约瑟芬域含有2 (JOSD2) 抑制作为对结直肠癌的泛KRAS突变向策略
Tao Yuan1, Yue Liu1, Ruilin Wu1
1Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Nature communications
|April 16, 2025
概括
研究人员确定含有2 (JOSD2) 的约瑟芬域是结直肠癌 (CRC) 中KRAS突变蛋白稳定性的关键调节者. 准JOSD2为治疗各种KRAS突变CRC病例提供了一个有希望的策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- KRAS突变在结直肠癌 (CRC) 中很常见,但有效的治疗方法仍然有限.
- 克拉斯突变体的稳定性有助于瘤生长,但机制尚不清楚.
研究的目的:
- 为了确定调节KRAS突变蛋白稳定性的二维基提纳酶 (DUB).
- 阐明JOSD2影响KRAS稳定性和CRC生长的机制.
- 评估JOSD2作为KRAS突变CRC的治疗点.
主要方法:
- 一个二维基因酶 (DUB) siRNA库的选.
- 研究JOSD2和KRAS突变体之间的相互作用.
- 评估JOSD2抑制对KRAS无化和降解的影响.
- 在临床前CRC模型 (PDCs,PDXs,PDOs) 中评估JOSD2抑制的疗效.
主要成果:
- 鉴定出JOSD2是一种稳定KRAS突变体的DUB,该突变体通过逆转ubiquitination来稳定KRAS突变.
- 发现了JOSD2和KRAS突变之间的积极反循环,促进CRC生长.
- 抑制JOSD2导致KRAS突变降解,并抑制了KRAS突变CRC的生长.
- 在JOSD2抑制的过程中,KRAS突变CRC受到了偏好的影响,而不是野生型KRAS CRC.
结论:
- 在KRAS突变CRC中,JOSD2在JOSD2/KRAS正反回路中发挥着关键作用.
- 向JOSD2代表了治疗CRC的潜在泛KRAS突变策略.
- 这项研究为广泛的CRC患者开发JOSD2抑制剂提供了理由.
更多相关视频
06:19Isolation of Circulating Tumor Cells in an Orthotopic Mouse Model of Colorectal Cancer
Published on: July 18, 2017
9.9K
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
17.5K
相关概念视频
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
7.2K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
7.2K
01:12Loss of Tumor Suppressor Gene Functions
4.6K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
4.6K
01:20The Retinoblastoma Gene
4.0K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.0K
01:35Cancer Cell Migration through Invadopodia
2.2K
Invadosome is a broad category of cell surface structures with proteolytic activity that degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However,...
2.2K
02:49Cancer Therapies
7.4K
Cancer therapies are various modes of treatment, such as surgery, radiation therapy, and chemotherapy that are administered to cancer patients.
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
7.4K
02:56Treatment Resistant Cancers
3.2K
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.2K