A glimpse of the ERM proteins

In all eukaryotes, the plasma membrane is critically important as it maintains the architectural integrity of the cell. Proper anchorage and interaction between the plasma membrane and the cytoskeleton is critical for normal cellular processes. The ERM (ezrin-radixin-moesin) proteins are a class of highly homologous proteins involved in linking the plasma membrane to the cortical actin cytoskeleton. This review takes a succinct look at the biology of the ERM proteins including their structure and function. Current reports on their regulation that leads to activation and deactivation was examined before taking a look at the different interacting partners. Finally, emerging roles of each of the ERM family members in cancer was highlighted

Hsulf‐1 regulates growth and invasion of pancreatic cancer cells

BACKGROUND: Hsulf‐1 is a newly identified enzyme with arylsulphatase activity that can regulate the sulphation state of cell‐surface heparan sulphate proteoglycans (HSPGs). In vitro overexpression of this enzyme in pancreatic cancer cells decreases responsiveness to fibroblastic growth factor‐2, as Hsulf‐1 is up regulated in primary pancreatic adenocarcinoma. AIM: To further analyse the functions of the Hsulf‐1 enzyme in vitro and in vivo with respect to growth, invasion and tumorigenicity. METHODS AND RESULTS: Transfection of Panc‐1 pancreatic cancer cells with a full‐length Hsulf‐1 expression vector resulted in increased invasiveness and adhesiveness. An in vivo xenograft nude mouse tumour model showed a markedly reduced growth potential of Hsulf‐1‐expressing Panc‐1 cells, which correlated with a considerably lower proliferation rate. Hsulf‐1‐positive nude mouse tumours showed better development of interstitial matrix structures, with increased blood vessel density in these tumours. In an orthotopic model, Hsulf‐1‐positive tumours exhibited enhanced local invasiveness. In human primary pancreatic cancers there was strong staining for sulphated HSPGs, which was markedly reduced in metastatic tissue samples. CONCLUSION: Hsulf‐1‐mediated desulphation of HSPGs reduces the growth ability of Panc‐1 pancreatic cancer cells, but increases the basal invasiveness of these cells, suggesting an important role of this enzyme in pancreatic cancer progression

Moesin dependent cytoskeleton remodeling is associated with an anaplastic phenotype of pancreatic cancer.

Cell motility is controlled by the dynamic cytoskeleton and its related proteins, such as members of the ezrin/radixin/moesin (ERM) family, which act as signaling molecules inducing cytoskeleton remodeling. Although ERM proteins have been identified as important factors in various malignancies, functional redundancy between these proteins has hindered the dissection of their individual contribution. The aim of the present study was to analyze the functional role of moesin in pancreatic malignancies. Cancer cells of different malignant lesions of human and transgenic mice pancreata were evaluated by immunohistochemistry. For functional analysis, cell growth, adhesion, and invasion assays were carried out after transient and stable knock-down of moesin expression in pancreatic cancer cells. In vivo tumorigenicity was determined using orthotopic and metastatic mouse tumor models. We now show that moesin knock-down increases migration, invasion, and metastasis and influences extracellular matrix organization of pancreatic cancer. Moesin-regulated migratory activities of pancreatic cancer cells were in part promoted through cellular translocation of beta-catenin, and re-distribution and organization of the cytoskeleton. Analysis of human and different transgenic mouse pancreatic cancers, demonstrated that moesin is a phenotypic marker for anaplastic carcinoma, suggesting that this ERM protein plays a specific role in pancreatic carcinogenesis

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma.

Perineural invasion, the growth of tumor cells along nerves, is a key feature of pancreatic cancer. The cardinal symptom of pancreatic cancer, abdominal pain often radiating to the back, as well as the high frequency of local tumor recurrence following resection are both attributed to the unique ability of pancreatic tumor cells to invade the neuronal system. The molecular mechanisms underlying the neuroaffinity of pancreatic tumors are not completely understood. In this study, we developed a novel method to monitor ex vivo perineural invasion into surgically resected rat vagal nerves by different human pancreatic tumor cell lines. Genome-wide transcriptional analyses were employed to identify the consensus set of genes differentially regulated in all highly nerve-invasive (nerve invasion passage 3) versus less invasive (nerve invasion passage 0) pancreatic tumor cells. The critical involvement of kinesin family member 14 (KIF14) and Rho-GDP dissociation inhibitor beta (ARHGDI beta) in perineural invasion was confirmed on RNA and protein levels in human pancreatic tumor specimens. We found significant up-regulation of KIF14 and ARHGDI beta mRNA levels in patients with pancreatic cancer, and both proteins were differentially expressed in tumor cells invading the perineural niche of pancreatic cancer patients as detected by immunohistochemistry. Moreover, functional knockdown of KIF14 and ARHGDI beta using small interfering RNA resulted in altered basal and/or perineural invasion of pancreatic tumor cells. Our work provides novel insights into the molecular determinants of perineural invasion in pancreatic cancer. The established nerve invasion model and the consensus signature of perineural invasion could be instrumental in the identification of novel therapeutic targets of pancreatic cancer as exemplified by KIF14 and ARHGDI beta