Genetically predicted vitamin C levels significantly affect patient survival and immunotypes in multiple cancer types.

Background: Recent observational studies and meta-analyses have shown that vitamin C reduces cancer incidence and mortality, but the underlying mechanisms remain unclear. We conducted a comprehensive pan-cancer analysis and biological validation in clinical samples and animal tumor xenografts to understand its prognostic value and association with immune characteristics in various cancers. Methods: We used the Cancer Genome Atlas gene expression data involving 5769 patients and 20 cancer types. Vitamin C index (VCI) was calculated using the expression of 11 genes known to genetically predict vitamin C levels, which were classified into high and low subgroups. The correlation between VCI and patient overall survival (OS), tumor mutational burden (TMB), microsatellite instability (MSI), and immune microenvironment was evaluated, using Kaplan-Meier analysis method and ESTIMATE (https://bioinformatics.mdanderson.org/estimate/). Clinical samples of breast cancer and normal tissues were used to validate the expression of VCI-related genes, and animal experiments were conducted to test the impact of vitamin C on colon cancer growth and immune cell infiltration. Results: Significant changes in expression of VCI-predicted genes were observed in multiple cancer types, especially in breast cancer. There was a correlation of VCI with prognosis in all samples (adjusted hazard ratio [AHR] = 0.87; 95% confidence interval [CI] = 0.78-0.98; P = 0.02). The specific cancer types that exhibited significant correlation between VCI and OS included breast cancer (AHR = 0.14; 95% CI = 0.05-0.40; P < 0.01), head and neck squamous cell carcinoma (AHR = 0.20; 95% CI = 0.07-0.59; P < 0.01), kidney clear cell carcinoma (AHR = 0.66; 95% CI = 0.48-0.92; P = 0.01), and rectum adenocarcinoma (AHR = 0.01; 95% CI = 0.001-0.38; P = 0.02). Interestingly, VCI was correlated with altered immunotypes and associated with TMB and MSI negatively in colon and rectal adenocarcinoma (P < 0.001) but positively in lung squamous cell carcinoma (P < 0.05). In vivo study using mice bearing colon cancer xenografts demonstrated that vitamin C could inhibit tumor growth with significant impact on immune cell infiltration. Conclusion: VCI is significantly correlated with OS and immunotypes in multiple cancers, and vitamin C might have therapeutic potential in colon cancer.

MicroRNA­192 acts as a tumor suppressor in colon cancer and simvastatin activates miR­192 to inhibit cancer cell growth.

Colon cancer is one of the most common malignant tumors worldwide. Understanding the underlying molecular mechanisms is crucial for the development of therapeutic strategies for the treatment of patients with colon cancer. In the present study, a novel tumor suppressive microRNA, miR­192, was demonstrated to be markedly downregulated in colon cancer cells compared with normal colon cells. By overexpressing miR­192 in colon cancer HCT­116 cells, the results of the present study revealed that miR­192 inhibits cell proliferation, migration and invasion. Bioinformatics were used to determine the target gene of miR­192 and Ras­related protein Rab­2A (RAB2A) was identified as a downstream target of miR­192. Following the determination of the role of the miR­192­RAB2A pathway in colon cancer, small molecules that may regulate miR­192 were screened and the results demonstrated that simvastatin is an activator of miR­192. Furthermore, simvastatin upregulated miR­192 and inhibited the expression of downstream targets of miR­192, which subsequently led to suppressed proliferation, migration and invasion of colon cancer cells. In conclusion, the present study identified a novel colon cancer cell suppressor, as well as a small­molecule activator of the tumor suppressor miR­192, which may represent a therapeutic strategy for the treatment of patients with colon cancer.

[Association of polymorphisms of 1772 (C-->T) and 1790 (G-->A) in HIF1A gene with hypoxia adaptation in high altitude in Sherpas].

OBJECTIVE: To investigate the association of single nucleotide polymorphisms (SNPs) of 1772 (C-->T) and 1790 (G-->A) in exon 12 of hypoxia-inducible factor 1, alpha subunit gene (HIF1A) with hypoxia adaptation in high altitude in Sherpas. METHODS: The blood samples were chosen from 148 Sherpas in Tibet high altitude and 90 Han nationality healthy people in Guangdong province, and from which genomic DNA was extracted. The single nucleotide polymorphisms of 1772(C-->T) and 1790(G-->A) in exon 12 of HIF1A gene were examined by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). RESULTS: The genotype frequency of HIF1A gene 1790 (G-->A) in Sherpas and Han nationality was 57.43% versus 75.56% in GG genotype, 37.84% versus 21.11% in GA genotype and 4.73% versus 3.33% in AA genotype. GG genotype frequency in Sherpas was lower than that in Han nationality (P<0.01), while GA genotype frequency in Sherpas was higher than that in Han nationality (P<0.01). No significant difference in CC, CT and TT genotype frequency of 1772(C-->T) was shown between two groups respectively. The total frequency of CC + GA, CT + AA, TT + GA and TT + AA in Sherpas was higher than that in Han nationality. CONCLUSION: Polymorphisms of HIF1A gene 1790 (G-->A) are associated with hypoxia adaptation in high altitude in Sherpas. GA and AA genotype may be benefit to hypoxia adaptation, and it is worthy of deep-going investigation.

[Single nucleotide polymorphisms study of surfactant protein A gene between Tibet Sherpas and Guangdong Chinese Hans].

AIM: To investigate the relationship between single nucleotide polymorphisms(SNPs) of surfactant protein A(SP-A) gene of Chinese Han and Sherpas and their adaptation to high altitude hypoxia. METHODS: The genotypes of 90 Chinese Han in Guangdong and 104 Sherpas in Tibet were analyzed by sequence special primer polymerase chain reaction(SSP-PCR) sequencing the surfactant protein A gene. RESULTS: The frequencies of genotypes and alleles at SP-A1 1544 locus showed no difference between the Sherpas and the Chinese Han (P>0.05). However, the frequencies of genotypes C/C, C/T and T/T at SP-A1 3241 locus were 75.0%, 22.1% and 2.9%, respectively in Sherpas, difference to Han population, they were 50.0%, 35.6% and 14.4%, respectirely(P<0.05). Whilst in Sherpas allele frequencies of C and T were 86.1% and 13.9% respectively but they were 67.8% and 32.2% respectively in the Chinese Han(P<0.05); The frequencies of C/C, A/C and A/A at SP-A2 3265 locus were 37.5%, 53.8%, and 8.7%, respectively in the Sherpas were also difference to Chinese Han, they were 63.3%, 30.0%, and 6.7%, respectively. Whilst allele frequencies of C and A were 64.4% and 35.6% in Sherpas but 78.3% and 21.7% in Chinese Han, which showed statistically difference between two groups(P<0.05). CONCLUSION: There were statistically differences of genotypes and alleles at SP-A2 3265 locus in Hans and Sherpas. SNP in SP-A2 at 3265 may be related to the adaptation of Sherpas to high altitude hypoxia.