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==Introduction== Squamous cell carcinoma antigen is a tumor associated protein of squamous cell carcinoma of various organs. SCCA was originally purified from SCC of the uterine cervix [1]. SCCA is a tumor marker to detect malignant tumor and to understand biological behaviors of squamous cells. SCCA is classified as a serine protease inhibitor called serpin B3. It also inhibits chymotripsin, cathepsin L, K and S and papain like cysteine proteases. In the case of tumor development SCCA 1 inhibits NK cells(natural killer), TNFalfa and apoptosis of tumor cells induced by treatment. It can also play a role in tumor growth. The chromosomal location is the locus 18q21.3.[2]
General structureSerpins are a superfamily of functionally distinct but structurally conserved proteins. [3] SerpinB3 means serin protease inhibitor, clade B (ovalbumin), member 3. The particularity of Serpin B3 is to target proteases wich have a nucleophilic cysteine instead of serine in their catalytic site. SCCA1 is a [4] . Like all for serpins, has three β sheets termed , and and [5] [6] . The most important part of Serpins is an exposed region of 20 amino acids near the C terminus named the reactive center loop (). The amino-acids of are very conservated for Serpin B3 and allow the specificity interaction of the inhibitor for the target protease[7].
Conformational changes of serpinsStructural studies on serpins revealed that inhibitory members of the family undergo an unusual conformational change, termed the Stressed to Relaxed (S to R) transition. During this structural transition the inserts into and forms an extra fourth β strand . The serpin conformational change is key to the mechanism of inhibition of target proteases. wich belong to a consensus sequence for inhibitory serpins are thought to permit efficient and rapid insertion of the into the .[8] FunctionCysteine proteases mecanismWhen attacking a substrate, proteases catalyze peptide bond cleavage in a two-step process. Initially, the catalytic cysteine performs a nucleophilic attack on the peptide bond of the substrate. This releases the new N-terminus and forms an new bond between the enzyme and the substrate. This covalent enzyme-substrate complex is called an acyl enzyme intermediate. Subsequent to this, this bond is hydrolysed and the new C-terminus is released. http://en.wikipedia.org/wiki/Serpin Protease inhibitionThe of a serpin acts as a substrate for its cognate protease. The is cleaved at a scissile bond between two residues . The are critical for serpin specificity and mutation of these residues results in the loss or conversion of inhibitory activity. The protease recognize that allow its docking. [9] http://genome.cshlp.org/content/10/12/1845 Prior to hydrolysis of the acyl-enzyme intermediate, the serpin rapidly undergoes the S-to-R transition. Since the is still covalently attached to the protease via the ester bond, the S-to-R transition moves the protease from the top to the bottom of the serpin. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0104935 At the same time, the protease is distorted into a conformation, where the acyl enzyme intermediate is hydrolysed extremely slowly. The the active site of the enzyme would be expected to break.The protease thus remains covalently attached to the target protease and is thereby inhibited. Image:Gb-2006-7-5-216-1-l - Copie.jpg Further, since the serpin has to be cleaved to inhibit the target protases, inhibition consumes the serpin as well. Serpins are therefore irreversible enzyme inhibitors. [10] The increase of the SCCA1 residing in the cytosol of squamous carcinoma cell may protect the tumor by neutralizing harmful proteases. The SCCA1 a tumor markerCancer is characterized by the abnormal proliferation of a cellular clone that will form a tumor in a tissue. Tumor cells can migrate to the serum or urin and invade other tissues. Cancer is caused by damaged genes. Cancer can have several origins due to exogenous factors (tobacco, alcohol, UV) or endogenous factors (failure in DNA repair). Tumor markers are compounds present in abnormal concentration in serum or urine in patients who develop a malignant tumor. Nevertheless tumor markers can appear in people who do not suffer from cancer or at low concentration in sick patients, this is called the false negative or false positive. Tumor markers are used to detect, prevent, diagnose, predict, determine, prognostic and therapeutic monitoring. Tumor markers need to be specific and sensitive. The dosage of several markers is necessary to establish the success or the failure of a treatment. The SCCA is secreted by the tumor itself, it is a marker of mature cells. The SCCA is a glycoprotein present in the epithelium cells and released in the serum during epidermoid cervical cancer but also in epidermoid cancers suchh as lung, mouth, larynx, pharynx and esophagus. The cooncentration threshold is inferior at 1.5 µg for healthy patient.[11] SCCA role as a tumor markerSCCA is particularly used for the detecction of cancer of the uterine cervix. The correlation between SCCA concentration and lung tumor was proved. SCCA concentration increases in the presence of epidermoid lung tumor, independently of the differentiation state of the tumor[12]. SCCA is especially used to prognostic and follow the effects of the treatment in the lung cancer as second tumor marker [13] . High concentration of SCCA in the blood suggests the epithelial cells direct serpin activity to blood. This pathway is an active secretory process[14]. SCCA and cancerSCCA is not specific of one type of cancer. It can be associated to mild broncho-pulmonarypathology, mild skin pathology. It does not depend on Tobacco consumption. SCCA is associated to cancer and non-malignant kidney pathology. It is quantified by immuno-analyzes, its half-life is 3 days. -In cervix cancer : The SCCA increase is linked to the tumor weight and state of disease. Nevertheless 40 % of patients suffering from cervix cancer have a high SCCA blood concentration, it is not use for screening. An increase of the initial rate can be a sign of disease recurrence or persistence. It allows to follow the treatment efficiency such as chemotherapy, radiotherapy in patients. -In epidermoid bronchopulmonary cancer : SCCA is not used for screening. [15] InteractionHepatite B virus (HBV) interactionThe SCCA may play a role of cellular receptor for hepatitis B virus. The SCCA expression enhances the binding and internalization of hepatitis B virus with hepatocyte or non-hepatocytes origin cells. The transfection of SCCA in hepatocyte generates more viruses DNA in infected cells. Besides the virus bound to transfected cell is protected against degradation by trypsin thanks to a partial internalization. The binding between HBV and hepatocytes is more marked than for the others types of cells like COS-7 (kidney cells of monkey transformed by antibody T of SV40). The binding complex of cells COS-7 with HBV seems to be more complex. The low density lipoprotein receptor-related protein (LRP) mediates the clearance of serpin-enzyme complex, the LRP may not enhance virus binding to transfected cells. SCCA may be a co-receptor for HBV, virus binding to the transfected cells doesn’t depend on the proteinase inhibitor function or the interaction receptor LRP but it may depend on of SCCA. [16] JNK1 interactionSCCA1 also acts as an inhibitor of UV-induced apoptosis via suppression of the activity of c-Jun NH(2)-terminal kinase (JNK1). It is known that JNK1 is responsible for UV-induced apoptotic cell death and SCCA-1 is up-regulated in UV-irradiated and sun-exposed cells. SCCA1 binds to phosphorylated JNK1 and is transferred into the nucleus after UV irradiation. [17] Indeed the reactive center loop () of SCCA1 is very flexible and located away from the center of SCCA1. The inhibitory effect of SCCA1 on the kinase activity of JNK1 is lost when the was truncated. Furthermore, a mutant protein created by replacing in maintain the suppressive activity to JNK1, whereas the inhibitory effect to proteinase is obviously decreased. [18] DiseaseAsthma is characterized by an obstruction of the interior respiratory tract and an excessive mucus secretion.[19] Experiments were performed on mice, mice lacking SerpinB3 showed a decrease of the mucus secretion. As a result serpinB3 may have a role in mucus hypersecretion in a house dust mist model of asthma. The SPDEF ( SAM pointed domain containing ETS transcription factor) expression causes the hyperplasia of goblet cell. The hyperplasia designates the abnormal augmentation of cells number in a tissue, the subexpression of goblet cells m ay induce cancer. Serpin B3 increase SPDEF expression and goblet cells hyperplasia. [20] RegulationThe E-cadherin can regulate the SCCA production in the squamous cell carcinoma of the uterin cervix. E-cadherins are transmembrane proteins, they have a role in cell adhesion because they are able to form adherens junctions. They have to bind a Ca++ ion to work. Using an anti-E-cadherin antibody induces the dissociation of the cervical squamous cell carcinoma. It also induces a decrease of SCCA in the cytosol and SCCA m RNA. Besides the phosphatidyl inositol 3 kinase is a mediator of E-cadherin. The E-cadherin mediates cell-cell adhesion and maintains SCCA production thanks to phosphatidyl inositol 3 kinase in squamous cell carcinoma.[21]
References
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