MiR-425-5p Mediation of Malignant Behavior and Immune Escape of Cervical Cancer Cells by Targeting NCAM1
Abstract
MicroRNA (miR)-425-5p is used as a molecular biomarker to identify cervical cancer (CxCa). However, few studies have examined the miR-425-5p-based modulation of the vital activities of CxCa cells.
The levels of neural cell adhesion molecule 1 (NCAM1) and miR-425-5p in CxCa tissues and cells were tested using western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR) tests. CxCa cells’ malignant phenotype was examined through clone formation tests, and transwell tests. CD8+T cells were co-cultured with CxCa cells and then analyzed for apoptosis rates and the expression of activation proteins (granzyme B (GZMB) and perforin) as well as immune factors (tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ)) using flow cytometry, western blot, and enzyme-linked immunosorbent assay (ELISA) methods. Finally, in nude mouse experiments, the tumor size was measured for subcutaneous tumors, and the expression of CD8+T cell-related factors was detected.
The NCAM1 and miR-425-5p were down-regulated and up-regulated in CxCa tissue and cells, respectively. After silencing miR-425-5p, CxCa cells showed attenuation in vitality, clone formation rate, and their capacities to migrate, penetrate, and evade immune responses. NCAM1 was targeted and silenced by miR-425-5p. When NCAM1 was silenced, it partially counteracted miR-425-5p’s inhibitory effects on the immune escape and proliferation. In nude mice, the tumor size and weight decreased after silencing miR-425-5p, and levels of CD8, IFN-γ, TNF-α, perforin, and GZMB were elevated. However, these changes were reversed when NCAM1 was silenced.
In conclusion, miR-425-5p mediates the biological behavior and immune evasion of CxCa cells by regulating NCAM1.
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3. McCluggage WG, Singh N, Gilks CB. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology. 2022;80(5):762–78.
4. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet‐Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012;30(Suppl 5):F12–23.
5. Wakeham K, Kavanagh K. The burden of HPV-associated anogenital cancers. Curr Oncol Rep. 2014;16(9):402.
6. Ferrall L, Lin KY, Roden RBS, Hung CF, Wu TC. Cervical Cancer Immunotherapy: Facts and Hopes. Clin Cancer Res. 2021;27(18):4953–73.
7. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48–58.
8. Wang K, Tepper JE. Radiation therapy-associated toxicity: Etiology, management, and prevention. CA Cancer J Clin. 2021;71(6):437–54.
9. Burmeister CA, Khan S, Czerniecki BJ, Erbeck K, Gawlik C, Jones HL, et al. Cervical cancer therapies: Current challenges and future perspectives. Tumour Virus Res. 2022;13:200-38.
10. Aftab M, Purohit H, Jain V, Bhowmick S, Verma RS. Urine miRNA signature as a potential non-invasive diagnostic and prognostic biomarker in cervical cancer. Sci Rep. 2021;11(1):10323.
11. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203–22.
12. Liu D, Zhang H, Cui M, Chen C, Feng Y. Hsa-miR-425-5p promotes tumor growth and metastasis by activating the CTNND1-mediated beta-catenin pathway and EMT in colorectal cancer. Cell Cycle. 2020;19(15):1917–27.
13. Liu S, Wang Q, Liu Y, Xia ZY. miR-425-5p suppresses tumorigenesis and DDP resistance in human-prostate cancer by targeting GSK3beta and inactivating the Wnt/beta-catenin signaling pathway. J Biosci. 2019;44.
14. Wu S, Mo Y, Peng M, Yang J, Tang T, Long Y, et al. Downregulation of ZC3H13 by miR-362-3p/miR-425-5p is associated with a poor prognosis and adverse outcomes in hepatocellular carcinoma. Aging (Albany NY). 2022;14(5):2304–19.
15. Xiao S, Zhu H, Luo J, Wu Z, Xie M. miR-425-5p is associated with poor prognosis in patients with breast cancer and promotes cancer cell progression by targeting PTEN. Oncol Rep. 2019;42(6):2550–60.
16. Yuan Z, Liu C, Wang L, Xie Q, Chen Y, Zheng X, et al. Long noncoding RNA LINC-PINT regulates laryngeal carcinoma cell stemness and chemoresistance through miR-425-5p/PTCH1/SHH axis. J Cell Physiol. 2019;234(12):23111–22.
17. Zhang Z, Zhang Y, Liu Y, Su J, Xie B. Clinical value of miR-425-5p detection and its association with cell proliferation and apoptosis of gastric cancer. Pathol Res Pract. 2017;213(8):929–37.
18. Zhao Y, Liu H, Sun Y, Zhang N, Ji S, Liu C, et al. LncRNA-MSC-AS1 inhibits the ovarian cancer progression by targeting miR-425-5p. J Ovarian Res. 2021;14(1):109.
19. Rao D, Guan S, Huang J, Chang Q, Duan S. miR-425-5p Acts as a Molecular Marker and Promoted Proliferation, Migration by Targeting RNF11 in Hepatocellular Carcinoma. Biomed Res Int. 2020;2020:6530973.
20. Wu Z, Liu W, Jiang X, Wang Y, Guo L, Li G, et al. MiR-425-5p accelerated the proliferation, migration, and invasion of ovarian cancer cells via targeting AFF4. J Ovarian Res. 2021;14(1):138.
21. Nascimento NPG, Gally TB, Borges GF, Campos LCG, Kaneto CM. Systematic review of circulating MICRORNAS as biomarkers of cervical carcinogenesis. BMC Cancer. 2022;22(1):862.
22. Zhang Y, Xu X, Ge R, Zhou Y, Ye M, Sun X. Downregulation of microRNA-425-5p suppresses cervical cancer tumorigenesis by targeting AIFM1. Exp Ther Med. 2019;17(6):4032–8.
23. Richart RM. A modified terminology for cervical intraepithelial neoplasia. Obstet Gynecol. 1990;75(1):131–3.
24. Uyar D, Rader J. Genomics of cervical cancer and the role of human papillomavirus pathobiology. Clin Chem. 2014;60(1):144–6.
25. Deng B, Qu L, Li J, Liu F, Tang Q, Yang Y, et al. MicroRNA-142-3p inhibits cell proliferation and invasion of cervical cancer cells by targeting FZD7. Tumour Biol. 2015;36(11):8065–73.
26. Kogo R, Mimori K, Tanaka F, Komune S, Mori M. The microRNA-218\~Survivin axis regulates migration, invasion, and lymph node metastasis in cervical cancer. Oncotarget. 2015;6(2):1090–100.
27. Shen S, Zhang S, Liu P, Wang J, Du H. Potential role of microRNAs in the treatment and diagnosis of cervical cancer. Cancer Genet. 2020;248–249:25–30.
28. Guan G, Zhang X, Liu H, Wang H, Wang Z. Upregulation of Neural Cell Adhesion Molecule 1 (NCAM1) by hsa-miR-141-3p Suppresses Ameloblastoma Cell Migration. Med Sci Monit. 2020;26\:e923491.
29. Kim HS, Kim S, Kim E, Lee H, Yang W, Lee YJ, et al. Directly reprogrammed natural killer cells for cancer immunotherapy. Nat Biomed Eng. 2021;5(12):1360–76.
30. Kriegsmann K, Warth A, Muley T, Harms A, Herpel E, Winter H, et al. Role of Synaptophysin, Chromogranin and CD56 in adenocarcinoma and squamous cell carcinoma of the lung lacking morphological features of neuroendocrine differentiation: a retrospective large-scale study on 1170 tissue samples. BMC Cancer. 2021;21(1):486.
31. Zhang Y, Wang X, Xu B, Ma X, Wang Y, Zhang R, et al. Baseline immunity and impact of chemotherapy on immune microenvironment in cervical cancer. Br J Cancer. 2021;124(3):414–24.
32. Gunesch JT, Dixon KO, Rahman R, Al-Attar A, Skov J, Lauron EJ, et al. CD56 regulates human NK cell cytotoxicity through Pyk2. Elife. 2020;9:e57346.
33. Van Acker HH, Capsomidis A, Smits EL, Van Tendeloo VF. CD56 in the Immune System: More Than a Marker for Cytotoxicity? Front Immunol. 2017;8:892.
34. Vayrynen JP, Vornanen JO, Sajanti SA, Böhm JP, Tuomisto A, Mäkinen MJ. Spatial Organization and Prognostic Significance of NK and NKT-like Cells via Multimarker Analysis of the Colorectal Cancer Microenvironment. Cancer Immunol Res. 2022;10(2):215–27.
35. Weber B, Bornhöfft D, Fölster-Holst R, Geisel J, Sterry W, Worm M. Distinct interferon-gamma and interleukin-9 expression in cutaneous and oral lichen planus. J Eur Acad Dermatol Venereol. 2017;31(5):880–6.
36. Fu C, Jiang A. Dendritic Cells and CD8 T Cell Immunity in Tumor Microenvironment. Front Immunol. 2018;9:3059.
37. Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–8.
38. Ramljak D, Pirš M, Seme K, Debeljak Z, Avčin T, Ihan A. Early Response of CD8+ T Cells in COVID-19 Patients. J Pers Med. 2021;11(3):221.
39. Corridoni D, Antanaviciute A, Gupta T, Ortiz-Muñoz G, Franzè E, Povey E, et al. Single-cell atlas of colonic CD8(+) T cells in ulcerative colitis. Nat Med. 2020;26(9):1480–90.
40. Kumar J, Kim K, Lee SH, Park S, Kim D, Han J, et al. Deletion of Cbl-b inhibits CD8(+) T-cell exhaustion and promotes CAR T-cell function. J Immunother Cancer. 2021;9(1):e001647.
41. Tang M, Tian L, Luo G, Yu X. Interferon-Gamma-Mediated Osteoimmunology. Front Immunol. 2018;9:1508.
42. Zheng Y, Wang X, Huang M. Metabolic Regulation of CD8(+) T Cells: From Mechanism to Therapy. Antioxid Redox Signal. 2022;37(17–18):1234–52.
43. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162(6):1229–41.
44. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162(6):1217–28.
45. Ottensmeier CH, Perry KL, Harden EL, Stasakova J, Jenei V, Fleming J, et al. Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma. Cancer Res. 2016;76(14):4136–48.
46. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162(6):1229-41.
47. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162(6):1217-28.
48. Ottensmeier CH, Perry KL, Harden EL, Stasakova J, Jenei V, Fleming J, et al. Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma. Cancer research. 2016;76(14):4136-48.
2. Ashrafizadeh M. Cell Death Mechanisms in Human Cancers: Molecular Pathways, Therapy Resistance and Therapeutic Perspective. J Cancer Biomol Ther. 2024;1(1):17–40.
3. McCluggage WG, Singh N, Gilks CB. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology. 2022;80(5):762–78.
4. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet‐Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012;30(Suppl 5):F12–23.
5. Wakeham K, Kavanagh K. The burden of HPV-associated anogenital cancers. Curr Oncol Rep. 2014;16(9):402.
6. Ferrall L, Lin KY, Roden RBS, Hung CF, Wu TC. Cervical Cancer Immunotherapy: Facts and Hopes. Clin Cancer Res. 2021;27(18):4953–73.
7. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48–58.
8. Wang K, Tepper JE. Radiation therapy-associated toxicity: Etiology, management, and prevention. CA Cancer J Clin. 2021;71(6):437–54.
9. Burmeister CA, Khan S, Czerniecki BJ, Erbeck K, Gawlik C, Jones HL, et al. Cervical cancer therapies: Current challenges and future perspectives. Tumour Virus Res. 2022;13:200-38.
10. Aftab M, Purohit H, Jain V, Bhowmick S, Verma RS. Urine miRNA signature as a potential non-invasive diagnostic and prognostic biomarker in cervical cancer. Sci Rep. 2021;11(1):10323.
11. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203–22.
12. Liu D, Zhang H, Cui M, Chen C, Feng Y. Hsa-miR-425-5p promotes tumor growth and metastasis by activating the CTNND1-mediated beta-catenin pathway and EMT in colorectal cancer. Cell Cycle. 2020;19(15):1917–27.
13. Liu S, Wang Q, Liu Y, Xia ZY. miR-425-5p suppresses tumorigenesis and DDP resistance in human-prostate cancer by targeting GSK3beta and inactivating the Wnt/beta-catenin signaling pathway. J Biosci. 2019;44.
14. Wu S, Mo Y, Peng M, Yang J, Tang T, Long Y, et al. Downregulation of ZC3H13 by miR-362-3p/miR-425-5p is associated with a poor prognosis and adverse outcomes in hepatocellular carcinoma. Aging (Albany NY). 2022;14(5):2304–19.
15. Xiao S, Zhu H, Luo J, Wu Z, Xie M. miR-425-5p is associated with poor prognosis in patients with breast cancer and promotes cancer cell progression by targeting PTEN. Oncol Rep. 2019;42(6):2550–60.
16. Yuan Z, Liu C, Wang L, Xie Q, Chen Y, Zheng X, et al. Long noncoding RNA LINC-PINT regulates laryngeal carcinoma cell stemness and chemoresistance through miR-425-5p/PTCH1/SHH axis. J Cell Physiol. 2019;234(12):23111–22.
17. Zhang Z, Zhang Y, Liu Y, Su J, Xie B. Clinical value of miR-425-5p detection and its association with cell proliferation and apoptosis of gastric cancer. Pathol Res Pract. 2017;213(8):929–37.
18. Zhao Y, Liu H, Sun Y, Zhang N, Ji S, Liu C, et al. LncRNA-MSC-AS1 inhibits the ovarian cancer progression by targeting miR-425-5p. J Ovarian Res. 2021;14(1):109.
19. Rao D, Guan S, Huang J, Chang Q, Duan S. miR-425-5p Acts as a Molecular Marker and Promoted Proliferation, Migration by Targeting RNF11 in Hepatocellular Carcinoma. Biomed Res Int. 2020;2020:6530973.
20. Wu Z, Liu W, Jiang X, Wang Y, Guo L, Li G, et al. MiR-425-5p accelerated the proliferation, migration, and invasion of ovarian cancer cells via targeting AFF4. J Ovarian Res. 2021;14(1):138.
21. Nascimento NPG, Gally TB, Borges GF, Campos LCG, Kaneto CM. Systematic review of circulating MICRORNAS as biomarkers of cervical carcinogenesis. BMC Cancer. 2022;22(1):862.
22. Zhang Y, Xu X, Ge R, Zhou Y, Ye M, Sun X. Downregulation of microRNA-425-5p suppresses cervical cancer tumorigenesis by targeting AIFM1. Exp Ther Med. 2019;17(6):4032–8.
23. Richart RM. A modified terminology for cervical intraepithelial neoplasia. Obstet Gynecol. 1990;75(1):131–3.
24. Uyar D, Rader J. Genomics of cervical cancer and the role of human papillomavirus pathobiology. Clin Chem. 2014;60(1):144–6.
25. Deng B, Qu L, Li J, Liu F, Tang Q, Yang Y, et al. MicroRNA-142-3p inhibits cell proliferation and invasion of cervical cancer cells by targeting FZD7. Tumour Biol. 2015;36(11):8065–73.
26. Kogo R, Mimori K, Tanaka F, Komune S, Mori M. The microRNA-218\~Survivin axis regulates migration, invasion, and lymph node metastasis in cervical cancer. Oncotarget. 2015;6(2):1090–100.
27. Shen S, Zhang S, Liu P, Wang J, Du H. Potential role of microRNAs in the treatment and diagnosis of cervical cancer. Cancer Genet. 2020;248–249:25–30.
28. Guan G, Zhang X, Liu H, Wang H, Wang Z. Upregulation of Neural Cell Adhesion Molecule 1 (NCAM1) by hsa-miR-141-3p Suppresses Ameloblastoma Cell Migration. Med Sci Monit. 2020;26\:e923491.
29. Kim HS, Kim S, Kim E, Lee H, Yang W, Lee YJ, et al. Directly reprogrammed natural killer cells for cancer immunotherapy. Nat Biomed Eng. 2021;5(12):1360–76.
30. Kriegsmann K, Warth A, Muley T, Harms A, Herpel E, Winter H, et al. Role of Synaptophysin, Chromogranin and CD56 in adenocarcinoma and squamous cell carcinoma of the lung lacking morphological features of neuroendocrine differentiation: a retrospective large-scale study on 1170 tissue samples. BMC Cancer. 2021;21(1):486.
31. Zhang Y, Wang X, Xu B, Ma X, Wang Y, Zhang R, et al. Baseline immunity and impact of chemotherapy on immune microenvironment in cervical cancer. Br J Cancer. 2021;124(3):414–24.
32. Gunesch JT, Dixon KO, Rahman R, Al-Attar A, Skov J, Lauron EJ, et al. CD56 regulates human NK cell cytotoxicity through Pyk2. Elife. 2020;9:e57346.
33. Van Acker HH, Capsomidis A, Smits EL, Van Tendeloo VF. CD56 in the Immune System: More Than a Marker for Cytotoxicity? Front Immunol. 2017;8:892.
34. Vayrynen JP, Vornanen JO, Sajanti SA, Böhm JP, Tuomisto A, Mäkinen MJ. Spatial Organization and Prognostic Significance of NK and NKT-like Cells via Multimarker Analysis of the Colorectal Cancer Microenvironment. Cancer Immunol Res. 2022;10(2):215–27.
35. Weber B, Bornhöfft D, Fölster-Holst R, Geisel J, Sterry W, Worm M. Distinct interferon-gamma and interleukin-9 expression in cutaneous and oral lichen planus. J Eur Acad Dermatol Venereol. 2017;31(5):880–6.
36. Fu C, Jiang A. Dendritic Cells and CD8 T Cell Immunity in Tumor Microenvironment. Front Immunol. 2018;9:3059.
37. Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–8.
38. Ramljak D, Pirš M, Seme K, Debeljak Z, Avčin T, Ihan A. Early Response of CD8+ T Cells in COVID-19 Patients. J Pers Med. 2021;11(3):221.
39. Corridoni D, Antanaviciute A, Gupta T, Ortiz-Muñoz G, Franzè E, Povey E, et al. Single-cell atlas of colonic CD8(+) T cells in ulcerative colitis. Nat Med. 2020;26(9):1480–90.
40. Kumar J, Kim K, Lee SH, Park S, Kim D, Han J, et al. Deletion of Cbl-b inhibits CD8(+) T-cell exhaustion and promotes CAR T-cell function. J Immunother Cancer. 2021;9(1):e001647.
41. Tang M, Tian L, Luo G, Yu X. Interferon-Gamma-Mediated Osteoimmunology. Front Immunol. 2018;9:1508.
42. Zheng Y, Wang X, Huang M. Metabolic Regulation of CD8(+) T Cells: From Mechanism to Therapy. Antioxid Redox Signal. 2022;37(17–18):1234–52.
43. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162(6):1229–41.
44. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162(6):1217–28.
45. Ottensmeier CH, Perry KL, Harden EL, Stasakova J, Jenei V, Fleming J, et al. Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma. Cancer Res. 2016;76(14):4136–48.
46. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162(6):1229-41.
47. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162(6):1217-28.
48. Ottensmeier CH, Perry KL, Harden EL, Stasakova J, Jenei V, Fleming J, et al. Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma. Cancer research. 2016;76(14):4136-48.
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How to Cite
1.
Xiang M, Yu Y, Gao Q, Xing J. MiR-425-5p Mediation of Malignant Behavior and Immune Escape of Cervical Cancer Cells by Targeting NCAM1. Iran J Allergy Asthma Immunol. 2025;:1-17.
