytoplasmic tail of CD44 to the actin-based cytoskeleton and is functionally involved in migration and adhesion that are prerequisites for metastasis. To assess the importance of ezrin and its associated protein osteopontin for the progression of endometrioid carcinoma in FIGO stage I, we analyzed paraffin-embedded tissue from 164 patients by immunohistochemistry and correlated these data with clinicopathological parameters. Ezrin was expressed in normal proliferating endometrial glands, as was confirmed by quantitative PCR and immunohistochemistry. In endometrioid carcinoma, enhanced ezrin expression correlated with a reduced overall survival in univariate analysis (P ¼ 0.041). In contrast, no significant correlation was found for osteopontin. In multivariate survival analysis, among FIGO grade 3 and age, ezrin was still found to be an independent risk factor (relative risk 2.2, confidence interval 1.0-5.4, P ¼ 0.047). Hence, elevated ezrin expression is a new independent prognostic marker in FIGO stage I endometrioid carcinoma, and thus provides further evidence for an important role of ezrin in tumor progression.

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High Levels of Ezrin Expressed by Human Pancreatic Adenocarcinoma Cell Lines with High Metastatic Potential

Cited by 131 publications

References 19 publications

Altered Expression of the ERM Proteins in Lung Adenocarcinoma

Altered Expression of the ERM Proteins in Lung Adenocarcinoma

Pleiotropic function of ezrin in human metastatic melanomas

Ezrin expression is related to poor prognosis in FIGO stage I endometrioid carcinomas

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