SOX15 Transcriptionally Decreases the Level of MMP2 and Inhibits Vasculogenic Mimicry to Slow Down the Progression of Ovarian Cancer

IF 2.4 4区生物学 Q4 CELL BIOLOGY

Biology of the Cell Pub Date : 2025-08-20 DOI:10.1111/boc.70031

Xiaodan Zhao, Xinjia Wang, Chao Wang, Huiyu Tian, Yang Zhou, Lihong Gong

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引用次数: 0

Abstract

Background Information

Vascular mimicry (VM) is pivotal for promoting tumor cell proliferation and invasion in ovarian (OV) cancer patients. Sex-determining region Y-box 15 (SOX15) suppresses the malignant growth of tumor cells. However, the function of SOX15 in OV cancer remains undefined. Using SKOV-3 and ES2 cell lines, along with xenograft models in nude mice, we investigated the effects of SOX15 on tumor cell growth and VM formation in OV cancer, as well as the underlying mechanisms.

Results

We found that SOX15 inhibited the proliferation, migration, and invasion of SKOV-3 cells. SOX15 overexpression reduced VM formation in SKOV-3 cells, accompanied by decreased levels of VE-cadherin and vascular endothelial growth factor A (VEGFA). Similarly, SOX15 suppressed ES2 cell proliferation and motility. Additionally, xenograft experiments demonstrated that SOX15 knockdown increased tumor volume in mice, along with upregulated expression of Ki67 and matrix metalloproteinase-2 (MMP2) in tumor tissues. CD31/PAS double staining revealed that silencing SOX15 promoted VM formation in tumors. Mechanistically, SOX15 overexpression downregulated MMP2 at both mRNA and protein levels, suppressing VM formation and thereby slowing OV cancer progression. Dual-luciferase reporter assays revealed that SOX15 overexpression inhibited MMP2 promoter activity, and chromatin immunoprecipitation followed by PCR (ChIP-PCR) confirmed the direct binding of SOX15 to the MMP2 promoter.

Conclusions

Our results indicate that SOX15 transcriptionally represses MMP2 expression, thereby inhibiting VM formation and ultimately suppressing OV cancer initiation and progression.

Significance

We establish a theoretical foundation for developing novel therapeutic approaches targeting the SOX15/MMP2 axis in OV cancer treatment.

Abstract Image

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SOX15通过转录降低MMP2水平和抑制血管生成模拟来减缓卵巢癌的进展

背景信息血管拟态（Vascular mimmimi， VM）是促进卵巢癌患者肿瘤细胞增殖和侵袭的关键机制。性别决定区Y-box 15 （SOX15）抑制肿瘤细胞的恶性生长。然而，SOX15在OV癌中的功能尚不明确。利用SKOV-3和ES2细胞系以及裸鼠异种移植模型，我们研究了SOX15对OV癌肿瘤细胞生长和VM形成的影响及其潜在机制。结果SOX15能抑制SKOV-3细胞的增殖、迁移和侵袭。SOX15过表达减少了SKOV-3细胞中VM的形成，同时VE-cadherin和血管内皮生长因子A （VEGFA）水平降低。同样，SOX15抑制ES2细胞的增殖和运动。此外，异种移植实验表明，SOX15敲低会增加小鼠的肿瘤体积，同时上调Ki67和基质金属蛋白酶2 （MMP2）在肿瘤组织中的表达。CD31/PAS双染色显示，沉默SOX15可促进肿瘤中VM的形成。从机制上讲，SOX15过表达在mRNA和蛋白水平上下调MMP2，抑制VM形成，从而减缓OV癌症进展。双荧光素酶报告基因检测显示，SOX15过表达抑制MMP2启动子活性，染色质免疫沉淀PCR （ChIP-PCR）证实SOX15与MMP2启动子直接结合。结论SOX15通过转录抑制MMP2的表达，从而抑制VM的形成，最终抑制OV癌的发生和进展。意义为开发靶向SOX15/MMP2轴的OV肿瘤治疗新方法奠定了理论基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biology of the Cell 生物-细胞生物学

CiteScore

5.30

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： The journal publishes original research articles and reviews on all aspects of cellular, molecular and structural biology, developmental biology, cell physiology and evolution. It will publish articles or reviews contributing to the understanding of the elementary biochemical and biophysical principles of live matter organization from the molecular, cellular and tissues scales and organisms. This includes contributions directed towards understanding biochemical and biophysical mechanisms, structure-function relationships with respect to basic cell and tissue functions, development, development/evolution relationship, morphogenesis, stem cell biology, cell biology of disease, plant cell biology, as well as contributions directed toward understanding integrated processes at the organelles, cell and tissue levels. Contributions using approaches such as high resolution imaging, live imaging, quantitative cell biology and integrated biology; as well as those using innovative genetic and epigenetic technologies, ex-vivo tissue engineering, cellular, tissue and integrated functional analysis, and quantitative biology and modeling to demonstrate original biological principles are encouraged.