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. 2021 Feb;35(2):e23617.
doi: 10.1002/jcla.23617. Epub 2020 Oct 14.

Dysregulation of vitamin D synthesis pathway genes in colorectal cancer: A case-control study

Hossein Sadeghi  1 , Zeeba Kamaliyan  2 , Roohollah Mohseni  3 , Unes Sahebi  4 , Ehsan Nazemalhosseini-Mojarad  5 , Naser Aghaei  6 , Mohammad Reza Zali  5 , Hamid Asadzadeh Aghdaei  5 , Reza Mirfakhraie  1   2 , Arfa Moshiri  5
Affiliations

Dysregulation of vitamin D synthesis pathway genes in colorectal cancer: A case-control study

Hossein Sadeghi et al. J Clin Lab Anal. 2021 Feb.

Abstract

Background: The cytochromes P450 are a superfamily of enzymes that control the synthesis of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3. These enzymes contribute to the formation of 1,25-dihydroxyvitamin D3, which starts with a 25-hydroxylation by CYP2R1 and CYP27A1 and a subsequent 1α-hydroxylation via CYP27B1.

Methods: By using quantitative real-time polymerase chain reaction (qRT-PCR), we analyzed the expression ratio of CYP2R1, CYP27A1 and CYP27B1 genes within the vitamin D metabolic pathway in a total of 75 colorectal cancer (CRC) tissues compared to the adjacent tissues. Furthermore, we evaluated the association of CYP27B1 rs4646536 and CYP2R1 rs12794714 and rs10766196 polymorphisms with CRC risk in a total of 490 subjects, including 245 CRC patients and 245 non-cancer controls. The genotyping was performed using tetra-primer amplification refractory mutation system polymerase chain reaction (TP-ARMS-PCR) method.

Results: The results indicated 2.3 and 2.7 upregulation of CYP2R1 and CYP27B1 genes in colorectal cancer tissues compared to the adjacent tissues, respectively. Rs12794714 AG genotype increased the risk of CRC (P = .03). Furthermore, a significant association was observed under the dominant inheritance model (P = .039).

Conclusion: CYP2R1 and CYP27B1 genes were over-expressed in CRC samples compared to the adjacent control tissues. Furthermore, CYP2R1 rs12794714 variant was associated with the risk of CRC in the studied samples. CYP2R1 rs10766196 and CYP27B1 rs4646536 are not responsible for CYP2R1 and CYP27B1 genes expression alteration, respectively, but CYP2R1 rs12794714 polymorphism may be the reason of CYP2R1 upregulation and increased the risk of CRC.

Keywords: CYP27B1; CYP2R1; colorectal cancer; single-nucleotide polymorphism; vitamin D.

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Figures

FIGURE 1
FIGURE 1
The relative expression levels (ΔCt) of CYP2R1 (A), CYP27B1 (B), and CYP27A1 (C) genes in CRC samples compared to controls. A and B suggest that CYP2R1 and CYP27B1 genes were upregulated in CRC samples compared with controls. The mean ± standard deviation (SD) for CYP2R1 CRC tissues and adjacent tissues were 8.31 ± 6.53 and 12.21 ± 5.85, respectively. The mean ± SD for CYP27B1 CRC tissues and adjacent tissues were 7.78 ± 3.76 and 12.21 ± 5.59, respectively. As shown in C the expression of CYP27A1 gene was not different between the studied groups. The mean ± SD for CYP27A1 CRC tissues and adjacent tissues were 4.01 ± 14.73 and 5.07 ± 13.95, respectively. The relative expression levels comparison between CRC samples and controls was applied by paired t test. The asterisk sign (*) represents P < .05
FIGURE 2
FIGURE 2
A representative 2% agarose gel electrophoresis of for identification of the CYP2R1 rs12794714 genotypes. Lane L, 100 bp DNA ladder; lanes 1 and 2: AG genotype; lanes 3: AA genotype; and lanes 4: GG genotype
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