CD147 AND CD200 EXPRESSION IN HUMAN BREAST CANCER CELLS: BIOINFORMATIC ANALYSIS AND In vitro STUDY
DOI:
https://doi.org/10.15407/oncology.2025.01.051Keywords:
cancer, mammary gland, molecular subtypes, survival, CD147, CD200, in silico, cell lines of human tumors, flow cytometryAbstract
Summary. Breast cancer (BC) is a highly heterogeneous disease with different morphological variants and molecular subtypes as well as varying clinical and phenotypic features and treatment response. The cell surface proteins involved in the communications between tumor cells and the component of their microenvironment are currently the focus of attention. The study was aimed at the in silico and in vitro analysis of the patterns of CD147 and CD200 expression in BC cells of different molecular subtypes. Objects and methods: the expression and co-expression of BSG and CD200 in normal mammary gland and breast cancer tissue as well as their prognostic importance were analyzed based on UALCAN, GEPIA, TIMER2.0, and KM-Plotter web resources. The GEPIA tool was also used to identify the top 20 genes with similar expression patterns to BSG or CD200 in BC. The protein–protein interaction networks of CD147 or CD200 were constructed using the STRING v.12 database. GSCA platform was used for evaluating the association between BSG and CD200 expression and their involvements in the key cell processes/pathways in BC cells. Expression of CD147 and CD200 in MDA-MB-231, MCF-7, and T-47D cells was assessed by direct immunofluorescence technique using flow cytometry. Results: according to the bioinformatic analysis, BSG mRNA expression increased significantly in BC tissue as compared to the normal mammary gland tissue. This holds true for each of the analyzed molecular subtypes of BC. On the contrary, CD200 mRNA expression decreased in BC tissue. Additionally, the majority of genes co-expressed with BSG in BC were located in the proximity of BSG on chromosome 19 at p13 locus. Nevertheless, a protein–protein interaction network of CD147 did not include any of the proteins coded by these genes. The overall survival in BC of luminal A or B subtypes was significantly shorter in patients with BSG mRNA expression in tumors exceeding its median level, while for CD200 expression this association was the reverse one. In all studied BC cell lines, most cells were CD147-positive, while CD200 expression was detected only on single cells. Conclusions: the oppositely directed association of the survival of BC patients with the expression of CD147 or CD200 has been revealed. This is in line with the opposite patterns of their expression in malignant cells.
References
Naleskina LA, Lukyanova NYu, Chekhun VF. Molecular- genetic bases of clinical heterogeneity of breast cancer (lite- rature review). Oncology (Kyiv) 2017; 19 (3): 171–9 (in Ukrainian).
Miyauchi T, Kanekura T, Yamaoka A, et al. Basigin, a new, broadly distributed member of the immunoglobulin super- family, has strong homology with both the immunoglobu- lin V domain and the beta-chain of major histocompat- ibility complex class II antigen. J Biochem 1990; 107 (2): 316–23. https://doi.org/10.1093/oxfordjournals.jbchem. a123045.
Muramatsu T. Basigin (CD147), a multifunctional trans- membrane glycoprotein with various binding partners. J Biochem 2016; 159 (5): 481–90. https://doi.org/10.1093/ jb/mvv127.
Han JM, Jung HJ. Cyclophilin A/CD147 interaction: A promising target for anticancer therapy. Int J Mol Sci 2022; 23 (16): 9341. https://doi.org/10.3390/ij 3169341.
Kong LM, Liao CG, Zhang Y, et al. A regulatory loop in- volving miR-22, Sp1, and c-Myc modulates CD147 expres- sion in breast cancer invasion and metastasis. Cancer Res 2014; 74 (14): 3764–78. https://doi.org/10.1158/0008-5472. CAN-13-3555.
Yang J, Wang R, Li H et al. Lentivirus mediated RNA in- terference of EMMPRIN (CD147) gene inhibits the pro- liferation, matrigel invasion and tumor formation of breast cancer cells. Cancer Biomark 2016; 17 (2): 237–47. https:// doi.org/10.3233/CBM-160636.
Amit-Cohen BC, Rahat MM, Rahat MA. Tumor cell-mac- rophage interactions increase angiogenesis through secre- tion of EMMPRIN. Front Physiol 2013; 4: 178. https:// doi.org/ 10.3389/fphys.2013.00178.
Li F, Wang J, Yan YQ, et al. CD147 promotes breast cancer migration and invasion by inducing epithelial-mesenchymal transition via the MAPK/ERK signaling pathway. BMC Cancer 2023; 23 (1): 1214. https://doi.org/ 10.1186/s12885- 023-11724-2.
McCaughan GW, Clark MJ, Barclay AN. Characterization of the human homolog of the rat MRC OX-2 membrane gly- coprotein. Immunogenetics 1987; 25 (5): 329–35. https:// doi.org/ 10.1007/BF00404426.
Nip C, Wang L, Liu C. CD200/CD200R: Bidirectional role in cancer progression and immunotherapy. Biomedicines
; 11 (12): 3326. https://doi.org/10.3390/biomedicines
Shin SP, Goh AR, Kang HG, et al. CD200 induces epithelial- to-mesenchymal transition in head and neck squamous cell carcinoma via β-catenin-mediated nuclear transloca- tion. Cancers (Basel). 2019; 11 (10): 1583. https://doi.org/ 10.3390/cancers11101583.
Khan IZ, Del Guzzo CA, Shao A, et al. The CD200-CD200R axis promotes squamous cell carcinoma metastasis via regu- lation of cathepsin K. Cancer Res 2021; 81 (19): 5021–32. https://doi.org/10.1158/0008-5472.CAN-20-3251.
Chandrashekar DS, Karthikeyan SK, Korla PK, et al. UALCAN: An update to the integrated cancer data analy- sis platform. Neoplasia 2022; 25: 18–27. https://doi.org/ 10.1016/j.neo.2022.01.001.
Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analy- ses. Nucleic Acids Res 2017; 45 (W1): W98–W102. https:// doi.org/10.1093/nar/gkx247.
Hänzelmann S, Castelo R, Guinney J. GSVA: gene set varia- tion analysis for microarray and RNA-seq data. BMC Bio- informatics 2013; 14: 7. https://doi.org/10.1186/1471-2105- 14-7.
Győrff B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Comput Struct Biotechnol J 2021; 19: 4101–9. https://doi.org/10.1016/j.csbj.2021.07.014.
Li T, Fu J, Zeng Z, et al. TIMER2.0 for analysis of tumor- infiltrating immune cells. Nucleic Acids Res 2020; 48 (W1): W509–W514. https://doi.org/10.1093/nar/gkaa407.
Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res 2023; 51 (D1): D638–D646. https://doi.org/10.1093/nar/gkac1000.
Li Y, Xu J, Chen L, et al. HAb18G (CD147), a cancer-as- sociated biomarker and its role in cancer detection. Histo- pathology 2009; 54 (6): 677–87. https://doi.org/10.1111/ j.1365-2559.2009.03280.x.
Liu F, Cui L, Zhang Y, et al. Expression of HAb18G is as- sociated with tumor progression and prognosis of breast carcinoma. Breast Cancer Res Treat 2010; 124 (3): 677–88. https://doi.org/10.1007/s10549-010-0790-6.
Liu Y, Xin T, Jiang QY, et al. CD147, MMP9 expression and clinical significance of basal-like breast cancer. Med Oncol 2013; 30 (1): 366. https://doi.org/10.1007/s12032- 012-0366-x.
Wang C, Shan M, Niu RJ, et al. Expression of CD147 in triple negative breast cancer and its relationship with prog- nosis. J Shanghai Jiaotong Univ (Med Sci) 2017; 37 (1): 55–9. https://doi.org/10.3969/j.issn.1674-8115.2017.01. 012.
Li F, Zhang J, Guo J, et al. RNA interference targeting CD147 inhibits metastasis and invasion of human breast cancer MCF-7 cells by downregulating MMP-9/VEGF expression. Acta Biochim Biophys Sin (Shanghai) 2018; 50 (7): 676–84. https://doi.org/10.1093/abbs/gmy062.
Chen M, Liu Z, Zheng K, et al. The potential mechanism of HIF-1α and CD147 in the development of triple-negative breast cancer. Medicine (Baltimore) 2024; 103 (23): e38434. https://doi.org/10.1097/MD.0000000000038434.
Siva A, Xin H, Qin F, et al. Immune modulation by mela- noma and ovarian tumor cells through expression of the immunosuppressive molecule CD200. Cancer Immunol Immunother 2008; 57 (7): 987–96. https://doi.org/10.1007/ s00262-007-0429-6.
Li L, Tian Y, Shi C, et al. Over-expression of CD200 predicts poor prognosis in cutaneous squamous cell carcinoma. Med
Sci Monit 2016; 22: 1079–84. https://doi.org/10.12659/ msm.895245.
Bisgin A, Meng WJ, Adell G, et al. Interaction of CD200 overexpression on tumor cells with CD200R1 overexpres- sion on stromal cells: An escape from the host immune response in rectal cancer patients. J Oncol 2019; 2019: 5689464. https://doi.org/10.1155/2019/5689464.
Rexin P, Tauchert A, Hänze J, et al. The immune check- point molecule CD200 is associated with tumor grading and metastasis in bladder cancer. Anticancer Res 2018; 38 (5): 2749–54. https://doi.org/10.21873/anticanres.12517.
Gao L, Zhong JC, Huang WT, et al. Integrative analysis of BSG expression in NPC through immunohistochemistry and public high-throughput gene expression data. Am J Transl Res 2017; 9 (10): 4574–92. PMID: 29118919.
Zhu X, Wang S, Shao M, et al. The origin and evolution of Basigin(BSG) gene: A comparative genomic and phy- logenetic analysis. Dev Comp Immunol 2017; 72: 79–88. https://doi.org/10.1016/j.dci.2017.02.007.
Toole BP. The CD147-hyaluronan axis in cancer. Anat Rec (Hoboken) 2020; 303 (6): 1573–83. https://doi.org/10.1002/ ar.24147.
Philchenkov AA. Basigin as a tumor-associated glycopro- tein with prognostic value. Oncology (Kyiv) 2025; 27 (1):
