Interrelationships among genetic <i><scp>C</scp>677<scp>T</scp></i> polymorphism of 5,10‐methylenetetrahydrofolate reductase, biochemical folate status, and lymphocytic <i>p53</i> oxidative damage in association with tumor malignancy and survivals of patients with hepatocellular carcinoma

Kuo, Chang-Sheng; Huang, Chi-Yun; Kuo, Hsing‐Tao; Cheng, Chin‐Chi; Chen, Chien‐Hung; Lu, Chin-Li; Yang, Feili-Lo; Huang, Rachel

doi:10.1002/mnfr.201200479

Cited by 16 publications

(13 citation statements)

References 55 publications

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“…In animal models of breast cancer, a high dose of folic acid has been reported to enhance tumour growth (7) , while withdraw of folate is thought to cause a reduction in growth rate of hepatoma cells (12) . A Taiwan study observed that higher erythrocyte folate levels were associated with inferior survival among 232 HCC patients who had a median erythrocyte folate level of 688 ng/ml (57) . Notably, our observations also suggest that patients in the top quartile of serum folate tend to experience an increased risk of liver cancer-specific and overall mortality, although not statistically significant.…”

Section: Discussionmentioning

confidence: 99%

Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort study

et al. 2019

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Existing data on folate status and hepatocellular carcinoma (HCC) prognosis are scarce. We prospectively examined whether serum folate concentrations at diagnosis were associated with liver cancer-specific survival (LCSS) and overall survival (OS) among 982 patients with newly diagnosed, previously untreated HCC, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study between September 2013 and February 2017. Serum folate concentrations were measured using chemiluminescent microparticle immunoassay. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95 % CI by sex-specific quartile of serum folate. Compared with patients in the third quartile of serum folate, patients in the lowest quartile had significantly inferior LCSS (HR = 1·48; 95 % CI 1·05, 2·09) and OS (HR = 1·43; 95 % CI 1·03, 1·99) after adjustment for non-clinical and clinical prognostic factors. The associations were not significantly modified by sex, age at diagnosis, alcohol drinking status and Barcelona Clinic Liver Cancer (BCLC) stage. However, there were statistically significant interactions on both multiplicative and additive scale between serum folate and C-reactive protein (CRP) levels or smoking status and the associations of lower serum folate with worse LCSS and OS were only evident among patients with CRP > 3·0 mg/l or current smokers. An inverse association with LCSS were also observed among patients with liver damage score ≥3. These results suggest that lower serum folate concentrations at diagnosis are independently associated with worse HCC survival, most prominently among patients with systemic inflammation and current smokers. A future trial of folate supplementation seems to be promising in HCC patients with lower folate status.

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Section: Discussionmentioning

confidence: 99%

Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort study

et al. 2019

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“…Increased plasma homocysteine levels have been indicated to enhance in vivo and in vitro oxidative stress ( P53 oxidative lesions)/endothelial dysfunction. Reduced MTHFR activities are associated with a high-risk for the development of HCC and are correlated with lower risks for late-stage HCC and a favorable survival of patients with HCC [7–9]. …”

Section: Introductionmentioning

confidence: 99%

Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes

Liu

et al. 2017

PLoS ONE

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Background/AimsFolic acid (FA) is a core micronutrient involved in DNA synthesis/methylation, and the metabolism of FA is responsible for genomic stability. MicroRNAs may affect gene expression during folate metabolism when cellular homeostasis is changed. This study aimed to reveal the relationship between FA deficiency and the expression of miR-22-p/miR-149-5p and the targeted regulation of miR-22-3p/miR-149-5p on the key folate metabolic gene Methylenetetrahydrofolate reductase (MTHFR).MethodsNormal (HL-7702 cells) and cancerous (QGY-7703 cells) human hepatocytes were intervened in modified RPMI 1640 with FA deficiency for 21 days. The interaction between MTHFR and the tested miRNAs was verified by Dual-Luciferase Reporter Assays. The changes in the expression of miR-22-3p/miR-149-5p in response to FA deficiency were detected by Poly (A) Tailing RT-qPCR, and the expression of MTHFR at both the transcriptional and translational levels was determined by RT-qPCR and Western blotting, respectively.ResultMiR-22-3p/miR-149-5p directly targeted the 3’UTR sequence of the MTHFR gene. FA deficiency led to an upregulation of miR-22-3p/miR-149-5p expression in QGY-7703/HL-7702 cells, while the transcription of MTHFR was decreased in QGY-7703 cells but elevated in HL-7702 cells. Western blotting showed that FA deficiency resulted in a decline of the MTHFR protein in QGY-7703 cells, whereas in HL-7702 cells, the MTHFR protein level remained constant.ConclusionThe results suggested that miR-22-3p/miR-149-5p exert different post-transcriptional effects on MTHFR under conditions of FA deficiency in normal and cancerous human hepatocytes. The results also implied that miR-22-3p/miR-149-5p might exert anticancer effects in cases of long-term FA deficiency.

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“…For RBC folate, one study used immunoassay, 49 four used radioimmunoassay 27,64,69,80 and four used microbiologic assay. 72,74,75,81 Ninety-one percent of studiesthat examined serum folate-reported a high serum folate cutoff 35 -48,50,52 -68, 71 -74,76 -79,82,83 that was within the range of values considered clinically normal, or possibly deficient, using macrocytic anemia as a metabolic indicator (7-45 nmol/l). 3 There is no established normal range for RBC folate, but 33% of the studies examining RBC folate reporting a high cutoff 64,74,80 concentrations were close to 305 nmol/l, the deficiency cutoff established by the Institute of Medicine.…”

Section: Resultsmentioning

confidence: 99%

“…47 Other measurement methods for reported high serum folate cutoff showed a decreased risk of cognitive impairment, 78 prostate cancer 77 and anencephaly 79 in offspring of women with the methylenetetrahydrofolate reductase (MTHFR) TT genotype, though an increased risk in stroke risk was found in one of these studies. 78 There were five studies with significant results in the RBC folate category, three measured by radioimmunoassay, 27,64,80 one by microbiologic assay 81 and one by immunoassay. 49 The highest reported RBC folate cutoff (!1853 nmol/ l), which demonstrated a significant association, was measured by microbiologic assay and was positively associated with the risk of advanced hepatocellular carcinoma.…”

Section: Resultsmentioning

confidence: 99%

Systematic review of adverse health outcomes associated with high serum or red blood cell folate concentrations

Colapinto¹,

O'Connor²,

Sampson³

et al. 2015

J Public Health

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Our interpretation was complicated by methodological variability. High folate cutoffs varied and often corresponded with normal or desirable blood concentrations. In general, a negative association appeared to exist between reported high folate status and adverse health outcomes. Consistent methods and definitions are needed to examine high folate status and ultimately inform public health interventions.

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Interrelationships among genetic C677T polymorphism of 5,10‐methylenetetrahydrofolate reductase, biochemical folate status, and lymphocytic p53 oxidative damage in association with tumor malignancy and survivals of patients with hepatocellular carcinoma

Cited by 16 publications

References 55 publications

Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort study

Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort study

Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes

Systematic review of adverse health outcomes associated with high serum or red blood cell folate concentrations

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