Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma.
Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma.
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DOI：
10.1186/s12967-023-04794-0
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发表时间：
2024-01-16
影响因子：
7.4
通讯作者：
中科院分区：
文献类型：
--
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骨肉瘤是婴幼儿和青少年最常见的恶性原发性骨肿瘤。由于对骨肉瘤进展和转移的分子机制缺乏了解，导致目前治疗方法的发展处于停滞状态。内质网（ER）应激已成为肿瘤恶性进展的一个重要因素，但其在骨肉瘤进展中的潜在调控机制尚不清楚。在这项研究中，我们收集了TCGA，GSE 21257和GSE 33382队列中骨肉瘤的RNA测序和临床数据。差异表达分析和最小绝对收缩和选择算子回归分析进行识别预后基因和构建ER应激相关的预后信号（ERSRPS）。进行生存分析和时间依赖性ROC分析以评估构建的预后标志的预测性能。使用“ESTIMATE”软件包和ssGSEA算法评估组间免疫细胞浸润的差异。通过CCK-8、集落形成、transwell实验和共培养系统等细胞实验，观察靶基因和小分子药物对骨肉瘤的作用。采用动物模型评价小分子药物的抗骨肉瘤作用。通过对BLC 2、MAGEA 3、MAP 3 K5、STC 2、TXNDC 12 5个基因的克隆，构建了ERSRPS基因。ER应激相关基因Stanniocalcin 2（STC 2）被鉴定为该签名中的风险基因。此外，STC 2敲低显著抑制骨肉瘤细胞增殖、迁移和侵袭。此外，ER应激相关基因STC 2可下调骨肉瘤细胞MHC-I类分子的表达，并通过影响CD 8 + T细胞的浸润和调节其功能介导免疫应答。按风险评分分类的患者显示出不同的免疫状态和免疫治疗反应。随后通过CMap数据库筛选和体外和体内实验相结合，ISOX被确定并验证为有效的抗骨肉瘤药物。ERSRPS可以指导骨肉瘤的个性化治疗决策，ISOX有望在骨肉瘤治疗中重新利用。在线版本包含补充材料，可通过10.1186/s12967-023-04794-0获得。
Osteosarcoma is the most common malignant primary bone tumor in infants and adolescents. The lack of understanding of the molecular mechanisms underlying osteosarcoma progression and metastasis has contributed to a plateau in the development of current therapies. Endoplasmic reticulum (ER) stress has emerged as a significant contributor to the malignant progression of tumors, but its potential regulatory mechanisms in osteosarcoma progression remain unknown. In this study, we collected RNA sequencing and clinical data of osteosarcoma from The TCGA, GSE21257, and GSE33382 cohorts. Differentially expressed analysis and the least absolute shrinkage and selection operator regression analysis were conducted to identify prognostic genes and construct an ER stress-related prognostic signature (ERSRPS). Survival analysis and time dependent ROC analysis were performed to evaluate the predictive performance of the constructed prognostic signature. The “ESTIMATE” package and ssGSEA algorithm were utilized to evaluate the differences in immune cells infiltration between the groups. Cell-based assays, including CCK-8, colony formation, and transwell assays and co-culture system were performed to assess the effects of the target gene and small molecular drug in osteosarcoma. Animal models were employed to assess the anti-osteosarcoma effects of small molecular drug. Five genes (BLC2, MAGEA3, MAP3K5, STC2, TXNDC12) were identified to construct an ERSRPS. The ER stress-related gene Stanniocalcin 2 (STC2) was identified as a risk gene in this signature. Additionally, STC2 knockdown significantly inhibited osteosarcoma cell proliferation, migration, and invasion. Furthermore, the ER stress-related gene STC2 was found to downregulate the expression of MHC-I molecules in osteosarcoma cells, and mediate immune responses through influencing the infiltration and modulating the function of CD8+ T cells. Patients categorized by risk scores showed distinct immune status, and immunotherapy response. ISOX was subsequently identified and validated as an effective anti-osteosarcoma drug through a combination of CMap database screening and in vitro and in vivo experiments. The ERSRPS may guide personalized treatment decisions for osteosarcoma, and ISOX holds promise for repurposing in osteosarcoma treatment. The online version contains supplementary material available at 10.1186/s12967-023-04794-0.
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影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
影响因子：
7.4
作者：
Wang, Hufei;Li, Zhi;Tao, Yangbao;Ou, Suwen;Ye, Jinhua;Ran, Songlin;Luo, Kangjia;Guan, Zilong;Xiang, Jun;Yan, Guoqing;Wang, Yang;Ma, Tianyi;Yu, Shan;Song, Yanni;Huang, Rui
通讯作者：
Huang, Rui
影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM
影响因子：
28.2
作者：
Lin, Youpei;Peng, Lihua;Gao, Qiang
通讯作者：
Gao, Qiang
影响因子：
28.2
作者：
Gu SS;Zhang W;Wang X;Jiang P;Traugh N;Li Z;Meyer C;Stewig B;Xie Y;Bu X;Manos MP;Font-Tello A;Gjini E;Lako A;Lim K;Conway J;Tewari AK;Zeng Z;Sahu AD;Tokheim C;Weirather JL;Fu J;Zhang Y;Kroger B;Liang JH;Cejas P;Freeman GJ;Rodig S;Long HW;Gewurz BE;Hodi FS;Brown M;Liu XS
通讯作者：
Liu XS