借力推动前列腺癌 CAR-T 细胞治疗进展
Piggybacking toward Progress for CAR T-Cell Therapy in Prostate Cancer.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
ncRNA 介导的泛素特异性蛋白酶 13 过表达通过调节 AR 信号传导、DNA 损伤修复和免疫浸润促进前列腺癌进展
英文原题：ncRNA-mediated overexpression of ubiquitin-specific proteinase 13 contributes to the progression of prostate cancer via modulating AR signaling, DNA damage repair and immune infiltration.
查看英文原题
ncRNA-mediated overexpression of ubiquitin-specific proteinase 13 contributes to the progression of prostate cancer via modulating AR signaling, DNA damage repair and immune infiltration.
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中文摘要
转移性去势抵抗性前列腺癌（mCRPC）是一种致命的前列腺癌，其进展的分子机制尚未得到充分阐明。CAR-T 细胞疗法、T细胞治疗和免疫检查点阻断等免疫疗法已在血液系统恶性肿瘤和实体瘤中显示出良好的抗肿瘤作用；然而，针对mCRPC尚未观察到令人鼓舞的应答。去泛素化酶USP13在多种人类癌症中发挥肿瘤抑制作用，因为它可维持PTEN和TP53蛋白稳定性；但其在前列腺癌（PCa）中的作用，以及与DNA损伤和雄激素受体（AR）信号传导的关系，仍不清楚。
本研究基于TCGA数据库探讨USP13在PCa中的预后价值，并利用TCGA数据和本研究队列分析USP13在PCa组织及邻近正常组织中的表达。结果提示，USP13在PCa肿瘤中过表达，可能成为前列腺癌患者总生存期的独立生物标志物。富集分析还显示，USP13可能参与AR通路和PI3K/Wnt信号通路，这些通路与PCa进展密切相关。基于TCGA_PRAD数据集，研究发现USP13表达与AR相关基因、DNA损伤修复（DDR）基因和错配修复基因显著相关，进一步支持USP13在PCa的AR活化和DNA损伤应答中的关键作用。研究还发现USP13富集于蛋白NEDD8化相关过程，其表达与免疫细胞浸润和免疫调节因子表达显著相关。
综上，本研究揭示了USP13通过参与多条致癌信号通路、DNA损伤应答及免疫抑制性肿瘤微环境，促进PCa进展的重要作用。靶向USP13可能抑制肿瘤生长，并与DDR抑制剂和免疫治疗协同带来额外获益。
展开英文摘要原文
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer, and the molecular mechanism driving mCRPC progression has not yet been fully elucidated. Immunotherapies such as chimeric antigen receptor, T-cell therapy and immune checkpoint blockade have exerted promising antitumor effects in hematological and solid tumor malignancies; however, no encouraging responses have been observed against mCRPC.
The deubiquitinase USP13 functions as a tumor suppressor in many human cancers, as it sustains the protein stability of PTEN and TP53; however, its role in prostate cancer (PCa) and involvement in DNA damage and AR signaling remain unclear.
In the current study, we explored the prognostic value of USP13 in PCa based on the TCGA database, and we analyzed the expression of USP13 in PCa tissues and adjacent normal tissues based on TCGA and our cohort. The results suggested that USP13 is overexpressed in PCa tumors and has the potential to be an independent biomarker for the overall survival of PCa patients.
Additionally, enrichment analysis indicated that USP13 may participate in the AR pathway and PI3k/Wnt signaling, which are closely related to PCa progression.
We also observed a significant correlation between the expression of USP13 and AR-related genes, DDR genes and mismatch repair genes based on the TCGA_PRAD dataset, which further supported the critical role of USP13 in AR activation and the DNA damage response of PCa. USP13 was also found to be enriched in protein neddylation, and expression of USP13 was significantly associated with infiltration of immune cells and expression of immunomodulators.
Taken together, our study revealed a key role of USP13 in contributing to PCa progression by participating in multiple oncogenic signaling pathways, the DNA damage response and the immunosuppressive tumor microenvironment. Targeting USP13 may inhibit tumor growth and provide additional benefits in cooperation with DDR inhibitors and immunotherapy.
论文信息
- 作者
- Cui X、Yu H、Yao J、Li J、Li Z、Jiang Z
- 第一作者单位
- Department of Urology, First hospital of China Medical University, Shenyang, 110001, China.China
- 通讯作者单位
- Department of Urology, First hospital of China Medical University, Shenyang, 110001, China. jiangzmcmu@126.com.China
- 期刊
- BMC cancer2022 Dec 23
- 原文标识
- PubMed 36564767 · DOI 10.1186/s12885-022-10424-7
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