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HNF1A 作为 POU5F1 的下游调节结直肠癌的进展和耐药性。

HNF1A regulates colorectal cancer progression and drug resistance as a downstream of POU5F1.

机构信息

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan.

Innovative Oncology Research and Translational Medicine, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka, 541-8567, Japan.

出版信息

Sci Rep. 2021 May 14;11(1):10363. doi: 10.1038/s41598-021-89126-2.

DOI:10.1038/s41598-021-89126-2
PMID:33990627
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8121855/
Abstract

POU5F1-expressing cells can self-renew and differentiate, contributing to metastasis formation in colorectal cancer (CRC), but it plays an important role in normal pluripotent stem cells. Here, we identified the CRC-specific gene, HNF1A, which is the downstream of POU5F1. HNF1A associates with fatty acid and glucose metabolism, and CRC cells highly expressed it. In 198 CRC patients, high HNF1A expression was an independent predictor of disease-free (P = 0.031) and overall (P = 0.007) survival. HNF1A-knockdown showed significantly reduced cell growth, increased apoptosis, and improved anticancer drug sensitivity. We revealed that HNF1A regulated controlled GLUT1 expression via HIF1A and multidrug resistance protein function to suppress SRI. HNF1A expression was elevated in persister cells after exposure to anticancer drugs, and anticancer drug sensitivity was also improved in persister cells via the inhibition of HNF1A. In conclusion, HNF1A expression can reflect resistance to anticancer drug treatment, and its suppression improves anticancer drug sensitivity as a new therapeutic target.

摘要

POU5F1 表达细胞能够自我更新和分化，促进结直肠癌（CRC）的转移形成，但它在正常多能干细胞中起着重要作用。在这里，我们鉴定了 CRC 特异性基因 HNF1A，它是 POU5F1 的下游基因。HNF1A 与脂肪酸和葡萄糖代谢有关，CRC 细胞高表达它。在 198 名 CRC 患者中，高 HNF1A 表达是无病生存（P=0.031）和总生存（P=0.007）的独立预测因子。HNF1A 敲低显示出明显降低的细胞生长、增加的细胞凋亡和提高的抗癌药物敏感性。我们揭示了 HNF1A 通过 HIF1A 和多药耐药蛋白功能调节控制 GLUT1 的表达，以抑制 SRI。在暴露于抗癌药物后，持久性细胞中 HNF1A 的表达上调，并且通过抑制 HNF1A，持久性细胞中的抗癌药物敏感性也得到改善。总之，HNF1A 的表达可以反映对抗癌药物治疗的耐药性，其抑制作用提高了抗癌药物敏感性，是一个新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/7faea2288d17/41598_2021_89126_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/05337472e3f7/41598_2021_89126_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/b4d7fca0a6d6/41598_2021_89126_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/704e99f1ab14/41598_2021_89126_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/7faea2288d17/41598_2021_89126_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/05337472e3f7/41598_2021_89126_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/b4d7fca0a6d6/41598_2021_89126_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/704e99f1ab14/41598_2021_89126_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d36d/8121855/7faea2288d17/41598_2021_89126_Fig4_HTML.jpg

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