Study on the Role of EPHB6 in Inhibiting the Malignant Progression of Cervical Cancer C33A Cells by Binding to CBX7.

Publisher: Humana Press Country of Publication: United States NLM ID: 9701934 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-0283 (Electronic) Linking ISSN: 10859195 NLM ISO Abbreviation: Cell Biochem Biophys Subsets: MEDLINE

Original Publication: Totowa, NJ : Humana Press, c1996-

Uterine Cervical Neoplasms*/metabolism ; Uterine Cervical Neoplasms*/pathology ; Cell Proliferation* ; Cell Movement* ; Polycomb Repressive Complex 1*/metabolism ; Polycomb Repressive Complex 1*/genetics; Humans ; Female ; Cell Line, Tumor ; Receptors, Eph Family/metabolism ; Protein Binding

Cervical cancer stands as the most frequently diagnosed malignancy affecting the female reproductive. The erythropoietin-producing hepatocyte (Eph) family tyrosine kinases play important roles in tumorigenesis and cancer aggression. However, the exact role of EPHB6 in cervical cancer remains unknown. The present study investigated the role of EPHB6 in the malignant process of cervical cancer. GEPIA, tnmplot and kmplot database was used to study the expression of EPHB6 in cervical cancer tissues. western blotting was used to detect the expression of EPHB6, CyclinD, CDK4, CDK6, CBX7, MMP2 and MMP9. CCK8 and EDU staining were used to detect cell proliferation. Wound healing and transwell were used to detect cell proliferation and migration. Flow cytometry was used to detect cell cycle level. The linkedomics database was used to predict the correlation of EPHB6 and CBX7 in cervical cancer. Subsequently, HDOCK server was used to predict the combination of EPHB6 and CBX7. Our current results suggested that the expression of EPHB6 is reduced in cervical cancer tissues and cell lines, and the lower the expression, the worse the prognosis. Moreover, overexpression of EPHB6 inhibits cell proliferation, invasion and migration and cycle acceleration of C33A cells. Furthermore, EPHB6 and CBX7 bind to each other in C33A cells, and EPHB6 inhibits cell proliferation, invasion, migration and cell cycle acceleration in cervical cancer by binding to CBX7. EPHB6 expression is reduced in cervical cancer tissues and cells. Its overexpression inhibits proliferation, invasion, migration, and cell cycle acceleration in C33A cells, exhibiting synergy when bound to CBX7.
Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Barar, J., Kafil, V., Majd, M. H., Barzegari, A., Khani, S., Johari-Ahar, M. et al. (2015). Multifunctional mitoxantrone-conjugated magnetic nanosystem for targeted therapy of folate receptor-overexpressing malignant cells.Journal of Nanobiotechnology, 13, 26.
Brisson, M., Kim, J. J., Canfell, K., Drolet, M., Gingras, G., Burger, E. A. et al. (2020). Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries. Lancet, 395(10224), 575–590. https://doi.org/10.1016/S0140-6736(20)30068-4 .
Rahangdale, L., Mungo, C., O’Connor, S., Chibwesha, C. J., & Brewer, N. T. (2022). Human papillomavirus vaccination and cervical cancer risk. BMJ, 379, e070115 https://doi.org/10.1136/bmj-2022-070115 . (PMID: 10.1136/bmj-2022-07011536521855)
Yoon, S., Choi, J. H., Kim, S. J., Lee, E. J., Shah, M., Choi, S. et al. (2019). EPHB6 mutation induces cell adhesion-mediated paclitaxel resistance via EPHA2 and CDH11 expression. Experimental & Molecular Medicine. 51(6), 1–12. https://doi.org/10.1038/s12276-019-0261-z .
Haimovici, A., Hofer, C., Badr, M. T., Bavafaye Haghighi, E., Amer, T., Boerries, M. et al. (2022). Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse. Cell Death Disease, 13(4), 315. https://doi.org/10.1038/s41419-022-04768-y .
Wang, L., Qu, H., Ma, X. & Liu, X. (2022). Identification of oxidative stress-associated molecular subtypes and signature for predicting survival outcome of cervical squamous cell carcinoma. Oxidative Medicine and Cellular Longevity, 2022, 1056825 https://doi.org/10.1155/2022/1056825 . (PMID: 10.1155/2022/1056825362251799550421)
Burd, E. M. (2003). Human papillomavirus and cervical cancer. Clinical Microbiology Reviews, 16(1), 1–17. https://doi.org/10.1128/CMR.16.1.1-17.2003 . (PMID: 10.1128/CMR.16.1.1-17.200312525422145302)
Feng, D., Yan, K., Zhou, Y., Liang, H., Liang, J., Zhao, W. et al. (2016). Piwil2 is reactivated by HPV oncoproteins and initiates cell reprogramming via epigenetic regulation during cervical cancer tumorigenesis. Oncotarget, 7(40), 64575–64588. https://doi.org/10.18632/oncotarget.11810 .
Tushaus, J., Muller, S. A., Shrouder, J., Arends, M., Simons, M., & Plesnila, N. et al. (2021). The pseudoprotease iRhom1 controls ectodomain shedding of membrane proteins in the nervous system. FASEB Journal, 35(11), e21962 https://doi.org/10.1096/fj.202100936R . (PMID: 10.1096/fj.202100936R34613632)
Peng, L., Tu, P., Wang, X., Shi, S., Zhou, X. & Wang, J. (2014). Loss of EphB6 protein expression in human colorectal cancer correlates with poor prognosis. The Journal of Molecular Histology, 45(5), 555–563. https://doi.org/10.1007/s10735-014-9577-0 .
Cui, Z., Tang, J., Chen, J. & Wang, Z. (2014). Hsa-miR-574-5p negatively regulates MACC-1 expression to suppress colorectal cancer liver metastasis. Cancer Cell International, 14, 47. https://doi.org/10.1186/1475-2867-14-47 .
Liu, J., Xu, B., Xu, G., Zhang, X., Yang, X. & Wang, J. (2017). Reduced EphB6 protein in gastric carcinoma and associated lymph nodes suggests EphB6 as a gastric tumor and metastasis inhibitor. Cancer Biomark, 19(3), 241–248. https://doi.org/10.3233/CBM-160256 .
Kang, M., Shi, J., Li, B., Luo, M., Xu, S. & Liu, X. (2019). LncRNA DGCR5 regulates the non-small cell lung cancer cell growth, migration, and invasion through regulating miR-211-5p/EPHB6 axis. Biofactors, 45(5), 788–794. https://doi.org/10.1002/biof.1539 .
Toosi, B. M., El Zawily, A., Truitt, L., Shannon, M., Allonby, O. & Babu, M. (2018). EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours. Oncogene, 37(30), 4073–4093. https://doi.org/10.1038/s41388-018-0228-x .
Xiang, S., Wei, M., Zhao, L., Lin, A., & Xiong, Z. (2023). Integrated analyses of the expression and prognostic value of EPHB6 in cervical cancer and its correlation with immune infiltrates. Journal of Oncology, 2023, 2258906 https://doi.org/10.1155/2023/2258906 . (PMID: 10.1155/2023/22589063710174710125771)
Marth, C., Landoni, F., Mahner, S., McCormack, M., Gonzalez-Martin, A., Colombo, N. et al. (2017). Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 28(suppl_4), iv72–iv83. https://doi.org/10.1093/annonc/mdx220 .
Arbyn, M., Weiderpass, E., Bruni, L., de Sanjose, S., Saraiya, M. & Ferlay, J. et al. (2020). Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. The Lancet Global Health, 8(2), e191–e203. https://doi.org/10.1016/S2214-109X(19)30482-6 . (PMID: 10.1016/S2214-109X(19)30482-631812369)
Huang, Y., Liu, R., Han, X., Hou, X., Tian, Y. & Zhang, W. (2022). Rab31 promotes the invasion and metastasis of cervical cancer cells by inhibiting MAPK6 degradation. The International Journal of Biological Sciences. 18(1), 112–123. https://doi.org/10.7150/ijbs.63388 .
Kim, J., Chung, J. Y., Kim, T. J., Lee, J. W., Kim, B. G. & Bae, D. S. et al. (2018). Genomic network-based analysis reveals pancreatic adenocarcinoma up-regulating factor-related prognostic markers in cervical carcinoma. Frontiers in Oncology, 8, 465 https://doi.org/10.3389/fonc.2018.00465 . (PMID: 10.3389/fonc.2018.00465304060316206228)
Zhang H. M., Qi F. F., Wang J., Duan Y. Y., Zhao L. L., Wang Y. D. et al. (2022) The m6A methyltransferase METTL3-mediated N6-methyladenosine modification of DEK mRNA to promote gastric cancer cell growth and metastasis. International Journal of Molecular Sciences, 23(12). https://doi.org/10.3390/ijms23126451 .
Takano, H., Nakamura, T., Tsuchikawa, T., Kushibiki, T., Hontani, K., Inoko, K. et al. (2015). Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice. Oncotarget, 6(38), 41063–41076. https://doi.org/10.18632/oncotarget.5729 .
Pasquale, E. B. (2010). Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nature Reviews Cancer, 10(3), 165–180. https://doi.org/10.1038/nrc2806 .
Liu, W., Ahmad, S. A., Jung, Y. D., Reinmuth, N., Fan, F., Bucana, C. D. et al. (2002). Coexpression of ephrin-Bs and their receptors in colon carcinoma. Cancer, 94(4), 934–939. https://doi.org/10.1002/cncr.10122 .
Truitt, L., Freywald, T., DeCoteau, J., Sharfe, N. & Freywald, A. (2010). The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells. Cancer Research, 70(3), 1141–1153. https://doi.org/10.1158/0008-5472.CAN-09-1710 .
Yu, J., Bulk, E., Ji, P., Hascher, A., Tang, M., Metzger, R. et al. (2010). The EPHB6 receptor tyrosine kinase is a metastasis suppressor that is frequently silenced by promoter DNA hypermethylation in non-small cell lung cancer. Clin Cancer Res, 16(8), 2275–2283. https://doi.org/10.1158/1078-0432.CCR-09-2000 .
Wang, Y., Zhang, Y., Mi, J., Jiang, C., Wang, Q., Li, X. et al. (2022). ANKFN1 plays both protumorigenic and metastatic roles in hepatocellular carcinoma. Oncogene, 41(29), 3680–3693. https://doi.org/10.1038/s41388-022-02380-0 .
Li, R., Yan, Q., Tian, P., Wang, Y., Wang, J. & Tao, N. et al. (2019). CBX7 inhibits cell growth and motility and induces apoptosis in cervical cancer cells. Molecular Therapy - Oncolytics, 15, 108–116. https://doi.org/10.1016/j.omto.2019.09.002 . (PMID: 10.1016/j.omto.2019.09.002317093046834976)

Keywords: CBX7; Cervical cancer cells; EPHB6; Malignant progression

0 (CBX7 protein, human)
EC 2.7.10.1 (EPHB6 protein, human)
EC 2.3.2.27 (Polycomb Repressive Complex 1)
EC 2.7.10.1 (Receptors, Eph Family)

Date Created: 20240925 Date Completed: 20241119 Latest Revision: 20241212

20241212

10.1007/s12013-024-01458-8

39322790