17p13.1

12-LOX,12S-LOX,LOG12

Inflammation and cancer

End product of arachidonic acid metabolism by the platelet-type 12-LOX 12(S)-Hydroxy eicosatetraenoic acid (12(S)-HETE) is shown to induce invasion, motility, and angiogenesis and protect tumour cells from apoptosis. Great many biological activities of 12(S)-HETE appear to be partly mediated by the activation of NFkappaB. NF-kappaB is a family of five DNA binding proteins that regulate the expression of a variety of genes involved in host immune responses and inflammation. A direct relationship between platelet-type 12-LOX overexpression and NF-kappaB activation is reported in prostate cancer cells.

Polymorphisms associated with diseases

Aberrant arachidonic acid metabolism by 12-lipoxygenase (12-LOX) is implicated in carcinogenesis. Genetic polymorphisms 12-LOX is therefore thought to influence its function and/or expression and may modify the risk for colorectal adenoma. One of the single nucleotide polymorphisms (SNPs) reported in the 12-LOX gene located in exon 6 resulting in an Arg to Gln substitution at amino acid 261 of 12-LOX is in a highly conserved region of the lipoxygenase domain. Data from a community-based, case-control study of incident, sporadic colorectal adenoma that included 162 cases and 211 controls have shown an inverse association between the Arg261Gln polymorphism in 12-LOX and colorectal adenoma (OR, 0.63; 95% CI, 0.40-1.00). A significant interaction also is observed between the 12-LOX polymorphism (Arg261Gln) and the use of nonsteroidal anti-inflammatory drugs. Another study argues that Gln261Arg in ALOX12 does not appear to be associated with colon cancer risk.
Studies have shown higher urinary excretion of the arachidonic acid-derived metabolite 12-(S)hydroxyeicosatetraenoic acid (12(S)-HETE) in essential hypertension. For analysis of the association of polymorphisms in ALOX12 with hypertension and urinary levels of 12(S)-HETE, a study with 200 patients with essential hypertension and 166 matched controls is performed and as a result, the distribution of genotypes of the R261Q (Arg to Gln) polymorphism is found to be significantly different between patients and controls. These results indicate that a nonsynonymous polymorphism in ALOX12 is associated to essential hypertension and to urinary levels of 12(S)-HETE.
Peak BMD is a major determinant of osteoporosis which is a complex disease with both genetic and environmental risk factors. In a population - and family - based association study of ALOX15 and ALOX12, SNPs distributed across the two genes are genotyped. Moderate evidence of association is found between spine BMD and six SNPs in the ALOX12 gene in both men and women. These data conclude that polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.

Alzheimers disease

Alzheimers disease (AD) is a chronic neurodegenerative disorder that impairs cognition and behavior. Although the initiating molecular events are not known, increasing evidence suggests that 12/15-LOX is a major source of oxidative stress which could play a functional role in pathogenesis. Quantitative Western blot analysis confirmed by immunohistochemical studies demonstrate that in affected frontal and temporal regions of AD brains, the amount of 12/15-LOX is higher compared to controls. Also metabolic products of 12/15-LOX are markedly elevated in AD brains compared to controls.

Bladder cancer

12-LOX expression is shown to be induced in bladder cancer tissues by an immunohistochemistry analysis. Also lipoxygenase inhibitors cause marked inhibition of bladder cancer cells in a concentration and time dependent manner. Cells treated with lipoxygenase inhibitors show chromatin condensation, cellular shrinkage, small membrane bound bodies (apoptotic bodies) and cytoplasmic condensation.

Testicular cancer

12-LOX is only slightly expressed in normal testis tissues, however, 12-LOX expression is found to be significant in testicular cancer tissues by immunohistochemistry studies. Specific LOX inhibitors have also been shown to inhibit the growth of testicular cancer in cell lines.

Prostate cancer

Research focusing on mechanisms of action of 12-lipoxygenase in prostate cancer cells revealed that overexpression of 12-lipoxygenase in PC-3 cells results in a 3-fold increase in VEGF protein level when compared with vector control cells and there is an increase in PI3-kinase activity in 12-LOX-transfected PC-3 cells.
The expression of 12-LOX is detected to be low in benign prostatic hyperplasia and normal prostate tissues, whereas marked expression of 12-lipoxygenase is detected in prostatic intraepithelial neoplasia and prostate cancer tissues. The LOX inhibitors cause marked cellular death through apoptosis in prostate cancer cells in a concentration and time-dependent manner.
Another effect of 12-LOX in prostate cancer cells is that increase in 12-LOX expression enhances the metastatic potential of human prostate cancer cells. 12-LOX transfected PC-3 cells show a significant change in cell adhesiveness, spreading, motility, and invasiveness.

Breast cancer

Total cellular RNA extraction from 64 frozen tissue samples of breast carcinoma and their corresponding normal adjacent tissues is performed for expression analysis of cyclooxygenase-2 and 12-lipooxygenase using RT-PCR. 62.5% of carcinoma samples showed over-expression of 12-lipooxygenase as compared to normal breast tissues. Results also reveal that and 12-lipooxygenase mRNA expressions are associated with TNM staging in human breast cancer.
A second study indicates that levels of 12- lipoxygenases together with 5-lipoxygenase are also particularly high in tumours from patients who died of breast cancer. Therefore raised level of 12-lipoxygenase might have prognostic value in patients with breast cancer.