WNKs (with-no-lysine [K]) are a family of serine-threonine protein kinases with an atypical placement of the catalytic lysine relative to all other protein kinases. The roles of WNK kinases in regulating ion transport were first revealed by the findings that mutations of two members cause a genetic hypertension and hyperkalemia syndrome. More recent studies suggest that WNKs are pleiotropic protein kinases with important roles in many cell processes in addition to ion transport. Here, we review roles of WNK kinases in the regulation of ion balance, cell signaling, survival, and proliferation, and embryonic organ development.
Amino Acid Sequence ; Animals ; Cell Proliferation ; Cell Survival ; Humans ; Hyperkalemia/enzymology/etiology/genetics ; Hypertension/enzymology/etiology/genetics ; Kidney/enzymology ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Neoplasms/enzymology/etiology/genetics ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*chemistry/genetics/*metabolism ; Pseudohypoaldosteronism/enzymology/etiology/genetics ; Sequence Homology, Amino Acid ; Signal Transduction ; Syndrome

MUTYH, one of base-excision repair enzymes, is associated with human genetic disorders. Inherited biallelic mutations in the human MUTYH gene are responsible for an autosomal recessive syndrome-adenomatous colorectal polyposis (MUTYH associated polyposis, MAP), which significantly increases the risk of colorectal cancer (CRC). In this article we review the relationship between BER and the oxidative damage to DNA, the functional overlap of BER with other repair proteins, the molecular mechanism of tumourigenesis in MAP, and delineate the MUTYH polyposis phenotype and its prevention.
Adenomatous Polyposis Coli ; complications ; enzymology ; genetics ; Colorectal Neoplasms ; enzymology ; etiology ; genetics ; DNA Damage ; DNA Glycosylases ; genetics ; Germ-Line Mutation ; Humans ; Mutation ; Risk Factors

Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiation. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) or overexpression of these enzymes plays an etiologic role in several clonal hematopoietic malignancies. Other than the causative effect of PTK product of the bcr/abl fusion gene on chronic myelogenous leukemia (CML), more evidence suggests that mutated tyrosine kinases are pivotal in the pathogenesis of most of other chronic myeloproliferative disorders, such as chronic myelomonocytic leukemia (CMML) and hypereosinophilic syndrome (HES). And the exciting results in several dependent groups in 2005 showed that a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) was found to be involved in the pathogenesis of polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (CIMF). In the leukogenesis of acute myeloid leukemias (AML), the losing of the control of the proliferation of hematopoietic progenitor cells was principally the results of the aberrant PTK activity, such as FLT3 and C-kit overexpression. It works together with the loss of function mutation genes in promoting progenitor cell differentiation to confer AML's phenotypes. These upregulated PTK molecules represent attractive disease-specific targets, to which a new class of therapeutic agents are being developed. This review focuses on abnormal tyrosine kinases that have been involved in the pathogenesis of hematopoietic malignancies.
Chromosome Aberrations ; Chromosomes, Human, Pair 22 ; genetics ; Chromosomes, Human, Pair 9 ; genetics ; Hematologic Neoplasms ; enzymology ; etiology ; genetics ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; enzymology ; etiology ; genetics ; Mutation ; Protein-Tyrosine Kinases ; genetics ; metabolism

OBJECTIVETo study the relation between cyclooxygenase-2 (COX-2) protein expression and biologic behavior of ovarian carcinoma.

METHODSThe level of COX-2 protein expression was detected by Western Blot assay in 54 biopsy specimens from ovarian serous tumor patients and 10 normal ovarian samples.

RESULTSThe level of COX-2 protein expression and relative quantity in ovarian serous carcinoma (81.8%, 20.08 +/- 3.53) were statistically higher than those in the benign ovarian serous tumor (0, 15.04 +/- 0.12) and in the normal ovary (0, 15.33 +/- 0.60) (P < 0.05). The level of COX-2 protein expression and relative quantity in borderline ovarian serous tumor (90.0%, 20.61 +/- 3.03) were statistically higher than those in benign ovarian serous tumor and the normal ovary (P < 0.05). The level of COX-2 protein expression and relative quantity were not significantly different from ovarian serous carcinoma and borderline ovarian serous tumor (P > 0.05); as they were between the benign ovarian serous tumor and the normal ovary (P > 0.05). The level of COX-2 protein expression and relative quantity were not significantly different among different clinical stages (I + II and III + IV), different histological grades, with or without ascites or lymphatic metastasis either.

CONCLUSIONCOX-2 overexpression may be significantly related to the oncogenesis and development of ovarian serous carcinoma, which may be an early diagnostic parameter and, hence, an attractive target for chemopreventive strategy in the treatment of ovarian serous carcinoma.

Adult ; Aged ; Blotting, Western ; Cyclooxygenase 2 ; analysis ; genetics ; physiology ; Female ; Humans ; Middle Aged ; Ovarian Neoplasms ; enzymology ; etiology

OBJECTIVETo investigate the expression and significance of nitric oxide synthase (cNOS) mRNA in primary hepatocellular carcinoma (HCC), cirrhotic liver and normal liver tissue.

METHODScNOS mRNA expression in 80 HCC, 40 cirrhotic liver and 20 normal liver tissue were observed by in situ hybridization. CD34 immunostain was used to measure the microvascular density (MVD) and Ki-67 immunostain to proliferative index.

RESULTSExpression of cNOS mRNA was observed in the liver cancer cells, endothelial cells in the non-cancerous liver tissues and mononuclear and/or phagocytes. Expression of cNOS mRNA in tumor cells of HCC was higher than that in the liver cells of cirrhotic liver (P < 0.01) which was higher than the normal liver tissue. Expression in the endothelial cells was higher in HCC and cirrhotic liver than those in the normal liver tissue (P < 0.01). HCC with positive cNOS mRNA expression in the endothelial cells showed higher extent of neovascularization and degree of proliferative index. The more MVD, the higher proliferative index, which increased in metastatic tumors.

CONCLUSIONcNOS mRNA expression was involved in oncogenesis, angiogenesis and progression of hepatocellular carcinoma.

Adolescent ; Adult ; Aged ; Carcinoma, Hepatocellular ; blood supply ; enzymology ; pathology ; Cell Proliferation ; Child ; Female ; Humans ; Liver ; blood supply ; enzymology ; Liver Neoplasms ; blood supply ; enzymology ; pathology ; Male ; Middle Aged ; Neovascularization, Pathologic ; etiology ; Nitric Oxide Synthase ; genetics ; physiology

ErbB receptor tyrosine kinase inhibitors (EGFR-TKI), gefitinib, erlotinib, icotinib and aftinib, which are approved as a frontline treatment for patients with non-small cell lung cancer (NSCLC) who have tumors harboring EGFR mutations in China. And osimertinib was approved in second line setting for patients with EGFRT 790M-positive NSCLC. Rash, paronychia, diarrhea, stomatitis, liver dysfunction and (interstitial lung disease, ILD) are frequently observed in patients treated with EGFR-TKI. Chinese Society of Lung Cancer, Chinese Anti-Cancer Association, organized Chinese experts to develop the Chinese expert consensus on EGFR-TKI adverse event (AE) management based on domestic diagnosis and treatment of ADR and also incorporating international updated theory and recommendations.
.
Antineoplastic Agents ; adverse effects ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; China ; Diarrhea ; etiology ; ErbB Receptors ; antagonists & inhibitors ; genetics ; metabolism ; Humans ; Liver Diseases ; etiology ; Lung Diseases ; etiology ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Stomatitis ; etiology

OBJECTIVETo investigate the relationship between sulfotransferase 1Al polymorphism, diet and colorectal cancer susceptibility.

METHODSA case-control study of 140 cancers and 343 health controls was conducted to investigate the role of sulfotransferase 1A1 polymorphism and meat consumption in colorectal carcinogenesis. Genotypes of sulfotransferase 1A1 polymorphism were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

RESULTSThere was no significant difference in allele frequency of SULT1A1 between the control and cancer patient populations. After adjustment for age, sex, smoking and history of diseases, red meat and well-done meat intake showed no significant association with colorectal cancer. Consumption of red meat more than 5 kg per year combined with SULT1Al slow sulfation (Arg/His and His/His) had a statistically significant association with the risk of rectal cancer ( OR = 3.78; 95% CI: 1.08 - 13. 20) compared to that consumed red meat less than 5 kg per year with fast sulfation (Arg/Arg).

CONCLUSIONThis study suggests that SULT1A1 slow sulfation combined with higher intake of red meat may be associated with an elevated risk of rectal cancer.

Aged ; Alleles ; Animals ; Arylsulfotransferase ; genetics ; Case-Control Studies ; Cattle ; Colonic Neoplasms ; enzymology ; etiology ; genetics ; Diet ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Meat ; adverse effects ; Middle Aged ; Polymorphism, Genetic ; Rectal Neoplasms ; enzymology ; etiology ; genetics ; Risk Factors ; Smoking ; adverse effects ; Swine

OBJECTIVETo explore the relationship between methyl-tetra-hydrofolic acid (MTHFR) 677 gene polymorphism and the risk of stomach cancer.

METHODSA population based case-control study was conducted and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect its genotypes.

RESULTSAmong cases with stomach cancer, the frequency of C/C, C/T, T/T genotype were 25.8%, 54.6%, 19.6%, compared with controls as 34.5%, 50.9%, 14.6% respectively. Using C/C genotype as reference, the OR of C/T or T/T genotype was 1.52 (95% CI: 1.04 - 2.23). 53.3% C and 46.7% T allele were distributed in stomach cancer cases, while 60.0% C and 40.0% T in controls. The OR for T allele in relation to C allele was 1.31 (1.02 - 1.69) when C allele was used as reference. In addition, the present study showed that MTHFR677 AnyT genotype might interact with smoking, moldy food intake, wheat porridge intake, eating salty food and Hp CagA infection to increase the risk of stomach cancer. No interaction was observed between MTHFR677 AnyT genotype and alcohol drinking or green tea intake.

CONCLUSIONMTHFR677 AnyT genotype, might increase the risk of stomach cancer development and the genotype might also interact with other environmental risk factors to increase the risk of stomach cancer.

Adult ; Alleles ; Case-Control Studies ; China ; epidemiology ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Life Style ; Male ; Methylenetetrahydrofolate Reductase (NADPH2) ; genetics ; Point Mutation ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Risk Factors ; Smoking ; adverse effects ; Stomach Neoplasms ; enzymology ; etiology ; genetics