投稿系统
PLA2G2D and CHIT1: Potential biomarkers for immune infiltration and prognosis in cervical squamous cell carcinoma
doi: 10.1515/fzm-2024-0012
-
Abstract:
Objective The aim of this study was to identify biomarkers associated with immunity and prognosis in patients with cervical cancer. Materials and methods Data from patients with cervical squamous cell carcinoma (CESC) were retrieved from the UCSC Xena database and subjected to analysis. Gene sets representing 22 types of immunocytes were acquired, and immunocytes relevant to prognosis were identified. Weighted gene co-expression network analysis (WGCNA) was utilized to identify gene modules associated with prognosis-related immunocytes and to construct immune-related gene markers. Differentially expressed genes were then screened, and the association between immune score and biological function of immune-related gene markers was analyzed. Furthermore, tissue samples from cervical cancer patients in Northeast China were collected to validate the expression of two genes using real-time PCR and immunohistochemistry. Results This study identified 10 immunocytes significantly correlated with overall survival time in patients. Six gene modules were identified as significantly associated with prognosis-related immunocytes, with gene module 6 showing relevance to all prognosis-related immunocytes. Gene module 6 was related to all prognosis-related immunocytes. Moreover, two genes (including PLA2G2D and CHIT1) were found to be significantly associated with overall survival in cancer patients. Patients with CESC were classified into high and low immune score groups based on the median score of gene markers. Correlation analysis of the immune score and biological function was performed. Immunohistochemistry and real-time PCR results revealed high expression of CHIT1 and PLA2G2D in CESC tumor tissues. Conclusion PLA2G2D and CHIT1 show promise as biomarkers for evaluating immune infiltration and prognosis in patients with cervical cancer. -
Key words:
- cervical cancer /
- immune cells /
- overall survival /
- immune score /
- genes
-
Figure 2. WGCNA analysis
(A) WGCNA determines optimal threshold; (B) WGCNA hierarchical clustering; (C) Correlation analysis map between gene module and immune cell score.
Figure 3. LASSO regression analysis
(A) The larger the lambda is, the closer the regression coefficient tends to zero; (B) The smaller the likelihood deviation is, the better the model fittingis; (C) Survival curve of immune-related gene marker scores.
Figure 4. Survival association analysis of immune-related gene markers
(A) Multivariate cox proportional risk model analysis; (B) Nomogram of survival prediction of cervical squamous cell carcinoma (CESC) patients; (C) ROC curve analysis.
Figure 5. The overall survival of the gene markers in stage Ⅱ and stage Ⅲ cervical squamous cell carcinoma (CESC) patients
Figure 6. Immune score differences between the high immune-related gene marker score group and the low immune-related gene marker score group
(A) Difference of immune score from ESTIMATE data resource; (B) Difference of immune score from TIDE data resource.
Figure 7. Analysis of biological function differences between the high immune-related gene marker score group and the low immune-related gene marker score group
(A) Biologic process function of differentially expressed genes; (B) Cellular components function of differentially expressed genes; (C) Molecular functions of differentially expressed genes; (D) KEGG pathway enrichment analysis of differentially expressed genes.
Figure 8. The expression of PLA2G2D and CHIT1 between cervical squamous cell carcinoma (CESC) patients and normal samples
Figure 9. Expression changes of PLA2G2D and CHIT1 in tumor tissues of cervical squamous cell carcinoma (CESC) patients and normal controls
(A) Negative expression of PLA2G2D in normal cervical epithelium; (B-C) Low and high expression of PLA2G2D in cervical squamous cell carcinoma; (D-E) Low and high expression of PLA2G2D in cervical adenocarcinoma; (F) Negative expression of CHIT1 in normal cervical epithelium; (G-H) Low and high expression of CHIT1 in cervical squamous cell carcinoma; (I-J) Low and high expression of CHIT1 in cervical adenocarcinoma (100x); (K-L) Immunohistochemical results of expression of PLA2G2D and CHIT1 in tumor tissues of CESC patients and normal controls.
-
[1] Cohen P, Jhingran A, Oaknin A, et al. Cervical cancer. Lancet, 2019; 393(10167): 169-182. doi: 10.1016/S0140-6736(18)32470-X [2] Mileshkin L, Moore K, Barnes E, et al. Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone: an international, openlabel, randomised, phase 3 trial. Lancet Oncol, 2023; 24(5): 468-482. doi: 10.1016/S1470-2045(23)00147-X [3] Xiao M, Xie L, Cao G, et al. CD4 T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy. J Immunother Cancer, 2022; 10(5): e004022. doi: 10.1136/jitc-2021-004022 [4] Oh D, Fong L. Cytotoxic CD4 T cells in cancer: Expanding the immune effector toolbox. Immunity, 2021; 54(12): 2701-2711. doi: 10.1016/j.immuni.2021.11.015 [5] Philip M, Schietinger A. CD8 T cell differentiation and dysfunction in cancer. Nat Rev Immunol, 2022; 22(4): 209-223. doi: 10.1038/s41577-021-00574-3 [6] Sharonov G, Serebrovskaya E, Yuzhakova D, et al. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol, 2020; 20(5): 294-307. doi: 10.1038/s41577-019-0257-x [7] Huntington N, Cursons J, Rautela J. The cancer-natural killer cell immunity cycle. Nat Rev Cancer, 2020; 20(8): 437-454. doi: 10.1038/s41568-020-0272-z [8] Kurmyshkina O, Kovchur P, Schegoleva L, et al. T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression. Infect Agent Cancer, 2017; 12: 56. [9] Zhang Y, Yu M, Jing Y, et al. Baseline immunity and impact of chemotherapy on immune microenvironment in cervical cancer. Br J Cancer, 2021; 124(2): 414-424. doi: 10.1038/s41416-020-01123-w [10] Zhang L, Zhang H, Huang Y, et al. Expression of immune cell markers and tumor markers in patients with cervical cancer. Int J Gynecol Cancer, 2020; 30(7): 969-974. doi: 10.1136/ijgc-2020-001254 [11] Sato H, Taketomi Y, Miki Y, et al. Secreted phospholipase PLA2G2D contributes to metabolic health by mobilizing ω3 polyunsaturated fatty acids in WAT. Cell Rep, 2020; 31(5): 107579. doi: 10.1016/j.celrep.2020.107579 [12] Murakami M, Yamamoto K, Miki Y, et al. The roles of the secreted phospholipase A gene family in immunology. Adv Immunol, 2016; 132: 91-134. doi: 10.1016/bs.ai.2016.05.001 [13] Miki Y, Yamamoto K, Taketomi Y, et al. Lymphoid tissue phospholipase A2 group ⅡD resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J Exp Med, 2013; 210(6): 1217-1234. doi: 10.1084/jem.20121887 [14] Miki Y, Kidoguchi Y, Sato M, et al. Dual roles of group ⅡD phospholipase A2 in inflammation and cancer. J Biol Chem, 2016; 291(30): 15588-155601. doi: 10.1074/jbc.M116.734624 [15] Liu H, Xu R, Gao C, et al. Metabolic molecule PLA2G2D is a potential prognostic biomarker correlating with immune cell infiltration and the expression of immune checkpoint genes in cervical squamous cell carcinoma. Front Oncol, 2021; 11: 755668. doi: 10.3389/fonc.2021.755668 [16] Di Francesco A, Verrecchia E, Manna S, et al. The chitinases as biomarkers in immune-mediate diseases. Clin Chem Lab Med, 2022; 61(8): 1363-1381. doi: 10.1515/cclm-2022-0767 [17] Chang D, Sharma L, Dela Cruz C. Chitotriosidase: a marker and modulator of lung disease. Eur Respir Rev, 2020; 29(156): 190143. doi: 10.1183/16000617.0143-2019 [18] Lee C, Herzog E, Ahangari F, et al. Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-β1 signaling. J Immunol. 2012; 189(5): 2635-2644. doi: 10.4049/jimmunol.1201115 [19] Koralewski R, Dymek B, Mazur M, et al. Discovery of, a First-in-Class chitinase inhibitor as potential new therapeutics for idiopathic pulmonary fibrosis. J Med Chem, 2020; 63(24): 15527-15540. doi: 10.1021/acs.jmedchem.0c01179 [20] Yu J, Zhang W, Ding D, et al. Bioinformatics analysis combined with experiments predicts PUDP as a potential prognostic biomarker for hepatocellular carcinoma through its interaction with tumor microenvironment. Front Oncol, 2022; 12: 830174. doi: 10.3389/fonc.2022.830174 [21] Wang Q, Xu Y. Comprehensive analysis of cuproptosis-related lncRNAs model in tumor immune microenvironment and prognostic value of cervical cancer. Front Pharmacol, 2022; 13: 1065701. doi: 10.3389/fphar.2022.1065701 [22] Wen H, Chen H, Xie L, et al. Macrophage-related molecular subtypes in lung adenocarcinoma identify novel tumor microenvironment with prognostic and therapeutic implications. Front Genet, 2022; 13: 1012164. doi: 10.3389/fgene.2022.1012164 [23] Zhou N, Kong D, Lin Q, et al. Unfolded protein response signature unveils novel insights into breast cancer prognosis and tumor microenvironment. Cancer Genet, 2023; 276-277: 17-29. doi: 10.1016/j.cancergen.2023.06.001 [24] Garlanda C, Mantovani A. Interleukin-1 in tumor progression, therapy, and prevention. Cancer Cell, 2021; 39(8): 1023-1027. doi: 10.1016/j.ccell.2021.04.011 [25] Verstockt B, Salas A, Sands B, et al. IL-12 and IL-23 pathway inhibition in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol, 2023; 20(7): 433-446. doi: 10.1038/s41575-023-00768-1 [26] Lewis N, Sia C, Kirwin K, et al. Exosome surface display of IL12 results in tumor-retained pharmacology with superior potency and limited systemic exposure compared with recombinant IL12. Mol Cancer Ther, 2021; 20(3): 523-534. doi: 10.1158/1535-7163.MCT-20-0484 [27] Jia Z, Ragoonanan D, Mahadeo K, et al. IL12 immune therapy clinical trial review: novel strategies for avoiding CRS-associated cytokines. Front Immunol, 2022; 13: 952231. doi: 10.3389/fimmu.2022.952231 [28] Goenka A, Khan F, Verma B, et al. Tumor microenvironment signaling and therapeutics in cancer progression. Cancer Commun (Lond), 2023; 43(5): 525-561. doi: 10.1002/cac2.12416 [29] Bule P, Aguiar S, Aires-Da-Silva F, et al. Chemokine-Directed tumor microenvironment modulation in cancer immunotherapy. Int J Mol Sci, 2021; 22(18): 9804. doi: 10.3390/ijms22189804 [30] Ren X, Chen C, Luo Y, et al. lncRNA-PLACT1 sustains activation of NF-κB pathway through a positive feedback loop with IκBα/E2F1 axis in pancreatic cancer. Mol Cancer, 2020; 19(1): 35. doi: 10.1186/s12943-020-01153-1 -
下载:
点击查看大图
计量
- 文章访问数: 171
- HTML全文浏览量: 95
- PDF下载量: 13
- 被引次数: 0
