Vitamin D Regulation of the Uridine Phosphorylase 1 Gene and Uridine-Induced DNA Damage in Colon in African Americans and European Americans

Bhasin, Nobel; Alleyne, Dereck; Gray, Olivia A.; Kupfer, Sonia S.

doi:10.1053/j.gastro.2018.06.049

Cited by 18 publications

(7 citation statements)

References 56 publications

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“…Note that previous studies involving colon organoids are often associated with much smaller sample sizes, typically ten or less [13,[17][18][19][20]. We performed differential expression analysis on pseudo-cohorts of multiples of five pairs generated by random sampling.…”

Section: Carcinogen Treatment Of Colon Organoids Leads To Consistent Patterns Of Differential Expressionmentioning

confidence: 99%

Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids

et al. 2021

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Tobacco smoke and red/processed meats are well-known risk factors for colorectal cancer (CRC). Most research has focused on studies of normal colon biopsies in epidemiologic studies or treatment of CRC cell lines in vitro . These studies are often constrained by challenges with accuracy of self-report data or, in the case of CRC cell lines, small sample sizes and lack of relationship to normal tissue at risk. In an attempt to address some of these limitations, we performed a 24-hour treatment of a representative carcinogens cocktail in 37 independent organoid lines derived from normal colon biopsies. Machine learning algorithms were applied to bulk RNA-sequencing and revealed cellular composition changes in colon organoids. We identified 738 differentially expressed genes in response to carcinogens exposure. Network analysis identified significantly different modules of co-expression, that included genes related to MSI-H tumor biology, and genes previously implicated in CRC through genome-wide association studies. Our study helps to better define the molecular effects of representative carcinogens from smoking and red/processed meat in normal colon epithelial cells and in the etiology of the MSI-H subtype of CRC, and suggests an overlap between molecular mechanisms involved in inherited and environmental CRC risk.

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Section: Carcinogen Treatment Of Colon Organoids Leads To Consistent Patterns Of Differential Expressionmentioning

confidence: 99%

Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids

et al. 2021

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“…UPP1, which is involved in pyrimidine metabolism, regulates uridine homeostasis and promotes pyrimidine salvage 47 . Previous studies have reported that UPP1 is involved in the pathogenesis of colon cancer 48 , glioma 26 , breast cancer 49 , thyroid cancer 50 , oral squamous cell carcinoma 51 , pancreatic cancer 52 , and lung adenocarcinoma 53 .…”

Section: Discussionmentioning

confidence: 99%

UPP1 enhances bladder cancer progression and gemcitabine resistance through AKT

Du,

Tu,

Zhang

et al. 2024

Int. J. Biol. Sci.

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UPP1, a crucial pyrimidine metabolism-related enzyme, catalyzes the reversible phosphorylation of uridine to uracil and ribose-1-phosphate. However, the effects of UPP1 in bladder cancer (BLCA) have not been elucidated. AKT, which is activated mainly through dual phosphorylation (Thr308 and Ser473), promotes tumorigenesis by phosphorylating downstream substrates. This study demonstrated that UPP1 promotes BLCA cell proliferation, migration, invasion, and gemcitabine resistance by activating the AKT signaling pathway in vitro and in vivo. Additionally, UPP1 promoted AKT activation by facilitating the binding of AKT to PDK1 and PDK2 and the recruitment of phosphatidylinositol 3,4,5-triphosphate to AKT. Moreover, the beneficial effects of UPP1 on BLCA tumorigenesis were mitigated upon UPP1 mutation with Arg94 or MK2206 treatment (AKT-specific inhibitor). AKT overexpression or SC79 (AKT-specific activator) treatment restored tumor malignancy and drug resistance. Thus, this study revealed that UPP1 is a crucial oncogene and a potential therapeutic target for BLCA and that UPP1 activates the AKT signaling pathway and enhances tumorigenesis and drug resistance to gemcitabine.

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“…Besides, 1,25(OH) 2 D 3 inhibited the protumoral activation of patient-derived colon normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) and a 1,25(OH) 2 D 3 -associated gene signature imposed in CAFs correlated with a better prognosis in CRC ( Ferrer-Mayorga et al, 2017 ). Nevertheless, there is still a lack of sufficient and potent evidence from prospective clinical trials at present, and nonresponse to vitamin D may result from molecular mutation and regulation of the cancer-associated pathway ( Barry et al, 2017 ; Bhasin et al, 2018 ). Thus, it is essential to further reveal the biological mechanisms illustrating the antitumor role of vitamin D 3 in CRC.…”

Section: Introductionmentioning

confidence: 99%

VDR Signaling via the Enzyme NAT2 Inhibits Colorectal Cancer Progression

et al. 2021

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Recent epidemiological and preclinical evidence indicates that vitamin D3 inhibits colorectal cancer (CRC) progression, but the mechanism has not been completely elucidated. This study was designed to determine the protective effects of vitamin D3 and identify crucial targets and regulatory mechanisms in CRC. First, we confirmed that 1,25(OH)2D3, the active form of vitamin D3, suppressed the aggressive phenotype of CRC in vitro and in vivo. Based on a network pharmacological analysis, N-acetyltransferase 2 (NAT2) was identified as a potential target of vitamin D3 against CRC. Clinical data of CRC patients from our hospital and bioinformatics analysis by online databases indicated that NAT2 was downregulated in CRC specimens and that the lower expression of NAT2 was correlated with a higher metastasis risk and lower survival rate of CRC patients. Furthermore, we found that NAT2 suppressed the proliferation and migration capacity of CRC cells, and the JAK1/STAT3 signaling pathway might be the underlying mechanism. Moreover, Western blot and immunofluorescence staining assays demonstrated that 1,25(OH)2D3 promoted NAT2 expression, and the chromatin immunoprecipitation assay indicated that the vitamin D receptor (VDR) transcriptionally regulated NAT2. These findings expand the potential uses of vitamin D3 against CRC and introduce VDR signaling via the enzyme NAT2 as a potential diagnostic and therapeutic target for CRC.

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Vitamin D Regulation of the Uridine Phosphorylase 1 Gene and Uridine-Induced DNA Damage in Colon in African Americans and European Americans

Cited by 18 publications

References 56 publications

Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids

Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids

UPP1 enhances bladder cancer progression and gemcitabine resistance through AKT

VDR Signaling via the Enzyme NAT2 Inhibits Colorectal Cancer Progression

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