The Regulatory Role of RTN4 in Proliferation, Apoptosis, and Migration of Cervical Cancer Cells

ZOU Zhi; LI Yike; LIU Bang; LIANG Yun; LI Lulu; SHI Yan

PDF(6087 KB)

Journal of Hunan Normal University(Medical Science) ›› 2025, Vol. 22 ›› Issue (6) : 8-16.

Basic Medicine

The Regulatory Role of RTN4 in Proliferation, Apoptosis, and Migration of Cervical Cancer Cells

ZOU Zhi^1,2, LI Yike¹, LIU Bang^1,2, LIANG Yun¹, LI Lulu¹, SHI Yan²

Author information +

History +

Abstract

Objective To investigate the effects of RTN4 on the proliferation, apoptosis, and migration of HeLa cells, providing a new theoretical basis for the molecular mechanisms and therapeutic targets in the development of cervical cancer. Methods The expression differences of RTN4 mRNA and protein in cervical cancer and adjacent tissues were identified through databases such as TCGA, GTEx, GEO, and HPA, as well as immunohistochemical staining. After upregulating and downregulating RTN4 levels in HeLa cells, the effects of RTN4 on cell proliferation, apoptosis, and migration were observed using qPCR, Western Blotting, CCK-8 assay, colony formation assay, scratch assay, invasion assay, and apoptosis assays. Results Database analysis revealed that the levels of RTN4 mRNA and protein were significantly decreased in cervical cancer tissues compared to adjacent tissues. Immunohistochemical staining results showed that RTN4 protein was significantly underexpressed in cervical cancer compared to adjacent tissues. In HeLa cells, upregulating RTN4 levels led to a significant decrease in cell proliferation, migration, and invasion abilities, along with a significant increase in apoptosis rate. Conversely, downregulating RTN4 levels resulted in a significant increase in cell proliferation, migration, and invasion abilities, while the apoptosis rate significantly decreased. Conclusion The expression of RTN4 mRNA and protein in cervical cancer tissues is significantly lower than that in adjacent tissues. In cervical cancer cells, overexpression of RTN4 can inhibit cell proliferation, migration, and invasion, while promoting apoptosis; downregulation of RTN4 exhibits the opposite phenotype. These results suggest that RTN4 may serve as a new target for targeted therapy in cervical cancer.

Key words

cervical cancer / RTN4 / proliferation / migration / apoptosis

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

ZOU Zhi, LI Yike, LIU Bang, LIANG Yun, LI Lulu, SHI Yan. The Regulatory Role of RTN4 in Proliferation, Apoptosis, and Migration of Cervical Cancer Cells[J]. Journal of Hunan Normal University(Medical Science). 2025, 22(6): 8-16

References

[1] Bray F, Laversanne M, Sung H, et al.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA: A Cancer Journal for Clinicians, 2024, 74(3): 229-263.
[2] Han C, Huang W, Ye M, et al.HPV prevalence and genotype distribution in 2 306 patients with cervical squamous cell carcinoma in central and eastern China[J]. Front Public Health, 2023, 11: 1225652.
[3] 王培宇, 黄祺, 王少东, 等. 《全球癌症统计数据2022》要点解读[J]. 中国胸心血管外科临床杂志, 2024, 31(07): 933-954.
[4] 涂雅涵, 刘旖旎, 黄思. 宫颈癌术后化疗病人心理痛苦与自我感受负担的相关性[J]. 全科护理, 2022, 20(09): 1285-1287.
[5] Xu H, He Y, Miao F, et al.Acupuncture treatment of postoperative urinary retention in cervical cancer: Systematic evaluation and meta-analysis[J]. Medicine, 2025, 104(8): e41520.
[6] Yang F C, Huang W, Yang W, et al.Cervical Cancer Surgery[J]. Gynecology and Minimally Invasive Therapy, 2021, 10(2): 75-83.
[7] Conte C, Della Corte L, Pelligra S, et al.Assessment of Salvage Surgery in Persistent Cervical Cancer after Definitive Radiochemotherapy: A Systematic Review[J]. Medicina (Kaunas), 2023, 59(2): 192.
[8] Li J, Liang L, Xiu L, et al.Establishment of a molecular risk model for the prognosis of cervical cancer based on microRNA expression[J]. Annals of Translational Medicine, 2022, 10(2): 125-125.
[9] Khosravanian M J, Mirzaei Y, Mer A H, et al.Nectin-4-directed antibody-drug conjugates (ADCs): Spotlight on preclinical and clinical evidence[J]. Life Sci, 2024, 352: 122910.
[10] Zhou W, Fang P, Yu D, et al.Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers[J]. Mol Cancer Ther, 2023, 22(8): 913-925.
[11] Zhang J, Liu R, Wang S, et al.Bulumtatug Fuvedotin (BFv, 9MW2821), a next-generation Nectin-4 targeting antibody-drug conjugate, in patients with advanced solid tumors: a first-in-human, open-label, multicenter, phase I/II study[J]. Ann Oncol, 2025, 36(8): 934-943.
[12] Fang P, You M, Cao Y, et al.Development and validation of bioanalytical assays for the quantification of 9MW2821, a nectin-4-targeting antibody-drug conjugate[J]. J Pharm Biomed Anal, 2024, 248: 116318.
[13] Fuentes L A, Marin Z, Tyson J, et al.The nanoscale organization of reticulon 4 shapes local endoplasmic reticulum structure in situ[J]. J Cell Biol, 2023, 222(10): e202301112.
[14] Konno T, Parutto P, Crapart C C, et al.Endoplasmic reticulum morphology regulation by RTN4 modulates neuronal regeneration by curbing luminal transport[J]. Cell Rep, 2024, 43(7): 114357.
[15] 张超, 周业, 谢黎明, 等. RTN4在胃癌发病机制中的作用[J]. 医学信息, 2018, 31(22): 55-59.
[16] Zhao H, Su W, Zhu C, et al.Cell fate regulation by reticulon‐4 in human prostate cancers[J]. Journal of Cellular Physiology, 2018, 234(7): 10372-10385.
[17] Zhao M M, Ren T T, Wang J K, et al.Endoplasmic reticulum membrane remodeling by targeting reticulon-4 induces pyroptosis to facilitate antitumor immune[J]. Protein Cell, 2025, 16(2): 121-135.
[18] Wang H, Huang R, Luo L, et al.Targeting Reticulin 4 (RTN4) Within Small Extracellular Vesicles Combats Metastasis and Reinforces Immunotherapy in Triple-Negative Breast Cancer[J]. J Extracell Vesicles, 2025, 14(8): e70154.
[19] Willis J, Anders R A, Torigoe T, et al.Multi-Institutional Evaluation of Pathologists’ Assessment Compared to Immunoscore[J]. Cancers, 2023, 15(16): 4045.
[20] Buskwofie A, David-West G, Clare C A.A Review of Cervical Cancer: Incidence and Disparities[J]. J Natl Med Assoc, 2020, 112(2): 229-232.
[21] Xiao P, Gu J, Xu W, et al.RTN4/Nogo-A-S1PR2 negatively regulates angiogenesis and secondary neural repair through enhancing vascular autophagy in the thalamus after cerebral cortical infarction[J]. Autophagy, 2022, 18(11): 2711-2730.
[22] Carter R J, Milani M, Beckett A J, et al.Novel roles of RTN4 and CLIMP-63 in regulating mitochondrial structure, bioenergetics and apoptosis[J]. Cell Death Dis, 2022, 13(5): 436.
[23] Levine B, Kroemer G.Biological Functions of Autophagy Genes: A Disease Perspective[J]. Cell, 2019, 176(1-2): 11-42.
[24] Chen R, Zou J, Zhong X, et al.HMGB1 in the interplay between autophagy and apoptosis in cancer[J]. Cancer Lett, 2024, 581: 216494.
[25] Wang X, Li X, Jiang W.High expression of RTN4IP1 predicts adverse prognosis for patients with breast cancer[J]. Transl Cancer Res, 2023, 12(4): 859-872.
[26] Feng J, Zhao L, Chen H, et al.The Overexpression of RTN4 Significantly Associated With an Unfavourable Prognosis in Patients With Lower-Grade Gliomas[J]. J Cell Mol Med, 2025, 29(4): e70418.
[27] Pourzand P, Tabasi F, Fayazbakhsh F,et al.The Reticulon-4 3-bp Deletion/Insertion Polymorphism Is Associated with Structural mRNA Changes and the Risk of Breast Cancer: A Population-Based Case-Control Study with Bioinformatics Analysis[J]. Life (Basel), 2023, 13(7): 1549.
[28] Wang N, Chen K, Xu J, et al.Association of CAA and TATC Insertion/Deletion Genetic Polymorphisms in RTN4 3’-UTR with Hepatocellular Carcinoma Risk[J]. Pathol Oncol Res, 2018, 24(1): 31-34.
[29] 周业. RTN4高表达对永生化胃粘膜上皮GES1细胞增殖的影响及机制[D], 2018.
[30] 杨梦恬, 袁菊懋. RTN4对于结肠癌细胞增殖的调控作用[J]. 生物技术进展, 2021, 11(02): 238-243.
[31] 刘丽果. RTN4在人前列腺癌发生发展中的作用及机制研究[D], 2019.
[32] Pathak G P, Shah R, Kennedy B E,et al.RTN4 Knockdown Dysregulates the AKT Pathway, Destabilizes the Cytoskeleton, and Enhances Paclitaxel-Induced Cytotoxicity in Cancers[J]. Mol Ther, 2018, 26(8): 2019-2033.
[33] Kang S, Yoo J, Myung K.PCNA cycling dynamics during DNA replication and repair in mammals[J]. Trends Genet, 2024, 40(6): 526-539.
[34] Wendel S O, Snow J A, Gu L, et al.The potential of PCNA inhibition as a therapeutic strategy in cervical cancer[J]. J Med Virol, 2023, 95(11): e29244.