Epithelial cell adhesion molecule promotes breast cancer resistance protein-mediated multidrug resistance in breast cancer by inducing partial epithelial–mesenchymal transition

Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial–mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/β-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/β-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.     

The role of adherens junctions in the developing neocortex

The disproportional enlargement of the neocortex through evolution has been instrumental in the success of vertebrates, in particular mammals. The neocortex is a multilayered sheet of neurons generated from a simple proliferative neuroepithelium through a myriad of mechanisms with substantial evolutionary conservation. This developing neuroepithelium is populated by progenitors that can generate additional progenitors as well as post-mitotic neurons. Subtle alterations in the production of progenitors vs. differentiated cells during development can result in dramatic differences in neocortical size. This review article will examine how cadherin adhesion proteins, in particular α-catenin and N-cadherin, function in regulating the neural progenitor microenvironment, cell proliferation, and differentiation in cortical development.     

Wnt and BMP signaling pathways co-operatively induce the differentiation of multiple myeloma mesenchymal stem cells into osteoblasts by upregulating EMX2

Osteoblast differentiation, defined as the process whereby a relatively unspecialized cell acquires the specialized features of an osteoblast, is directly linked to multiple myeloma (MM) bone disease. Wnt and bone morphogenetic protein (BMP) are proved to be implicated in the pathological or defective osteoblast differentiation process. This study aims to test the involvement of Wnt, bone morphogenetic proteins (BMP) pathways, and empty spiracles homeobox 2 (EMX2) in osteoblast differentiation and MM development. Initially, differentially expressed genes in bone marrow mesenchymal stem cells (MSCs) from MM patients and healthy donors were identified using microarray-based gene expression profiling. The functional role of Wnt and BMP in MM was determined. Next, we focused on the co-operative effects of Wnt and BMP on calcium deposition, alkaline phosphatase (ALP) activity, the number of mineralized nodules, and osteocalcin (OCN) content in MSCs. The expression patterns of Wnt and BMP pathway–related genes, EMX2 and osteoblast differentiation-related factors were determined to assess their effects on osteoblast differentiation. Furthermore, regulation of Wnt and BMP in ectopic osteogenesis was also investigated in vivo. An integrated genomic screen suggested that Wnt and BMP regularly co-operate to regulate EMX2 and affect MM. EMX2 was downregulated in MSCs. The activated Wnt and BMP resulted in more calcium salt deposits, mineralized nodules, and a noted increased in ALP activity and OCN content by upregulating EMX2, leading to induced differentiation of MSCs into osteoblasts. Collectively, this study demonstrated that Wnt and BMP pathways could co-operatively stimulate differentiation of MSCs into osteoblasts and inhibit MM progression, representing potential targets for MM treatment.     

Cloning and embryonic expression of six wnt genes in the medaka (Oryzias latipes) with special reference to expression of wnt5a in the pectoral fin buds

WNTs are secreted signaling molecules which control cell differentiation and proliferation. They are known to play essential roles in various developmental processes. Wnt genes have been identified in a variety of animals, and it has been shown that their amino acid sequences are highly conserved throughout evolution. To investigate the role of wnt genes during fish development from the evolutionary viewpoint, six medaka wnt genes (wnt4, wnt5a, wnt6, wnt7b, wnt8b and wnt8-like) were isolated and their embryonic expression was examined. These wnt genes were expressed in various tissues during embryonic development, and most of their expression patterns were conserved or comparable to those of other vertebrates. Thus, these wnt genes may be useful as molecular markers to investigate development and organogenesis using the medaka. Focus was on wnt5a, which was expressed in the pectoral fin buds, because its expression pattern was particularly comparable to that in tetrapod limbs. Its detailed expression pattern was further examined during pectoral fin bud development. The conservation and diversification of Wnt5a expression through the evolutionary transition from fish fins to tetrapod limbs is discussed.     

涡虫wnt基因的研究进展

涡虫具有强大的再生能力,对其再生机制等方面的研究一直是发育生物学研究的热点问题。Wnt信号途径是动物发育中关键的信号途径之一,对生物的生长发育有着至关重要的作用,近年来国内外对涡虫的wnt基因进行了不断的深入研究。从Wnt信号途径、涡虫wnt基因的种类及命名、涡虫wnt基因的表达及功能几方面对wnt基因在涡虫中的研究进展进行综述。     

APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development

Developmental signaling pathways hold the keys to unlocking the promise of adult tissue regeneration, and to inhibiting carcinogenesis. Patients with mutations in the Adenomatous Polyposis Coli (APC) gene are at increased risk of developing hepatoblastoma, an embryonal form of liver cancer, suggesting that Wnt affects hepatic progenitor cells. To elucidate the role of APC loss and enhanced Wnt activity in liver development, we examined APC mutant and wnt inducible transgenic zebrafish. APC^+/− embryos developed enlarged livers through biased induction of hepatic gene programs and increased proliferation. Conversely, APC^−/− embryos formed no livers. Blastula transplantations determined that the effects of APC loss were cell autonomous. Induction of wnt modulators confirmed biphasic consequences of wnt activation: endodermal pattern formation and gene expression required suppression of wnt signaling in early somitogenesis; later, increased wnt activity altered endodermal fate by enhancing liver growth at the expense of pancreas formation; these effects persisted into the larval stage. In adult APC^+/− zebrafish, increased wnt activity significantly accelerated liver regeneration after partial hepatectomy. Similarly, liver regeneration was significantly enhanced in APC^Min/+ mice, indicating the conserved effect of Wnt pathway activation in liver regeneration across vertebrate species. These studies reveal an important and time-dependent role for wnt signaling during liver development and regeneration.     

Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions.

Connexin 43 (Cx43alpha1) gap junction has been shown to have an essential role in mediating functional coupling of neural crest cells and in modulating neural crest cell migration. Here, we showed that N-cadherin and wnt1 are required for efficient dye coupling but not for the expression of Cx43alpha1 gap junctions in neural crest cells. Cell motility was found to be altered in the N-cadherin-deficient neural crest cells, but the alterations were different from that elicited by Cx43alpha1 deficiency. In contrast, wnt1-deficient neural crest cells showed no discernible change in cell motility. These observations suggest that dye coupling may not be a good measure of gap junction communication relevant to motility. Alternatively, Cx43alpha1 may serve a novel function in motility. We observed that p120 catenin (p120ctn), an Armadillo protein known to modulate cell motility, is colocalized not only with N-cadherin but also with Cx43alpha1. Moreover, the subcellular distribution of p120ctn was altered with N-cadherin or Cx43alpha1 deficiency. Based on these findings, we propose a model in which Cx43alpha1 and N-cadherin may modulate neural crest cell motility by engaging in a dynamic cross-talk with the cell's locomotory apparatus through p120ctn signaling.     

NDRG2在上皮性卵巢癌中的表达及与预后的关系

目的:探讨NDRG2在上皮性卵巢癌中的表达及其与预后的关系。方法:收集新鲜的上皮性卵巢癌和正常卵巢组织各15例,采用real-time PCR检测和比较其NDRG2 m RNA的表达。收集上皮性卵巢癌病理切片96例进行免疫组化检测其NDRG2蛋白的表达,并收集患者的临床病理资料,随访患者的生存情况,分析NDRG2蛋白的表达与上皮性卵巢癌患者临床病理特征和预后的关系。结果:上皮性卵巢癌组织中NDRG2 mRNA和蛋白的表达均显著低于正常卵巢组织(P0.05)。NDRG2在上皮性卵巢癌组织中的表达随着上皮性卵巢癌病理分期的升高而降低,而且其表达降低和患者不良预后显著相关(P=0.002),但其表达和不同上皮性卵巢癌的病理类型、分化程度以及年龄均无明显相关性。去除手术病理分期的影响,NDRG2表达下调和肿瘤细胞减灭术的满意程度以及术后规范化疗是三个影响上皮性卵巢癌预后的重要因素。结论:NDRG2在上皮性卵巢癌中的表达下降,并与患者的不良预后呈显著正相关。