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高甲基化同源盒A11（HOXA11）的过表达抑制肿瘤细胞生长并诱导宫颈癌细胞凋亡。

Overexpression of Hypermethylated Homeobox A11 (HOXA11) Inhibits Tumor Cell Growth and Induces Apoptosis in Cervical Cancer.

作者信息

Lee Seung-Yul, Oh Tae Jeong, An Sungwhan, Lee Seung-Hoon

机构信息

Genomictree, Daejeon 34027, Korea.

Department of Life Science, College of Health Science and Welfare, Yongin University, Yongin 17092, Korea.

出版信息

Dev Reprod. 2024 Jun;28(2):37-45. doi: 10.12717/DR.2024.28.2.37. Epub 2024 Jun 30.

DOI:10.12717/DR.2024.28.2.37
PMID:39055103
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11268892/
Abstract

This study aimed to elucidate the potential of Homeobox A11 (HOXA11) as a therapeutic target and a diagnostic methylation marker for cervical cancer. Gene expression analysis using cDNA microarray in cervical cancer cell lines revealed significantly reduced expression of the HOXA11 gene. Subsequent investigation of HOXA11 promoter methylation in samples from normal individuals and invasive cervical cancer patients showed over 53.2% higher methylation in cancer scrapes compared to normal scrapes. Furthermore, overexpression of HOXA11, which is downregulated in cervical cancer, strongly suppressed cell growth in cervical cancer cell lines, HeLa and HT3. Additionally, we performed transferase dUTP nick end labeling assay and confirmed that the inhibition of cervical cancer cell proliferation occurred via apoptosis. Mechanistically, overexpression of HOXA11 led to mitochondrial apoptosis characterized by PARP cleavage due to increased c-Myc and enhanced cytochrome C secretion into the cytoplasm. These findings suggest that HOXA11 could potentially serve as a methylation marker for diagnosing cervical cancer and as a novel therapeutic target for its treatment.

摘要

本研究旨在阐明同源框A11（HOXA11）作为宫颈癌治疗靶点和诊断性甲基化标志物的潜力。使用cDNA微阵列对宫颈癌细胞系进行基因表达分析，结果显示HOXA11基因表达显著降低。随后对正常个体和浸润性宫颈癌患者样本中HOXA11启动子甲基化的研究表明，癌组织刮片的甲基化水平比正常刮片高53.2%以上。此外，在宫颈癌中下调的HOXA11过表达可强烈抑制宫颈癌细胞系HeLa和HT3的细胞生长。此外，我们进行了转移酶dUTP缺口末端标记试验，并证实宫颈癌细胞增殖的抑制是通过凋亡发生的。从机制上讲，HOXA11的过表达导致线粒体凋亡，其特征是由于c-Myc增加和细胞色素C向细胞质的分泌增强而导致PARP裂解。这些发现表明，HOXA11有可能作为宫颈癌诊断的甲基化标志物及其治疗的新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/5e5718ddd07f/dr-28-2-37-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/57b197fecaf4/dr-28-2-37-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/0a8840ae4668/dr-28-2-37-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/85a6bf01762c/dr-28-2-37-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/5e5718ddd07f/dr-28-2-37-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/57b197fecaf4/dr-28-2-37-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/0a8840ae4668/dr-28-2-37-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/85a6bf01762c/dr-28-2-37-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3090/11268892/5e5718ddd07f/dr-28-2-37-g4.jpg

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本文引用的文献

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Mitochondria and cell death.线粒体与细胞死亡。
Nat Cell Biol. 2024 Sep;26(9):1434-1446. doi: 10.1038/s41556-024-01429-4. Epub 2024 Jun 20.
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Abnormal methylation of HOXA11 promoter promotes tumor progression in testicular germ cell tumor.HOXA11基因启动子的异常甲基化促进睾丸生殖细胞肿瘤的肿瘤进展。
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DNA Methylation: Genomewide Distribution, Regulatory Mechanism and Therapy Target.DNA甲基化：全基因组分布、调控机制与治疗靶点
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Role of HOX Genes in Stem Cell Differentiation and Cancer.HOX基因在干细胞分化和癌症中的作用。
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DNA methylation profiling identifies the HOXA11 gene as an early diagnostic and prognostic molecular marker in human lung adenocarcinoma.DNA甲基化分析将HOXA11基因鉴定为人类肺腺癌的早期诊断和预后分子标志物。
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