Khalid Samra, Hanif Rumeza
Atta-ur-Rahman School of Applied Biosciences (ASAB)/Assistant Professor/Healthcare Biotechnology, National University of Science and Technology, Islamabad, Pakistan.
PeerJ. 2017 Sep 15;5:e3822. doi: 10.7717/peerj.3822. eCollection 2017.
C-X-C chemokine ligand 12 (CXCL12) has important implications in breast cancer (BC) pathogenesis. It is selectively expressed on B and T lymphocytes and is involved in hematopoiesis, thymocyte trafficking, stem cell motility, neovascularization, and tumorigenesis. The single nucleotide polymorphism (SNP) rs1801157 of CXCL12 gene has been found to be associated with higher risk of BC.
Our study focuses on the genotypic and allelic distribution of SNP (rs1801157; G/A) in Pakistani population as well as its association with the clinico-pathological features. The association between rs1801157 genotypes (G/A) and BC risks was assessed by a multivariate logistic regression (MLR) analysis. Genotyping was performed in both healthy individuals and patients of BC using PCR-restriction fragment length polymorphism (PCR-RFLP) method. Furthermore, approaches were adapted to investigate the association of CXCL12 and its receptor CXCR4 with genes/proteins involved in BC signalling.
Significant differences in allelic and genotypic distribution between BC patients and healthy individuals of genotype (G/G) and (A/G) ( < 0.05) were observed. The frequency of the allele G in the BC group (77%) was significantly higher as compared to control group (61%) ( = 0.01). The association of genotype GG with clinico-pathological features including age, stages of cancer and organ (lung, liver, bones and brain) metastasis ( > 0.05) was assessed. In a MLR analysis, a number of variables including age, weight of an individual, affected lymph nodes, hormonal status (estrogen and progesterone receptor), alcohol consumption and family history associated with the GG genotype (GG:AA, odds ratio (OR) = 1.30, 95% CI [1.06-1.60]) were found to be independent risk factors for BC. Our results suggest that genotype GG is possibly increasing the risk of BC in Pakistani cohorts. analysis finds that CXCL12-CXCR4 is associated with an increased expression of PDZK1, PI3k and Akt which lead the breast tumor towards metastasis.
Multiple targets such as CXCL12, CXCR4, PDZK1, PI3k and Akt can be inhibited in combined strategies to treat BC metastasis.
C-X-C趋化因子配体12（CXCL12）在乳腺癌（BC）发病机制中具有重要意义。它在B淋巴细胞和T淋巴细胞上选择性表达，参与造血、胸腺细胞迁移、干细胞运动、新血管形成和肿瘤发生。已发现CXCL12基因的单核苷酸多态性（SNP）rs1801157与BC的较高风险相关。
我们的研究聚焦于巴基斯坦人群中SNP（rs1801157；G/A）的基因型和等位基因分布及其与临床病理特征的关联。通过多因素逻辑回归（MLR）分析评估rs1801157基因型（G/A）与BC风险之间的关联。使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对健康个体和BC患者进行基因分型。此外，采用多种方法研究CXCL12及其受体CXCR4与参与BC信号传导的基因/蛋白质之间的关联。
观察到BC患者与基因型为（G/G）和（A/G）的健康个体在等位基因和基因型分布上存在显著差异（P<0.05）。BC组中等位基因G的频率（77%）显著高于对照组（61%）（P=0.01）。评估了基因型GG与包括年龄、癌症分期以及器官（肺、肝、骨和脑）转移等临床病理特征之间的关联（P>0.05）。在MLR分析中，发现包括年龄、个体体重、受累淋巴结、激素状态（雌激素和孕激素受体）、饮酒和家族史等多个变量与GG基因型相关（GG:AA，比值比（OR）=1.30，95%置信区间[1.06-1.60]），这些变量是BC的独立危险因素。我们的结果表明，在巴基斯坦人群中，基因型GG可能会增加患BC的风险。分析发现CXCL12-CXCR4与PDZK1、PI3k和Akt的表达增加有关，这会导致乳腺肿瘤发生转移。
在联合治疗策略中，可以抑制多个靶点，如CXCL12、CXCR4、PDZK1、PI3k和Akt，以治疗BC转移。
