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RNF2通过调节CBX7的泛素化和降解促进软骨肉瘤进展。

RNF2 promotes chondrosarcoma progression by regulating ubiquitination and degradation of CBX7.

作者信息

Wu Yue, Huang Zheng, Luo Ping, Xiang Zhong, Zhang Meng, Chen Zhiwu, Zhou Yalu, Li Jiameng

机构信息

Department of Orthopedics, Beijing Chaoyang Hospital, No.8 Gongti South Rd, Chaoyang District, Beijing, 100020, China.

Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, No. 89 Taoyuan Road, Nanshan District, Shenzhen City, 210009, Guangdong, China.

出版信息

Cancer Metab. 2024 Oct 25;12(1):30. doi: 10.1186/s40170-024-00359-x.

DOI:10.1186/s40170-024-00359-x
PMID:39456039
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11520121/
Abstract

OBJECTIVE

Chondrosarcoma (CHS) is resistant to conventional chemotherapy and radiotherapy and currently lacks effective treatment options when in advanced stages. Accordingly, this research investigated the mechanism of RNF2/CBX7 in CHS to drive the development of molecularly targeted drugs for CHS.

METHODS

RNF2 and CBX7 levels were detected in CHS cells and tissues. RNF2 and CBX7 expression was modulated through cell transfection to examine their effects on cell proliferation, apoptosis, migration, and angiogenesis. The correlation between RNF2 and CBX7 levels was determined, and the ubiquitination level of CBX7 was tested. Protein synthesis was blocked in RNF2-knockdown/overexpressing cells with CHX to assess the effect of RNF2 on CBX7 stability. JJ012 cells transfected with LV-sh-RNF2 were subcutaneously injected into nu/nu nude mice to ascertain the action of RNF2 in the growth and metastasis of CHS.

RESULTS

RNF2 was highly expressed in CHS cells and tissues. RNF2 knockdown curbed CHS cell proliferation, migration, and angiogenesis while promoting apoptosis. RNF2 knockdown in JJ012 cells upregulated CBX7 protein levels and reduced CBX7 ubiquitination, whilst RNF2 had no effect on CBX7 mRNA expression. CBX7 knockdown partially nullified the repressing effects of RNF2 knockdown on CHS cell proliferation, migration, and angiogenesis, and CBX7 overexpression partially abolished the promotional effects of RNF2 overexpression. LV-sh-RNF2 prominently restricted tumor growth and weight and declined lung metastatic nodules and Ki-67-positive cells in mice.

CONCLUSION

RNF2 fosters CHS progression by elevating CBX7 degradation via the ubiquitination pathway.

摘要

目的

软骨肉瘤(CHS)对传统化疗和放疗具有抗性,在晚期时目前缺乏有效的治疗选择。因此,本研究调查了RNF2/CBX7在CHS中的作用机制,以推动CHS分子靶向药物的开发。

方法

检测CHS细胞和组织中RNF2和CBX7的水平。通过细胞转染调节RNF2和CBX7的表达,以检查它们对细胞增殖、凋亡、迁移和血管生成的影响。确定RNF2和CBX7水平之间的相关性,并检测CBX7的泛素化水平。用环己酰亚胺(CHX)阻断RNF2敲低/过表达细胞中的蛋白质合成,以评估RNF2对CBX7稳定性的影响。将转染了LV-sh-RNF2的JJ012细胞皮下注射到裸鼠体内,以确定RNF2在CHS生长和转移中的作用。

结果

RNF2在CHS细胞和组织中高表达。RNF2敲低抑制了CHS细胞的增殖、迁移和血管生成,同时促进了细胞凋亡。JJ012细胞中RNF2敲低上调了CBX7蛋白水平并降低了CBX7的泛素化,而RNF2对CBX7 mRNA表达没有影响。CBX7敲低部分抵消了RNF2敲低对CHS细胞增殖、迁移和血管生成的抑制作用,而CBX7过表达部分消除了RNF2过表达的促进作用。LV-sh-RNF2显著抑制了小鼠的肿瘤生长和重量,并减少了肺转移结节和Ki-67阳性细胞。

结论

RNF2通过泛素化途径提高CBX7的降解,从而促进CHS进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/9f12bd287414/40170_2024_359_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/5ad10d7cd747/40170_2024_359_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/9a14d682a8ce/40170_2024_359_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/f8e5df9d5312/40170_2024_359_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/421701525bb2/40170_2024_359_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/7e065debeabc/40170_2024_359_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/1147c9b9e746/40170_2024_359_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/9f12bd287414/40170_2024_359_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/5ad10d7cd747/40170_2024_359_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/9a14d682a8ce/40170_2024_359_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/f8e5df9d5312/40170_2024_359_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/421701525bb2/40170_2024_359_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/7e065debeabc/40170_2024_359_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/1147c9b9e746/40170_2024_359_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7324/11520121/9f12bd287414/40170_2024_359_Fig5_HTML.jpg

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