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HNF1A 通过靶向 53BP1 调节胰腺癌对奥沙利铂的耐药性。

HNF1A regulates oxaliplatin resistance in pancreatic cancer by targeting 53BP1.

机构信息

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.

Department of Pancreas Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, P.R. China.

出版信息

Int J Oncol. 2023 Apr;62(4). doi: 10.3892/ijo.2023.5493. Epub 2023 Feb 24.

DOI:10.3892/ijo.2023.5493
PMID:36825600
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9990585/
Abstract

DNA double‑strand break repair is critically involved in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). Hepatocyte nuclear factor 1 homeobox A (HNF1A) has received increased attention regarding its role in cancer progression. The present study explored the role of HNF1A in oxaliplatin resistance in PDAC. The results revealed that HNF1A expression was negatively associated with oxaliplatin chemoresistance in PDAC tissues and cell lines. HNF1A inhibition promoted the proliferation, colony formation and stemness of PDAC cells, and suppressed their apoptosis. Furthermore, HNF1A inhibition switched nonhomologous end joining to homologous recombination, thereby enhancing genomic stability and oxaliplatin resistance. Mechanistically, HNF1A transcriptionally activates p53‑binding protein 1 (53BP1) expression by directly interacting with the 53BP1 promoter region. Upregulation of HNF1A and 53BP1 induced significant inhibition of PDAC growth and oxaliplatin resistance in patient‑derived PDAC xenograft models and orthotopic models. In conclusion, the findings of the present study suggested that HNF1A/53BP1 may be a promising PDAC therapeutic target for overcoming oxaliplatin resistance.

摘要

DNA 双链断裂修复在胰腺导管腺癌 (PDAC) 的奥沙利铂耐药中起着至关重要的作用。肝细胞核因子 1 同源盒 A (HNF1A) 在癌症进展中的作用受到了越来越多的关注。本研究探讨了 HNF1A 在 PDAC 中奥沙利铂耐药中的作用。结果表明，HNF1A 的表达与 PDAC 组织和细胞系中奥沙利铂耐药呈负相关。HNF1A 抑制促进了 PDAC 细胞的增殖、集落形成和干性，并抑制了它们的凋亡。此外，HNF1A 抑制将非同源末端连接切换为同源重组，从而增强了基因组稳定性和奥沙利铂耐药性。在机制上，HNF1A 通过直接与 53BP1 启动子区域相互作用，转录激活 p53 结合蛋白 1 (53BP1) 的表达。HNF1A 和 53BP1 的上调显著抑制了患者来源的 PDAC 异种移植模型和原位模型中 PDAC 的生长和奥沙利铂耐药性。总之，本研究的结果表明，HNF1A/53BP1 可能是克服奥沙利铂耐药性的有前途的 PDAC 治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/8148cf00f974/IJO-62-4-05493-g06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/65ed7438eb06/IJO-62-4-05493-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/45a998f11ce8/IJO-62-4-05493-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/a3baadee4dc3/IJO-62-4-05493-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/b1cd92d697bf/IJO-62-4-05493-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/5c555d50d1b1/IJO-62-4-05493-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/b9c6b56c98eb/IJO-62-4-05493-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/8148cf00f974/IJO-62-4-05493-g06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/65ed7438eb06/IJO-62-4-05493-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/45a998f11ce8/IJO-62-4-05493-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/a3baadee4dc3/IJO-62-4-05493-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/b1cd92d697bf/IJO-62-4-05493-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/5c555d50d1b1/IJO-62-4-05493-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/b9c6b56c98eb/IJO-62-4-05493-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba3/9990585/8148cf00f974/IJO-62-4-05493-g06.jpg

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