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Recurrence and progression rates vary widely among different histological subtypes of bladder cancer (BC). Normal-appearing mucosa in non-muscle invasive bladder cancer and muscle-invasive bladder cancer in cystoscopy and histopathology is a factor in staging and treatment. Telocytes (TCs) are spindle-shaped cells that connect with other cell types allowing communication though cytoskeletal signaling. They are involved in tissue regeneration and pathogenesis of diseases and cancer. In this study, 12 normal-appearing tissues from urinary bladder with BC, both invasive and non-invasive were evaluated in patients who had either trans-urethral resection of bladder tumor or cystectomy. In each case, cystoscopy, intraoperative inspection, and histopathology all confirmed the absence of cancerous elements. Five patients with neurogenic bladder were used as a control group. Immunohistochemistry revealed that c-Kit + cells were intensively distributed in bladder layers from BC samples, while they were seldom detected in the control group. Ultrastructural examination of reprocessed tissue showed an intense distribution of TCs and telopodes in the submucosa and between smooth muscle cells in BC. Telopodes were numerous, arborizing, and intercommunicating. Whereas TCs and telopodes were scarce in the neurogenic bladder. Also, cancerous tissue had the highest expression level of ezrin protein, and this level gradually decreased as we moved away from the tumor. Our finding of TCs number in normal-appearing tissues in conjunction with ezrin expression may compete invasiveness and possibly a trail to reduce recurrence rates. [ABSTRACT FROM AUTHOR]

Introduction: Podoplanin and ezrin connection through Rho-A phosphorylation have been suggested as part of the activation pathway, in the process of tumor invasion and cell movement in oral squamous cell carcinomas. Objective: The aim of this study was to evaluate the correlation among podoplanin, ezrin, and Rho-A immunoexpressions in 91 squamous cells carcinomas of the lower lip and their influence in patient's prognosis. Material and methods: The immunoexpressions of podoplanin, ezrin, and Rho-A were evaluated through a semi-quantitative score method, based on the capture of 10 microscopic fields at the front of tumor invasion. The association and correlation of these proteins with the clinicopathological features were verified by Fischer's exact test and Spearman's test. The prognostic values were analyzed by Kaplan-Meier method and log-rank test. Results: A statistically significant association between strong cytoplasmic podoplanin expression and alcohol ( p = 0.024), loco-regional recurrences ( p = 0.028), and lymph node metastasis (pN+) ( p = 0.010) was found. The membranous ( p = 0.000 and r = 0.384) and cytoplasmic ( p = 0.000 and r = 0.344) podoplanin expression was statistically correlated with ezrin expression. Also, membranous podoplanin was significantly correlated with Rho-A expression ( p = 0.006 and r = 0.282). The expressions of podoplanin, ezrin, and Rho-A were not significant prognostic factors for patients with squamous cell carcinomas of the lower lip. Conclusions: Therefore, our results confirm a correlation among podoplanin, ezrin, and Rho-A expressions in squamous cell carcinoma of the lip suggesting a cooperative participation of these proteins in cell movement and invasion. Clinical relevance: Furthermore, strong cytoplasmic podoplanin expression could be helpful to identify patients with squamous cell carcinoma of the lip and lower risk of loco-regional recurrences. [ABSTRACT FROM AUTHOR]

Purpose: Cancer cells and cancer-associated fibroblasts (CAFs) together create the tumor microenvironment, which affects malignant behavior. Lung adenocarcinomas with CAFs expressing podoplanin (PDPN) are clinically aggressive, but the molecular mechanism underlying this phenomenon has not been established. So we identified the characteristic immunophenotype of lung adenocarcinoma cells coexisting with PDPN-expressing CAFs (PDPN-CAFs) and examined how it relates to an aggressive clinicopathological outcome. Methods: We analyzed the clinicopathological characteristics of 119 adenocarcinomas with a uniform size (2-3 cm). The expression levels of ten invasiveness-related proteins which related to cell adhesion and invasiveness, such as Ezrin, were examined in cancer cells from PDPN-CAFs (+) cases and from PDPN-CAFs (−) cases ( n = 20 each). To examine the functional importance of the identified protein on the invasion phenotype, we performed wound healing and a Matrigel invasion assay using shRNA-knockdown lung adenocarcinoma cells (PC-9). Results: The PDPN-CAFs (+) cases had significantly higher rates of node metastasis ( p < 0.01) and vascular invasion ( p < 0.01). The cancer cells from the PDPN-CAFs (+) cases also had a significantly higher staining score for Ezrin ( p < 0.01) than those from the PDPN-CAFs (−) cases. The migration and invasion activities of the shEzrin-induced PC-9 cells were significantly lower than those of the control cells. Conclusions: Our results indicated that within a tumor microenvironment composed of PDPN-CAFs, increased Ezrin expression in cancer cells might play a key role in the invasiveness of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Desmoglein 3 (Dsg3), the pemphigus vulgaris antigen, has recently been shown to be upregulated in squamous cell carcinoma (SCC) and has been identified as a good tumor-specific marker for clinical staging of cervical sentinel lymph nodes in head and neck SCC. However, little is known about its biological function in cancer. The actin-binding protein Ezrin and the activator protein 1 (AP-1) transcription factor are implicated in cancer progression and metastasis. Here, we report that Dsg3 regulates the activity of c-Jun/AP-1 as well as protein kinase C (PKC)-mediated phosphorylation of Ezrin-Thr567, which contributes to the accelerated motility of cancer cells. Ectopic expression of Dsg3 in cancer cell lines caused enhanced phosphorylation at Ezrin-Thr567 with concomitant augmented membrane protrusions, cell spreading and invasive phenotype. We showed that Dsg3 formed a complex with Ezrin at the plasma membrane that was required for its proper function of interacting with F-actin and CD44 as Dsg3 knockdown impaired these associations. The increased Ezrin phosphorylation in Dsg3-overexpressing cells could be abrogated substantially by various pharmacological inhibitors for Ser/Thr kinases, including PKC and Rho kinase that are known to activate Ezrin. Furthermore, a marked increase in c-Jun S63 phosphorylation, among others, was found in Dsg3-overexpressing cells and the activation of c-Jun/AP-1 was further supported by a luciferase reporter assay. Taken together, our study identifies a novel Dsg3-mediated c-Jun/AP-1 regulatory mechanism and PKC-dependent Ezrin phosphorylation that could be responsible for Dsg3-associated cancer metastasis. [ABSTRACT FROM AUTHOR]

L1, a neuronal cell adhesion receptor of the immunoglobulin-like protein family is expressed in invading colorectal cancer (CRC) cells as a target gene of Wnt/β-catenin signaling. Overexpression of L1 in CRC cells enhances cell motility and proliferation, and confers liver metastasis. We recently identified ezrin and the IκB-NF-κB pathway as essential for the biological properties conferred by L1 in CRC cells. Here, we studied the underlying molecular mechanisms and found that L1 enhances ezrin phosphorylation, via Rho-associated protein kinase (ROCK), and is required for L1-ezrin co-localization at the juxtamembrane domain and for enhancing cell motility. Global transcriptomes from L1-expressing CRC cells were compared with transcriptomes from the same cells expressing small hairpin RNA (shRNA) to ezrin. Among the genes whose expression was elevated by L1 and ezrin we identified insulin-like growth factor-binding protein 2 (IGFBP-2) and showed that its increased expression is mediated by an NF-κB-mediated transactivation of the IGFBP-2 gene promoter. Expression of a constitutively activated mutant ezrin (Ezrin567D) could also increase IGFBP-2 levels in CRC cells. Overexpression of IGFBP-2 in CRC cells lacking L1-enhanced cell proliferation (in the absence of serum), cell motility, tumorigenesis and induced liver metastasis, similar to L1 overexpression. Suppression of endogenous IGFBP-2 in L1-transfected cells inhibited these properties conferred by L1. We detected IGFBP-2 in a unique organization at the bottom of human colonic crypts in normal mucosa and at increased levels throughout human CRC tissue samples co-localizing with the phosphorylated p65 subunit of NF-κB. Finally, we found that IGFBP-2 and L1 can form a molecular complex suggesting that L1-mediated signaling by the L1-ezrin-NF-κB pathway, that induces IGFBP-2 expression, has an important role in CRC progression. [ABSTRACT FROM AUTHOR]

The development of pulmonary metastasis is the major cause of death in osteosarcoma, and its molecular basis is poorly understood. In this study, we show that β4 integrin is highly expressed in human osteosarcoma cell lines and tumor samples. Furthermore, highly metastatic MNNG-HOS cells have increased levels of β4 integrin. Suppression of β4 integrin expression by shRNA and disruption of β4 integrin function by transfection of dominant-negative β4 integrin was sufficient to revert this highly metastatic phenotype in the MNNG-HOS model without significantly affecting primary tumor growth. These findings suggest a role for β4 integrin expression in the metastatic phenotype in human osteosarcoma cells. In addition, we identified a previously uncharacterized interaction between β4 integrin and ezrin, a membrane-cytoskeletal linker protein that is implicated in the metastatic behavior of osteosarcoma. The β4 integrin–ezrin interaction appears to be critical for maintenance of β4 integrin expression. These data begin to integrate ezrin and β4 integrin expression into a model of action for the mechanism of osteosarcoma metastases. [ABSTRACT FROM AUTHOR]

The change of cell mobility is one of the preconditions of tumor metastasis. Cell skeleton alteration and rearrangement of F-actin was closely related to cell mobility. Ezrin is a membrane-cytoskeleton organizer that can mediate the rearrangement and the function of F-actin. In this paper, we investigated the effect of ezrin on hepatocellullar carcinoma cell growth and invasiveness. Hepatocellular carcinoma cell lines such as MHCC-1, MHCC97-H, SF7721, SMMC7721, Hep3B, and HepG2 were chosen in this study. We first examined the expression and the distribution of ezrin and F-actin in these cell lines using immunofluorescence, RT–PCR, and the western blot. Next we used small interfering RNA (siRNA) to down-regulate ezrin expression in MHCC-1, MHCC97-H, SF7721, and HepG2 to investigate the role of ezrin in tumor cell growth and invasiveness. Our preliminary results showed that the expression of ezrin and γ-actin in MHCC-1, MHCC97-H, and SF7721 with higher metastatic potential were obviously up-regulated than those in SMMC7721, Hep3B, and HepG2 with lower potential. No different expression of β-actin was found in the above tumor cell lines. The outcome of RNAi indicated that decreasing ezrin expression can notably inhibit the proliferation of the four hepatocellular carcinoma cell lines ( p < 0.01, n = 10). The proportion of cells in G2-M phase also decreased after RNAi. The number of pseudopods decreased as well after RNAi treatment ( p < 0.01, n = 5). The mobility and invasiveness of cancer cells decreased with decreasing ezrin expression tested by transwell assay ( p < 0.01, n = 8). Ezrin plays an important role in the process of hepatocellular carcinoma cell proliferation, migration, and invasiveness. [ABSTRACT FROM AUTHOR]