Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1α,25-dihydroxyvitamin D(3) (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which ...1,25-VD prevents tumorigenesis remains incomplete. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation. In this model, 1,25-VD promoted expression of the DNA repair genes RAD50 and ATM, both of which are critical for mediating the signaling responses to DNA damage. Correspondingly, 1,25-VD protected cells from genotoxic stress and growth inhibition by promoting double-strand break DNA repair. Depletion of the vitamin D receptor (VDR) reduced these genoprotective effects and drove malignant transformation that could not be prevented by 1,25-VD, defining an essential role for VDR in mediating the anticancer effects of 1,25-VD. Notably, genotoxic stress activated ATM and VDR through phosphorylation of VDR. Mutations in VDR at putative ATM phosphorylation sites impaired the ability of ATM to enhance VDR transactivation activity, diminishing 1,25-VD-mediated induction of ATM and RAD50 expression. Together, our findings identify a novel vitamin D-mediated chemopreventive mechanism involving a positive feedback loop between the DNA repair proteins ATM and VDR.
Although most advanced prostate cancer patients respond to androgen-deprivation therapy (ADT), the efficacy is widely variable. We investigated whether the host genetic variations in sex hormone ...pathway genes are associated with the efficacy of ADT. A cohort of 645 patients with advanced prostate cancer treated with ADT was genotyped for 18 polymorphisms across 12 key genes involved in androgen and estrogen metabolism. We found that after adjusting for known risk factors in multivariate Cox regression models, AKR1C3 rs12529 and AR-CAG repeat length remained significantly associated with prostate cancer-specific mortality (PCSM) after ADT (P ≤ 0.041). Furthermore, individuals carrying two unfavorable genotypes at these loci presented a 13.7-fold increased risk of PCSM compared with individuals carrying zero (P<0.001). Our results identify two candidate molecular markers in key genes of androgen and estrogen pathways associated with PCSM after ADT, establishing the role of pharmacogenomics in this therapy.
MST3 is involved in ENaC-mediated hypertension Lu, Te-Jung; Kan, Wei-Chih; Yang, Sung-Sen ...
American journal of physiology. Renal physiology,
07/2019, Letnik:
317, Številka:
7
Journal Article
Recenzirano
Liddle syndrome is an inherited form of human hypertension caused by increasing epithelial Na
channel (ENaC) expression. Increased Na
retention through ENaC with subsequent volume expansion causes ...hypertension. In addition to ENaC, the Na
-K
-Cl
cotransporter (NKCC) and Na
-Cl
symporter (NCC) are responsible for Na
reabsorption in the kidneys. Several Na
transporters are evolutionarily regulated by the Ste20 kinase family. Ste20-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 phosphorylate downstream NKCC2 and NCC to maintain Na
and blood pressure (BP) homeostasis. Mammalian Ste20 kinase 3 (MST3) is another member of the Ste20 family. We previously reported that reduced MST3 levels were found in the kidneys in spontaneously hypertensive rats and that MST3 was involved in Na
regulation. To determine whether MST3 is involved in BP stability through Na
regulation, we generated a MST3 hypomorphic mutation and designated MST3
and MST3
mice to examine BP and serum Na
and K
concentrations. MST3
mice exhibited hypernatremia, hypokalemia, and hypertension. The increased ENaC in the kidney played roles in hypernatremia. The reabsorption of more Na
promoted more K
secretion in the kidney and caused hypokalemia. The hypernatremia and hypokalemia in MST3
mice were significantly reversed by the ENaC inhibitor amiloride, indicating that MST3
mice reabsorbed more Na
through ENaC. Furthermore, Madin-Darby canine kidney cells stably expressing kinase-dead MST3 displayed elevated ENaC currents. Both the in vivo and in vitro results indicated that MST3 maintained Na
homeostasis through ENaC regulation. We are the first to report that MST3 maintains BP stability through ENaC regulation.
Objective
The aim of this study was to explore whether palliative gastrectomy is suitable for gastric cancer patients with peritoneal metastasis, and for patients in whom the type of peritoneal ...metastasis should be selected to receive palliative gastrectomy.
Methods
A total of 747 patients diagnosed with gastric adenocarcinoma with peritoneal metastasis at our centers between January 2000 and April 2014 were retrospectively analyzed. After propensity score matching, the clinicopathologic characteristics and clinical outcomes of patients with peritoneal dissemination were analyzed.
Results
After propensity score matching, the median overall survival (OS) of patients in the gastrectomy group was longer than that for patients in the non-gastrectomy group (11.87 vs. 9.27 months;
p
= 0.020). Patients who received first-line chemotherapy had a significantly longer median OS than those who did not (11.97 vs. 7.03 months;
p
< 0.001); among these patients, those undergoing more than eight periods of first-line chemotherapy benefited the most (
p
< 0.001). Subgroup analyses revealed that patients classified as P1 who were undergoing chemotherapy benefited from gastrectomy (
p
= 0.024), and patients without multisite metastasis also benefited from gastrectomy with regard to OS (
p
= 0.007). In the multivariate survival analysis, multisite distant metastasis was the independent poor prognostic factor (
p
< 0.001), while palliative gastrectomy (
p
= 0.006) and a period of first-line chemotherapy (
p
< 0.001) were good prognostic factors. Morbidity rates in the gastrectomy and non-gastrectomy groups were 10.4 and 1.0 %, respectively (
p
= 0.003); however, no difference in mortality was noted between the two groups (
p
= 0.590).
Conclusions
Palliative gastrectomy can prolong the survival of P1 patients without multisite distant metastasis when combined with more than five periods, and particularly more than eight periods, of first-line chemotherapy.
Noise exposure is associated with elevated blood pressure, but the effects on susceptible workers have not been reported. This repeated-measure study investigated the effects of noise exposure on ...24-h ambulatory blood pressure among hypertensive, pre-hypertensive, and normotensive adults.
We enrolled 113 volunteers in an occupational cohort in 2009. Individual noise exposure and personal blood pressure were measured simultaneously over 24 h on working and non-working days. Linear mixed-effects regressions were used to estimate the effects on SBP and DBP by controlling for potential confounders.
Each A-weighted decibel (dBA) increase in a 30-min time-lagged exposure was associated with transient elevations of work-time SBP 0.30 (95% confidence interval: 0.06, 0.54) mmHg on working days as well as sleep-time SBP 0.39 (0.12, 0.66) mmHg and DBP 0.33 (0.14, 0.51) mmHg on non-working days among 19 hypertensive adults. In contrast, 46 normotensive workers had transient increases in work-time SBP 0.16 (0.03, 0.29) mmHg and DBP 0.25 (0.15, 0.34) mmHg on working days as well as sleep-time SBP 0.17 (0.06, 0.29) mmHg and DBP 0.21 (0.14, 0.29) mmHg on non-working days caused by a 1-dBA increase in the current exposure. All groups had sustained increases in 24-h average ambulatory SBP and DBP induced by noise exposure on 2 days, but the hypertensive workers had the most pronounced increase in SBP.
Hypertensive adults are more susceptible to noise exposure with a greater effect on ambulatory SBP. These results suggest a need for more protection for this subpopulation.
Abstract Background The relationship between inherited germ-line variations in the 5α-reductase pathways of androgen biosynthesis and the risk of biochemical recurrence (BCR) after radical ...prostatectomy (RP) remains an unexplored area. Objective To determine the link between germ-line variations in the steroid-5α-reductase, α-polypeptide 1 ( SRD5A1 ) and steroid-5α-reductase, α-polypeptide 2 ( SRD5A2 ) genes and BCR. Design, settings, and participants We studied retrospectively two independent cohorts composed of 526 white (25% BCR) and 320 Asian men (36% BCR) with pathologically organ-confined prostate cancer who had a median follow-up of 88.8 and 30.8 mo after surgery, respectively. Measurements Patients were genotyped for 19 haplotype-tagging single nucleotide polymorphisms (htSNPs) in SRD5A1 and SRD5A2 genes, and their prognostic significance on prostate-specific antigen recurrence was assessed using Kaplan-Meier analysis and the Cox regression model. Results and limitations After adjusting for all clinicopathologic risk factors, four SNPs (rs2208532, rs12470143, rs523349, and rs4952197) were associated with BCR in both whites and Asians. The strongest effect was conferred by the SRD5A2 V89L nonsynonymous SNP (rs523349C) with a hazard ratio (HR) of 2.87 (95% confidence interval CI, 2.07–4.00; p = 4 × 10−10 ; 48% BCR). In addition, in whites, the combination of two SNPs, rs518673T in SRD5A1 and rs12470143A in SRD5A2, was associated with a reduced BCR rate for carriers of three or four alleles (HR: 0.37; 95% CI, 0.19–0.71; p = 0.003;16% BCR) compared with noncarriers (38% BCR), whereas the SRD5A2 rs12470143A was significant in Asians (HR: 0.46; 95% CI, 0.28–0.73; p = 0.001). Limitations of our study include few events of androgen-deprivation resistance or cancer-specific death. Conclusions Our study is the first to show positive associations of several SRD5A1 and SRD5A2 variations as independent predictors of BCR after RP.
Background/Aim: This study aimed to identify the genes that cause biochemical recurrence (BCR) following radical prostatectomy (RP) in men with localized prostate cancer. Patients and Methods: A ...two-stage genetic association study of 19 single-nucleotide polymorphisms in 11 key cell cycle regulation genes was carried out. BCR-free survival after RP was evaluated in a discovery cohort of 458 patients with prostate cancer, and replication was investigated in another cohort of 185 patients. Results: A consistent association was found between BCR and rs2290291 (discovery: p=0.008; replication: p=0.029). rs2290291 is located in the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), and was predicted to possess a regulatory function that affected YWHAZ expression. Furthermore, YWHAZ expression was frequently up-regulated in advanced tumours, and associated with poorer survival in patients with prostate cancer. Conclusion: YWHAZ rs2290291 was found to be associated with BCR. YWHAZ may function as a putative oncogene during prostate cancer progression.
Accumulating evidence suggests the roles of glutamate metabotropic receptors (GRMs) in cancer, in addition to synaptic signalling. The present study assessed the associations of genetic variants in ...eight GRM genes with regard to risk and overall survival (OS) in 780 renal cell carcinoma (RCC) patients and controls. After adjustment for known risk factors, GRM5 rs7102764 T was associated with an increased risk of RCC (P = 0.006). Additional analysis has provided evidence that rs7102764 T was correlated with a higher expression of GRM5, which is consistently found to be upregulated in tumours, compared to normal tissues. Furthermore, the GRM3 rs701332 C, GRM4 rs2499707 T, and GRM4 rs4713742 T alleles were significantly associated with a poorer OS (P ≤ 0.030). The three loci were also observed to have strong cumulative effects on OS. Additional analysis has revealed a significant genotype‐expression correlation of rs2499707 T with increased GRM4 expression, which in turn leads to poorer OS in patients with RCC. GRMs might be involved in RCC development and progression, and genetic variants in GRMs might be promising biomarkers.
This study assesses the associations of genetic variants in eight glutamate metabotropic receptor (GRM) genes with risk and survival of renal cell carcinoma. It was fond that several variants affect the expression of GRMs, which in turn is correlated with tumour aggressiveness and patient prognosis.
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