Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma
Abstract Background 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 reti...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04794-0 |
| _version_ | 1797349755260502016 |
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| author | Weidong Chen Yan Liao Pengxiao Sun Jian Tu Yutong Zou Ji Fang Ziyun Chen Hongbo Li Junkai Chen Yuzhong Peng Lili Wen Xianbiao Xie |
| author_facet | Weidong Chen Yan Liao Pengxiao Sun Jian Tu Yutong Zou Ji Fang Ziyun Chen Hongbo Li Junkai Chen Yuzhong Peng Lili Wen Xianbiao Xie |
| author_sort | Weidong Chen |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusion The ERSRPS may guide personalized treatment decisions for osteosarcoma, and ISOX holds promise for repurposing in osteosarcoma treatment. |
| first_indexed | 2024-03-08T12:34:58Z |
| format | Article |
| id | doaj.art-f8eaf870c7734aec8eda8bfd1a052a22 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-08T12:34:58Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-f8eaf870c7734aec8eda8bfd1a052a222024-01-21T12:33:14ZengBMCJournal of Translational Medicine1479-58762024-01-0122111910.1186/s12967-023-04794-0Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcomaWeidong Chen0Yan Liao1Pengxiao Sun2Jian Tu3Yutong Zou4Ji Fang5Ziyun Chen6Hongbo Li7Junkai Chen8Yuzhong Peng9Lili Wen10Xianbiao Xie11Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityState Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical UniversityDepartment of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityMacau University of Science and TechnologyDepartment of Anesthesiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen UniversityAbstract Background 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. Methods 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. Results 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. Conclusion The ERSRPS may guide personalized treatment decisions for osteosarcoma, and ISOX holds promise for repurposing in osteosarcoma treatment.https://doi.org/10.1186/s12967-023-04794-0OsteosarcomaER stressPrognostic signatureSTC2Tumor microenvironmentISOX |
| spellingShingle | Weidong Chen Yan Liao Pengxiao Sun Jian Tu Yutong Zou Ji Fang Ziyun Chen Hongbo Li Junkai Chen Yuzhong Peng Lili Wen Xianbiao Xie Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma Journal of Translational Medicine Osteosarcoma ER stress Prognostic signature STC2 Tumor microenvironment ISOX |
| title | Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma |
| title_full | Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma |
| title_fullStr | Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma |
| title_full_unstemmed | Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma |
| title_short | Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma |
| title_sort | construction of an er stress related prognostic signature for predicting prognosis and screening the effective anti tumor drug in osteosarcoma |
| topic | Osteosarcoma ER stress Prognostic signature STC2 Tumor microenvironment ISOX |
| url | https://doi.org/10.1186/s12967-023-04794-0 |
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