Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
Central Molecular Lab, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
Mol Cell Biochem. 2023 Oct;478(10):2379-2394. doi: 10.1007/s11010-023-04667-6. Epub 2023 Jan 31.
The function of ABC transporters in the body is manifold; such as maintenance of homeostasis, effect on multi-drug resistance and their role in tumor initiation & progression. Evidence pointing towards the direct or indirect role of ABC transporter genes in particular; ABCB1 and ABCG2 in cancer genesis is increasing. However, their role in gallbladder cancer is unexplored. Therefore, we investigated the methylation status and expression pattern of ABCB1 and ABCG2in gallbladder carcinogenesis. The methylation and expression study of ABCB1/MDR1 and ABCG2/BCRP was performed in tumour and normal fresh tissue samples collected from 61 histopathologically diagnosed gallbladder cancer patients. The methylation status was analysed by Methylation-Specific PCR and expression was determined by Real-Time PCR and Immunohistochemistry. Hypomethylation of ABCB1 and ABCG2 was found in 44 (72.13%) and 48 (78.6%) cases, respectively. ABCB1 hypomethylation pattern showed association with female patients (p = 0.040) and GradeII tumors (p = 0.036) while, ABCG2 hypomethylation was more frequent in early tumors (T1-T2). The mRNA expression ofABCB1 and ABCG2 was up-regulated in 33 (54.10%) and 41 (67.21%) patients with fold change of 4.7 and 5.5, respectively. The mRNA expression of both genes showed association with Grade II tumours and the increased fold change of ABCG2 was higher in (T1-T2) depth of invasion (p = 0.02) and Stage I-II disease (p = 0.08). The protein expression on IHC was strongly positive for ABCB1/MDR1and ABCG2/BCRP in 32 (52.46%) and 45 (73.77%) patients, respectively. The protein expression in ABCG2 showed association with patients age > 50 years (p = 0.04) and GradeII differentiation (p = 0.07). Interestingly, the hypomethylation of both the genes showed significant correlation with increased expression. ABCB1/MDR1 and ABCG2/BCRP hypomethylation and overexpression could have a potential role in gallbladder cancer tumorigenesis especially in early stages. The epigenetic change might be a plausible factor for altered gene expression of ABCB1 and ABCG2 in gallbladder cancer.
ABC 转运蛋白在体内的功能多种多样；例如维持体内平衡、影响多药耐药以及在肿瘤发生和进展中的作用。越来越多的证据表明，ABC 转运蛋白基因，尤其是 ABCB1 和 ABCG2，直接或间接地参与了癌症的发生。然而，它们在胆囊癌中的作用尚未得到探索。因此，我们研究了 ABCB1 和 ABCG2 在胆囊癌发生中的甲基化状态和表达模式。对 61 例经组织病理学诊断的胆囊癌患者的肿瘤和正常新鲜组织样本进行了 ABCB1/MDR1 和 ABCG2/BCRP 的甲基化和表达研究。通过甲基化特异性 PCR 分析甲基化状态，通过实时 PCR 和免疫组织化学测定表达。发现 44 例（72.13%）和 48 例（78.6%）患者的 ABCB1 和 ABCG2 呈低甲基化。ABCB1 低甲基化模式与女性患者（p=0.040）和 II 级肿瘤（p=0.036）相关，而 ABCG2 低甲基化则更常见于早期肿瘤（T1-T2）。ABCB1 和 ABCG2 的 mRNA 表达在 33 例（54.10%）和 41 例（67.21%）患者中上调，倍数变化分别为 4.7 和 5.5。这两个基因的 mRNA 表达与 II 级肿瘤有关，ABCG2 的倍数变化在 T1-T2 浸润深度（p=0.02）和 I-II 期疾病（p=0.08）中更高。免疫组化的蛋白表达在 32 例（52.46%）和 45 例（73.77%）患者中 ABCB1/MDR1 和 ABCG2/BCRP 均为强阳性。ABCG2 蛋白表达与患者年龄>50 岁（p=0.04）和 II 级分化（p=0.07）有关。有趣的是，这两个基因的低甲基化与表达增加均有显著相关性。ABCB1/MDR1 和 ABCG2/BCRP 的低甲基化和过表达可能在胆囊癌的肿瘤发生中发挥作用，特别是在早期阶段。表观遗传改变可能是 ABCB1 和 ABCG2 在胆囊癌中基因表达改变的一个合理因素。
