Wnt5a Protein Regulation

Epithelial-mesenchymal transition (EMT) is a cellular process that is essential for normal processes in many organisms, including embryonic development and wound healing, and is recapitulated in human disease, contributing to organ fibrosis and cancer progression (Thiery et al. 2009; Yang and Weinberg 2008). EMT describes the conversion of a cell with an epithelial phenotype to one with mesenchymal characteristics and can be a partial or complete transformation. Epithelial cells form the borders of tissues and organs, and are characterized by apical-basal polarity, contact with a basement membrane, and strong adherence to other epithelial cells through intercellular junctions including adherens junctions, tight junctions, and desmosomes. Conversely, mesenchymal cells have front-rear polarity and generally lack cell-cell contact, allowing them to be motile. During human embryonic development, EMT is essential for the formation of a variety of tissues, including mesoderm, neural crest, somites, palate, pancreas, liver, reproductive tracts, and heart valves (Thiery et al. 2009; Yang and Weinberg 2008). After development, partial EMT also contributes to wound healing (Thiery et al. 2009). However, EMT can also play a more insidious role by factoring into tumour progression.

CDKN2A: it is a tumoursuppressor gene that regulates G1-S phase of the cell cycle(4), in pancreatic tumour the CDKN2A gene has undergone inactivation which leads to unregulated and uncontrolled growth and differentiation.

By secreting this protein, VEGF receptors in the vasculature then activate the extracellular kinase and mitogen-activated protein (MAP) kinase signal transduction pathway. This induces proteins that breakdown the blood vessels basement membrane, allowing endothelial cells to invade. The breakdown of the membrane allows fluid and proteins to escape through the vasculature. One of these proteins, matrix metalloproteinase (MMP), breaks down the extracellular matrix between the tumour and blood vessel and allows the VEGF to stimulate receptors on the new endothelial cells. This causes proliferation of the endothelial cells, tube formation and migration towards the area signalling VEGF (the tumour cells), allowing the growth of new blood vessels into the tumour. (Spyridopoulos, I. 2002).

Signaling pathways that result in cell migration are often useful in understanding how cancer cells metastasize. The researchers of Swaminathan et al., 2016 examine how adhesion site assembly occurs while Nader et al., 2016 focuses primarily on the adhesion turnover both are fundamental processes in cell migration. Integrins play a dominant role in nascent integrin-mediated adhesions (NAs) which are important in lamellipodium protrusion and generating traction at focal adhesion points involved in cell motility. Integrins have been extensively studied and are linked to wound healing as well as metastasis in cancer cells (Lawson et al., 2012). When extracellular signals, either chemical or physical, contact the cell surface it triggers a response that induces movement. If the signaling molecule is a growth factor (ex. Epidermal Growth Factor) it could activate a GTPase protein coupled receptor (GPCR). The next is a signal cascade often led by Rabs or Ras (small G-proteins) proteins that are powered by GTPase hydrolysis, which often recruits and activates Wiskott–Aldrich Syndrome protein (WASP) or Scar. Previous studies identified cancer cell that use Rab-coupling to control cell motility by regulating B-intgrins trafficking (Nader et al., 2016). WASP recruits Actin related protein 2 and 3 (Arp2/3) complex to the cell membrane and activates it

Specific enzymes make this phase successful. They protect the body from the chemical carcinogenesis that occurs during the early stage of cancer.

Introduction: Provide background information on cell migration and its importance. Then I will discuss the different factors that have an effect on cell migration. I will focus on the different influences that prevent successful cell migration. The three main points are cancer cells, MIIP, a cytoskeleton regulator, and development of tumors

Scn5a is a part of the sodium channel gene family. A gene family is a group of genes that share important characteristics. In many cases, genes in a gene family share a similar sequence of nucleotides. These genes provide instructions for making proteins that have a similar structure or function. The

Cancer metastasis in the main character and hallmark of cancer progression [6]. Metastasis is a multi-step process beginning from detachments of cancer cells from the primary tumor, disruption of the basement membrane for invading to surrounding tissue. Subsequently, the cancer cells able entry to the blood and lymphatic system to spread into other part of the body and extravasation for growth and proliferate in distant sites [7]. Matrix metalloproteinase (MMP) is a zinc-dependent endopeptidase which responsible in degradation the component of extracellular matrix (ECM) proteins including collagen, elastin, fibronectin. MMP can secrete by inflammatory cells, osteoblast, fibroblast, and also cancer cells. MMP has a pivotal role in promoting

In the absence of Wnt, cytoplasmic β-catenin protein is constantly degraded by the action of the Axin complex. β-catenin protein binds to the Axin complex where is phosphorylated by CK1 and GSK3 and this results in its proteasomal degradation and prevents it from reaching the nucleus to activate Wnt target gene expression (He et al., 2004). The Wnt/β-Catenin pathway is activated when a Wnt ligand binds to the receptors Frizzled (Fz) and LRP5/6 (low-density lipoprotein receptor-related protein 5/6) The formation of a likely Wnt-Fz-LRP6 complex, together with the recruitment of the protein Dishevelled (Dvl), results in β-catenin phosphorylation and stabilization, which then, accumulates and travels to the nucleus to activates Wnt target gene expression (Figure 1b) (MacDonald et al.,

Local invasion represents the first step of the metastatic cascade and requires profound changes in cell-cell adhesion, cell-ECM interactions, proteolysis of ECM components and acquisition of migratory properties. Cancer cells can deploy different types of cell migration, including collective migration and single cell migration50. Predominantly, most epithelial cancer cells use collective cell migration, however some cancer cells may co-opt the biological program known as the EMT to migrate as single cells. EMT is a critical process for multiple aspects of normal embryonic development51. Since its discovery, there has been the realization that there are many parallels in the mechanisms that govern EMT in embryonic development and in cancer

CN’s dimeric structure results in high reactivity in platelet protein phosphorylation, allowing CN to bind to IIb3 and inhibiting platelet aggregation. It is also known that CN is able to bind to 1 and 3 subclasses, inhibiting many types of integrins (Lin et al. 2010). Research has shown that the two integrins that are expressed in angiogenesis and cancer metastasis are v3 and v5. Blocking v5 results in blocking the vascular endothelial growth factor, or VEGF, angiogenesis because of its involvement in cell adhesion. This integrin requires an insulin growth factor to activate to mediate cell migration. Zhou et al. (2000) has shown that CN binding to vitronectin receptors allows the inhibition of melanoma and breast cancer cells to vitronectin. In addition, v3 commonly mediates tumor cell adhesion to vitronectin. However, antagonists to this integrin can inhibit angiogenesis in endothelial cells, with CN acting as an antagonist. Many studies have tested the efficacy of CN on tumors from breast cancer, prostate cancer, and bladder cancer. For example, CN was able to inhibit the adhesion of T24 bladder carcinoma cells to vitronectin (Zhou et

Interest in cancer has grown recently as it has been one of the most fatal causes of death yet; there has only recently been an advance in the understanding the cellular basis of cancer. Due to today’s understanding of cancer it has been acknowledges that the disease disregards the rules of normal cell division, as a group of abnormal cells grow uncontrollably. Cancer is described as being the unnecessary development of cells within the body. Individual’s genetic tendency contains a significant role in the cancerous growths, as the genetic information of an individual can’t be controlled. In order to understand the cellular basis of cancerous cells and there difference between normal cells, there are certain aspects in which need to be addressed that being; DNA replication and translation, oncogenes and protogenes, tumor suppression genes, how tumour cells work, apoptosis and cell death, blood vessel growth (angiogenesis) and metastasis.

The adherens junctions control cell-cell adhesion in live epithelial tissues. A various number of proteinacious molecules work with one another to create tissues. The molecules that form adherens junctions include: cadherin, vinculin, p120-catenin, beta-catenin, and -catenin (Jordan, 2008). The assembly of these molecules between two epithelial cells can be seen (Figure 1). These molecules responsible for adherens junctions were discovered roughly thirty years ago. Specifically, an immunoprecipitation experiment on cadherin proteins removed from epithelial cells through detergent precipitation (Pokutta et. al, 2008). The discovery of the transmembrane linked protein, cadherin lead to the

DKK1 interfere with canonical WNT activity by binding to LRP5/6. Studies have shown that loss of membrane expression of β-catenin may be significantly associated with poor prognosis and considered a biomarker for OSCC recurrence (Aguiar et al, 2007; Mahomed et al. 2007). p53 is a known tumour suppressor gene. Activation of the Wnt pathway and loss of p53 are frequently known mechanisms in cancer. However, the link between these two mechanisms has been studied by Kim et al in lung and breast cancer cells. Transactivation of miRNA 34 by p53, suppresses the trancriptional activity of β catenin -Tcf/Lef complexes. Loss of p53 increases the expression of endogenous β catenin, WNT1 and LRP6 thereby increasing canonical Wnt signaling (Kim et al,2011).

Epithelial cells are responsible for separating the human body from outside environment by forming a barrier usually line of ducts and organs. In two dimensional culture, epithelial cells form an intact cobblestone monolayer with high transepithelial electrical resistance. In three dimensional matrices such as collagen or matrigel, epithelial cells have a distinct cell polarity. The basal side of the epithelial cell attaches to the extracellular matrix through the basement membrane, and the apical side faces the lumen of the duct where it can secrete molecules into the lumen and control molecule uptake. This polarity is essential for the survival of the epithelial cell as detachment of the extracellular matrix leads to anoikis. Anoikis is programmed cell death upon the detachment from an extracellular matrix {Frisch, 1994 #115}. Epithelial cells form barriers through the interaction of specific epithelial proteins such as epithelial-cadherin (E-cadherin), claudins, occludins, and demsogleins {Baum, 2011 #5348;Turksen, 2011 #5346}. E-cadherin’s extracellular domain forms a homophilic interaction with other E-cadherin molecules of adjacent cells, forming adherens junctions. The cytosolic domain of E-cadherin is important for cortical actin assembly and the sequestration of β-catenin {Qin, 2005 #2184;Tian, 2011 #5344}. Claudins and occludins contribute to cell polarity by forming tight junctions which restrict integral membrane protein movement to