A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response
Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive.Methods:...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1101749/full |
| _version_ | 1797895475187154944 |
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| author | Yun-Long Ma Ya-Fei Yang Han-Chao Wang Chun-Cheng Yang Lun-Jie Yan Zi-Niu Ding Bao-Wen Tian Hui Liu Jun-Shuai Xue Cheng-Long Han Si-Yu Tan Jian-Guo Hong Yu-Chuan Yan Xin-Cheng Mao Dong-Xu Wang Tao Li Tao Li |
| author_facet | Yun-Long Ma Ya-Fei Yang Han-Chao Wang Chun-Cheng Yang Lun-Jie Yan Zi-Niu Ding Bao-Wen Tian Hui Liu Jun-Shuai Xue Cheng-Long Han Si-Yu Tan Jian-Guo Hong Yu-Chuan Yan Xin-Cheng Mao Dong-Xu Wang Tao Li Tao Li |
| author_sort | Yun-Long Ma |
| collection | DOAJ |
| description | Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive.Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells’ pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes’ expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation.Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines.Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time. |
| first_indexed | 2024-04-10T07:26:18Z |
| format | Article |
| id | doaj.art-5178977acb0f472eb2cff726a6e9c46e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T07:26:18Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-5178977acb0f472eb2cff726a6e9c46e2023-02-24T05:39:46ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-02-011410.3389/fphar.2023.11017491101749A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment responseYun-Long Ma0Ya-Fei Yang1Han-Chao Wang2Chun-Cheng Yang3Lun-Jie Yan4Zi-Niu Ding5Bao-Wen Tian6Hui Liu7Jun-Shuai Xue8Cheng-Long Han9Si-Yu Tan10Jian-Guo Hong11Yu-Chuan Yan12Xin-Cheng Mao13Dong-Xu Wang14Tao Li15Tao Li16Department of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaInstitute for Financial Studies, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of General Surgery, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of hepatobiliary surgery, The Second Hospital of Shandong University, Jinan, ChinaBackground: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive.Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells’ pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes’ expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation.Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines.Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.https://www.frontiersin.org/articles/10.3389/fphar.2023.1101749/fullcopper homeostasiscuproptosishepatocellular carcinomaprognostic modeltumor microenvironmentimmunocytes |
| spellingShingle | Yun-Long Ma Ya-Fei Yang Han-Chao Wang Chun-Cheng Yang Lun-Jie Yan Zi-Niu Ding Bao-Wen Tian Hui Liu Jun-Shuai Xue Cheng-Long Han Si-Yu Tan Jian-Guo Hong Yu-Chuan Yan Xin-Cheng Mao Dong-Xu Wang Tao Li Tao Li A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response Frontiers in Pharmacology copper homeostasis cuproptosis hepatocellular carcinoma prognostic model tumor microenvironment immunocytes |
| title | A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response |
| title_full | A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response |
| title_fullStr | A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response |
| title_full_unstemmed | A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response |
| title_short | A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response |
| title_sort | novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response |
| topic | copper homeostasis cuproptosis hepatocellular carcinoma prognostic model tumor microenvironment immunocytes |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1101749/full |
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