The Mitogen-activated Protein (MAP) Kinases p38 and Extracellular Signal-regulated Kinase (ERK) Are Involved in Hepatocyte-mediated Phenotypic Switching in Prostate Cancer Cells

The greatest challenge for the seeding of cancer in metastatic sites is integration into the ectopic microenvironment despite the lack of an orthotopic supportive environment and presence of pro-death signals concomitant with a localized “foreign-body” inflammatory response. In this metastatic location, many carcinoma cells display a reversion of the epithelial-to-mesenchymal transition that marks dissemination in the primary tumor mass. This mesenchymal to epithelial reverting transition (MErT) is thought to help seeding and colonization by protecting against cell death. We have previously shown that hepatocyte coculture induces the re-expression of E-cadherin via abrogation of autocrine EGFR signaling pathway in prostate cancer (PCa) cells and that this confers a survival advantage. Herein, we show that hepatocytes educate PCa to undergo MErT by modulating the activity of p38 and ERK1/2. Hepatocytes inhibited p38 and ERK1/2 activity in prostate cancer cells, which allowed E-cadherin re-expression. Introduction of constitutively active MEK6 and MEK1 to DU145 cells cocultured with hepatocytes abrogated E-cadherin re-expression. At least a partial phenotypic reversion can be achieved by suppression of p38 and ERK1/2 activation in DU145 cells even in the absence of hepatocytes. Interestingly, these mitogen-activated protein kinase activities were also triggered by re-expressed E-cadherin leading to p38 and ERK1/2 activity in PCa cells; these signals provide protection to PCa cells upon challenge with chemotherapy and cell death-inducing cytokines. We propose that distinct p38/ERK pathways are related to E-cadherin levels and function downstream of E-cadherin allowing, respectively, for hepatocyte-mediated MErT and tumor cell survival in the face of death signals.     

Patterns in Space: Coordinating Adhesion and Actomyosin Contractility at E-cadherin Junctions

Abstract

Cadherin adhesion receptors are fundamental determinants of tissue organization in health and disease. Increasingly, we have come to appreciate that classical cadherins exert their biological actions through active cooperation with the contractile actin cytoskeleton. Rather than being passive resistors of detachment forces, cadherins can regulate the assembly and mechanics of the contractile apparatus itself. Moreover, coordinate spatial patterning of adhesion and contractility is emerging as a determinant of morphogenesis. Here we review recent developments in cadherins and actin cytoskeleton cooperativity, by focusing on E-cadherin adhesive patterning in the epithelia. Next, we discuss the underlying principles of cellular rearrangement during Drosophila germband extension and epithelial cell extrusion, as models of how planar and apical–lateral patterns of contractility organize tissue architecture.     

Hepatitis C virus represses E-cadherin expression via DNA methylation to induce epithelial to mesenchymal transition in human hepatocytes

Hepatitis C virus (HCV) core protein is known to induce promoter hypermethylation of tumor suppressor genes including E-cadherin to repress their expression when overexpressed in human hepatocytes; however, its actual role during HCV infection is still unknown. Here, we report that infection with HCV derived from pJFH-1 replicon system that mimics natural infection elevates protein levels of DNA methyltransferase 1 and 3b to enhance DNMT activity in human hepatocytes. As a consequence, HCV induced promoter hypermethylation of E-cadherin, resulting in repression of its expression. In addition down-regulation of E-cadherin by HCV led to epithelial–mesenchymal transition that is known to be a critical event during the late stage of tumorigenesis.     

Small G protein signalling modulator 2 (SGSM2) is involved in oestrogen receptor-positive breast cancer metastasis through enhancement of migratory cell adhesion via interaction with E-cadherin

The function of small G protein signalling modulators (SGSM1/2/3) in cancer remains unknown. Our findings demonstrated that SGSM2 is a plasma membrane protein that strongly interacted with E-cadherin/β-catenin. SGSM2 downregulation enhanced the phosphorylation of focal adhesion kinase (FAK; Y576/577), decreased the expression of epithelial markers such as E-cadherin, β-catenin, and Paxillin, and increased the expression of Snail and Twist-1, which reduced cell adhesion and promoted cancer cell migration. Oestrogen and fibronectin treatment was found to promote the colocalization of SGSM2 at the leading edge with phospho-FAK (Y397). The BioGRID database showed that SGSM2 potentially interacts with cytoskeleton remodelling and cell-cell junction proteins. These evidences suggest that SGSM2 plays a role in modulating cell adhesion and cytoskeleton dynamics during cancer migration.     

基因沉默孤儿核受体ERR-alpha抑制前列腺癌细胞的体内转移

目的:研究孤儿核受体ERRα对前列腺癌细胞E-cadherin(上皮细胞钙粘蛋白)的表达水平和体内转移能力的影响。方法:利用慢病毒介导的sh RNA构建稳定下调ERRα表达的DU145-sh ERRα和PC-3M-sh ERRα前列腺癌细胞模型,同时用ERRα特异性抑制剂XCT790抑制其活性,并利用Western Blotting(免疫印迹)检测上皮细胞标志物E-cadherin的表达水平。将PC-3M-sh ERRα细胞和PC-3M-scramble对照细胞用荧光素酶标记后原位注射小鼠前列腺,8周以后通过体内成像系统检测原位瘤的形成及其体内转移情况。结果:基因沉默ERRα表达水平和用其特异性抑制剂XCT790处理DU145后,E-cadherin的表达水平明显降低。在PC-3M-sh ERRα细胞中,E-cadherin的表达水平明显低于对照组,同时由其构建的6只原位前列腺癌小鼠模型中没有发生转移,而由对照组细胞构建的7只原位前列腺癌小鼠模型中有4只发生了转移。结论:在前列腺癌细胞中下调ERRα的表达水平抑制其E-cadherin的表达和体内转移能力。     

宫颈癌细胞系中HPV病毒感染与P16和E-cadherin表达的相关性分析

目的探讨宫颈癌细胞系中HPV感染状态与P16和E-cadherin表达之间的相关性。方法应用免疫细胞化学染色、免疫荧光、Western-blot以及RT-PCR的方法检测HeLa、SiHa和C33A三个细胞系中P16和E-cadherin的表达情况。结果HPV阳性的两个细胞系HeLa和SiHa中P16的表达呈强阳性而E-cadherin的表达呈弱阳性,HPV阴性的细胞系C33A中P16的表达为弱阳性而E-cadherin呈强阳性表达。结论宫颈癌细胞系中HPV的感染与P16的表达呈正相关而与E-cadherin的表达呈负相关。     

E-cadherin 在肿瘤治疗中的研究进展

E-cadherin 参与形成细胞间黏附性连接,是胚胎发育过程中的一个关键因子。越来越多的研究表明,E-cadherin 在肿瘤的发生发 展过程中也发挥了至关重要的作用。在生物体内,E-cadherin 的表达和功能受到多个水平、多重因素的调控,而 E-cadherin 又可以影响 多条重要信号通路的活性,参与到多种生理病理过程中。E-cadherin 下调造成细胞间黏附性连接减少、极性减弱,细胞由上皮样转变为间 质样,这一变化是上皮间质转化（EMT）的重要标志之一。E-cadherin 与多种肿瘤的发生有一定的相关性。同时 E-cadherin 下调所引起 的 EMT 促进肿瘤细胞的迁移运动,肿瘤细胞侵袭力增强,促进转移的发生。近年来,大量研究关注到 E-cadherin 对肿瘤细胞的耐药及干 细胞特性的获得都有影响。综述 E-cadherin 在肿瘤发生发展中的作用,探讨以 E-cadherin 为靶点的肿瘤治疗的现状及展望。     

Aberrant Expression of Osteopontin and E-Cadherin Indicates Radiation Resistance and Poor Prognosis for Patients with Cervical Carcinoma

Radiotherapy is the first-line treatment for all stages of cervical cancer, whether it is used for radical or palliative therapy. However, radioresistance of cervical cancer remains a major therapeutic problem. Consequently, we explored if E-cadherin (a marker of epithelial-mesenchymal transition) and osteopontin could predict radioresistance in patients with locally advanced cervical squamous cell carcinoma (LACSCC). Patients were retrospectively reviewed and 111 patients divided into two groups (radiation-resistant and radiation-sensitive groups) according to progression-free survival (PFS). In pretreated paraffin-embedded tissues, we evaluated E-cadherin and osteopontin expression using immunohistochemical staining. The percentage of patients with high osteopontin but low E-cadherin expression in the radiation-resistant group was significantly higher than those in the radiation-sensitive group (p<0.001). These patients also had a lower 5-year PFS rate (p<0.001). Our research suggests that high osteopontin but low E-cadherin expression can be considered as a negative, independent prognostic factor in patients with LACSCC ([Hazard ratios (95% CI) 6.766 (2.940, 15.572)], p<0.001).