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Introduction to several tumor biomarkers for diseases—part two




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Introduction to several tumor biomarkers for diseases—part two

2. ADH5 Biomarker 
   Alcohol dehydrogenase (ADH), which is abundantly present in human and animal liver, plants and microbial cells, is a key enzyme in the metabolism of major short-chain alcohols in organisms, and it plays an important role in many physiological processes. It is a zinc-containing metalloenzyme with broad substrate specificity. In humans and mammals, alcohol dehydrogenase and aldehyde dehydrogenase (ALDH) constitute an alcohol dehydrogenase system, which is involved in the metabolism of ethanol in the body.
The ADH5 gene encodes glutathione-dependent formaldehyde dehydrogenase or class III alcohol dehydrogenase chi subunit, which belongs to the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class III alcohol dehydrogenase is a homodimer composed of 2 chi subunits. It has virtually no activity for ethanol oxidation but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione. Unlike other members of the ADH family with tissue-specific patterns of expression, ADH5 is ubiquitously expressed in both embryonic and adult tissues, suggesting a housekeeping function of this protein. This enzyme is an important component of cellular metabolism for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes lacrymation, rhinitis, pharyngitis, and contact dermatitis. ADH5, a well-conserved enzyme from bacteria to human, is involved in the metabolism of alcohols and aldehydes in mammalian cells. Gene expression analyses identify a constant reduction of ADH5 levels throughout neuronal development. Overexpression of ADH5 reduces both development and adult neuronal differentiation of mouse neurons. This effect depends on the catalytic activity of ADH5 and involves ADH5-mediated denaturization of histone deacetylase 2 (HDAC2). What's more, ADH5 has been found in several cancer types. The ADH5 stain may be helpful as a surrogate molecular marker for the classification of lymph cancers.
3. AK4 Biomarker
Adenylate kinase (AK) is a phosphotransferase enzyme that catalyzes the interconversion of adenine nucleotides, and plays an important role in cellular energy homeostasis. The enzyme has seven isoforms, and plays a critical role in energy transfer and distribution between mitochondria, cytosol and nucleus. Adenylate kinase (AK) catalyzes a reversible reaction: ATP+AMP↔ 2ADP. When the levels of ATP and ADP change, the level of AMP also changes, and the relative amplitude of AMP changes is much larger than ATP and ADP, which makes the enzymes and metabolic susceptors affected by AMP are more sensitive and accurate in responding to stress signals. Therefore, AK and AMP signals play an important role in sensing and maintaining the energy balance of organisms.
AK4 is the only member of the AK family that is currently found to have no AK catalytic activity. In AK4, Gln159 cannot interact with the phosphate group in the transfer to form a hydrogen bond like the Arg in other AK to stabilize the reaction intermediate state, so like other The AK-like phosphotransfer reaction did not occur in AK4, so AK4 did not exhibit any AK activity either in vitro in vitro or in vivo in a mutant complementation experiment. AK4 itself also has substrate binding ability. The phosphate group on GTP can be transferred to AMP, so AK4 can bind to nucleotides such as GTP, AMP, GDP and ADP. The parent AK4 does not have AK catalytic activity, but still has nucleotide binding ability, and AK4 can function as a carrier of nucleotides in vivo. The expression level of AK4 is greatly increased in the presence of cell pressure (such as Hypoxia). Therefore, AK4 may be a cell stress-responsive protein, which has a great influence on the growth, morphology and survival of AK4 cells in the presence of cell stress. The greater the effect of increasing the inhibition of AK4 expression; and the inhibition of AK4 protein expression leads to the difficulty in forming clones. Overexpression of AK4 protects cells against H2O2-induced cell death. AK4 may be a protein of cellular stress response. The expression of AK4 is important for cell growth and development, and the expression of AK4 protects cells. In the case of cells facing oxidative stress, the interaction between ANT and AK4 is enhanced, so we speculate that the interaction between ANT and AK4 may be involved in the process of AK4 protecting cells under oxidative stress. The alpha and beta subunits of the protein ATP synthase F1 complex that interacts with AK4. ANT mitochondrial inner membrane forms a large complex with ATP synthase (ATP synthasome). Studies on AK4 interacting proteins suggest that AK4 may be involved in ATP synthesis and transport related pathways in mitochondria. It can be seen that the structure of the AK4 has a very large flexibility, and the relative motion between the domains is large.
AK4 is up-regulated in cancer cells compared to normal cells. High AK4 expression is associated with advanced disease recurrence and poor prognosis. Loss of AK4 expression inhibits the invasive potential of cancer cell lines, while AK4 overexpression promotes invasion in vitro and in vivo. Thus AK4 is differentially expressed and is considered a potential biomarker.
4. ALK Biomarker
Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor tyrosine kinase family. The human ALK gene is located in the short arm 2 region 3 band of chromosome 2 and is a typical transmembrane protein. It is divided into signal peptide (SS) region, extracellular receptor binding region, transmembrane (TM) region and cell. Intrinsic kinase domain. Like most kinases, ALK kinases are distinguished by the N-lobe and C-lobe regions, and the two-part linkage is called the hinge region, forming a hydrophobic pocket that provides ATP binding. When ALK receives an external signal, it forms a dimer, which in turn binds to ATP, and is activated by phosphorylation of the catalytic domain; the ALK conformation detects changes, regulates the domain to complete assembly, and enters an active state, thereby performing certain physiological functions.
The ALK gene is generally dormant and is sporadically expressed only in endothelial cells, glial cells, and neuronal cells of the central nervous system, suggesting that ALK may be involved in the development of the nervous system. ALK knockout mice develop well, behave normally, and exhibit better antidepressant characteristics, suggesting that ALK may not be indispensable for life. The expression specificity and aptitude of the ALK gene indicates that it can be used as a drug target to avoid toxic side effects to a great extent. Studies have shown that ALK gene is abnormally active in a variety of tumor cells, mainly characterized by gene fusion, gene overexpression and gene point mutation. Among them, the EML4-ALK fusion gene was confirmed to be a driver gene of about 5% of patients with non-small cell lung cancer.
The ALK fusion gene has been proven to be a driver gene for non-small cell lung cancer, and has gradually achieved “personalized” and “precise” treatment for patients with genotype non-small cell lung cancer. However, like most kinase inhibitors, ALK inhibitors are inevitably clinically resistant to their clinical use.
[1] Leary R J, Kinde I, Diehl F, et al. Development of personalized tumor biomarkers using massively parallel sequencing.[J]. Science Translational Medicine, 2010, 2(20):20ra14.
[2] Sawyers C L. The cancer biomarker problem [J]. Nature, 2008, 452(7187):548-552.
[3] Liu Y, Daley S, Evdokimova V N, et al. Hierarchy of α Fetoprotein (AFP)-Specific T Cell Responses in Subjects with AFP-Positive Hepatocellular Cancer[J]. Journal of Immunology, 2006, 177(1):712-721.
[4] Ostberg L J, Strömberg P, Hedberg J J, et al. Analysis of mammalian alcohol dehydrogenase 5 (ADH5): characterisation of rat ADH5 with comparisons to the corresponding human variant.[J]. Chemico-Biological Interactions, 2013, 202(1-3):97-103.
[5] Kakkar A K, Haas S, Wolf H, et al. Evaluation of perioperative fatal pulmonary embolism and death in cancer surgical patients: the MC-4 cancer substudy.[J]. Thromb Haemost, 2005, 93(04):867-871.
[6] Soda M, Choi Y L, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer [J]. Nature, 2007, 448(7153):561-566.


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