Moudi Emadoddin, Heydari Mohammadkazem, Hosseinzadeh Colagar Abasalt
Clinical Research Development Unit of Shahid Beheshti Hospital, Babol University of Medical Sciences, Babol, Mazandaran, Iran.
Department of Molecular and Cell Biology, Faculty of Science, University of Mazandaran, Babolsar, PC: 47416-95447, Mazandaran, Iran.
Int J Mol Cell Med. 2023;12(3):275-287. doi: 10.22088/IJMCM.BUMS.12.3.275.
CD44, a cell-surface receptor and a key player in cellular signaling, can act as both tumor suppressor and promoter. This study aimed to investigate the association of rs13347C>T variants with prostate neoplasms, including both benign prostatic hyperplasia (BPH) and prostate cancers using a case-control and bioinformatics approach. Genomic DNA was extracted from 545 blood samples (225 BPH, 225 prostate cancers, and 95 control) and the rs13347C>T genotypes were identified using PCR-RFLP. We explored miRNA interactions using the miRNASNP-v3 database and GeneMANIA for co-expression networks. Results showed cancer patients had significantly higher PSA levels compared to both controls (p= 0.03) and BPH (p= 0.01). Additionally, digital rectal examination-positive and smoker BPH patients showed significantly the increased cancer risk (p= 0.004, p= 0.046). Prostate cancer group indicated significantly higher frequency of rs13347C>T mutant allele compared to control and BPH groups, particularly in TT and CT+TT genotypes (p < 0.05). miRNA SNP-v3 database predicted the mutant allele of rs13347C>T could lose 1 and gain 6 miRNAs for a new site created. Co-expression analysis revealed a direct interaction between CD44 and aryl hydrocarbon receptor (AHR), a gene known to be dysregulated in smokers. Furthermore, these genes alone display co-expression interactions with integrin subunit alpha 4 (ITGA4), protein plays a paradoxical role, both suppressing and promoting tumors. Based on the findings, the mutant allele of rs13347C>T may disrupt miRNA binding, which may potentially impact CD44, AHR, and ITGA4 expression in smokers, possibly contributing to prostate cancer progression.
CD44是一种细胞表面受体，也是细胞信号传导中的关键因子，它既可以作为肿瘤抑制因子，也可以作为肿瘤促进因子。本研究旨在采用病例对照和生物信息学方法，研究rs13347C>T变异与前列腺肿瘤（包括良性前列腺增生症（BPH）和前列腺癌）之间的关联。从545份血液样本（225例BPH、225例前列腺癌和95例对照）中提取基因组DNA，并使用PCR-RFLP鉴定rs13347C>T基因型。我们使用miRNASNP-v3数据库和GeneMANIA探索miRNA相互作用以构建共表达网络。结果显示，与对照组（p = 0.03）和BPH组（p = 0.01）相比，癌症患者的PSA水平显著更高。此外，直肠指检阳性和吸烟的BPH患者显示癌症风险显著增加（p = 0.004，p = 0.046）。与对照组和BPH组相比，前列腺癌组中rs13347C>T突变等位基因的频率显著更高，尤其是在TT和CT+TT基因型中（p < 0.05）。miRNA SNP-v3数据库预测，rs13347C>T的突变等位基因可能会因新创建的位点而失去1个miRNA并获得6个miRNA。共表达分析揭示了CD44与芳烃受体（AHR）之间的直接相互作用，AHR是一种已知在吸烟者中失调的基因。此外，这些基因单独与整合素亚基α4（ITGA4）显示共表达相互作用，ITGA4蛋白发挥着矛盾的作用，既抑制肿瘤又促进肿瘤。基于这些发现，rs13347C>T的突变等位基因可能会破坏miRNA结合，这可能会影响吸烟者中CD44、AHR和ITGA4的表达，可能导致前列腺癌进展。
