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Molecular aspects of ABCB1 and ABCG2 in Gallbladder cancer and its clinical relevance

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Abstract

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.

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Acknowledgements

The authors acknowledge DBT for providing the fund for fellowship and consumables for the research work under the project entitled “Establishment of Central Molecular Lab in GIPMER to study the diagnosis for precision medicine in order to understand the disease process and utilize it as Clinical Research Facility” (Grant no. BT/INF/22/SP33063/2019).

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Authors and Affiliations

  1. Department of Biosciences, Jamia Millia Islamia, New Delhi, India

    Nimisha & Syed Akhtar Husain

  2. Central Molecular Lab, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India

    Nimisha, Sundeep Singh Saluja, Abhay Kumar Sharma,  Apurva, Arun Kumar & Real Sumayya Abdul Sattar

  3. Department of Pathology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India

    Hasib Anjum & Vineeta Vijay Batra

  4. Department of Gastrointestinal Surgery, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India

    Sundeep Singh Saluja & Phani Kumar Nekarakanti

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  1. Nimisha
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Contributions

N, SSS and SAH has designed the study. N and SSS has written the manuscript. N,AKS,AA,AK,RSAS has contributed in the experimental work supervised by SSS and SAH. N and HA has performed IHC supervised and analysed by VVB. N, SSS and PKN has performed the analysis. SSS and SAH has edited the manuscript. All the authors has reviewed the manuscript.

Corresponding author

Correspondence to Syed Akhtar Husain.

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The authors have not disclosed any competing interests.

Ethical approval

The study acquired ethical approval from Institutional Ethical Committee Jamia Millia Islamia (Proposal No. 1/10/292/JMI/IEC/2020) and Institute Ethics Committee Maulana Azad Medical College and Associated Hospital, New Delhi (F.1/IEC/MAMC/77/05/2020/No.163).

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Nimisha, Saluja, S.S., Sharma, A.K. et al. Molecular aspects of ABCB1 and ABCG2 in Gallbladder cancer and its clinical relevance. Mol Cell Biochem 478, 2379–2394 (2023). https://doi.org/10.1007/s11010-023-04667-6

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