CRMP4 suppresses cervical cancer cell proliferation and EMT through the Wnt/β-catenin pathway

Cervical cancer is the 4th leading cause of tumor-related deaths among women, primarily due to high-risk Human Papillomavirus (HPV). The role of Collapsin Response Mediator Protein 4 (CRMP4) in cervical cancer remains poorly understood, despite its variable expression across various cancers. This study aimed to investigate the mechanisms by which CRMP4 regulates cervical cancer cell growth as well as Epithelial-Mesenchymal Transition (EMT). Based on transcriptome data from The Cancer Genome Atlas (TCGA), CRMP4 is significantly downregulated in cervical cancer tissues compared to normal tissues. Immunoblot assays revealed lower CRMP4 expression in cervical cancer cell lines. Cell Counting Kit-8 (CCK-8), colony formation and flowcytometry demonstrated that CRMP4 overexpression inhibited cell growth as well as stimulated apoptosis in HeLa as well as SiHa cells. In addition, CRMP4 overexpression increased Epithelial cadherin (E-cadherin) levels and decreased Neural cadherin (N-cadherin) and alpha-Smooth Muscle Actin (α-SMA) levels, indicating EMT suppression. CRMP4 overexpression downregulated the Wnt/β-catenin axis by reducing expressions of β-catenin, Wnt family member 3A (Wnt3a), c-Myc and cyclin D1. In summary, CRMP4 inhibits cervical cancer cell proliferation as well as EMT by mediating the Wnt/β-catenin axis. CRMP4 may therefore be a potential therapeutic target of cervical cancer.

Cervical cancer; Collapsin response mediator protein 4 (CRMP4); Proliferation; Epithelial-mesenchymal transition (EMT); Wnt/β-catenin

[1] Knaul FM, Rodriguez NM, Arreola-Ornelas H, Olson JR. Cervical cancer: lessons learned from neglected tropical diseases. The Lancet Global Health Home. 2019; 7: e299–e300.

[2] Zarocostas J. Renewed calls to scale-up cervical cancer screening. The Lancet. 2024; 403: 797.

[3] Yuan Y, Cai X, Shen F, Ma F. HPV post-infection microenvironment and cervical cancer. Cancer Letters. 2021; 497: 243–254.

[4] Perkins RB, Wentzensen N, Guido RS, Schiffman M. Cervical cancer screening: a review. JAMA. 2023; 330: 547–558.

[5] Sadri Nahand J, Moghoofei M, Salmaninejad A, Bahmanpour Z, Karimzadeh M, Nasiri M, et al. Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: a review. International Journal of Cancer. 2020; 146: 305–320.

[6] Maimon R, Ankol L, Gradus Pery T, Altman T, Ionescu A, Weissova R, et al. A CRMP4-dependent retrograde axon-to-soma death signal in amyotrophic lateral sclerosis. The EMBO Journal. 2021; 40: e107586.

[7] Boulan B, Ravanello C, Peyrel A, Bosc C, Delphin C, Appaix F, et al. CRMP4-mediated fornix development involves Semaphorin-3E signaling pathway. eLife. 2021; 10: e70361.

[8] Tonouchi A, Nagai J, Togashi K, Goshima Y, Ohshima T. Loss of collapsin response mediator protein 4 suppresses dopaminergic neuron death in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-stimulated mouse model of Parkinson’s disease. Journal of Neurochemistry. 2016; 137: 795–805.

[9] Gao X, Li LY, Rassler J, Pang J, Chen MK, Liu WP, et al. Prospective study of CRMP4 promoter methylation in prostate biopsies as a predictor for lymph node metastases. Journal of the National Cancer Institute. 2017; 109: djw282.

[10] Yazawa K, Nakamura F, Masukawa D, Sato S, Hiroshima Y, Yabushita Y, et al. Low incidence of high-grade pancreatic intraepithelial neoplasia lesions in a CRMP4 gene-deficient mouse model of pancreatic cancer. Translational Oncology. 2020; 13: 100746.

[11] Zhao S, Huang L, Basu P, Domingo EJ, Supakarapongkul W, Ling WY, et al. Cervical cancer burden, status of implementation and challenges of cervical cancer screening in Association of Southeast Asian Nations (ASEAN) countries. Cancer Letters. 2022; 525: 22–32.

[12] Adiga D, Eswaran S, Pandey D, Sharan K, Kabekkodu SP. Molecular landscape of recurrent cervical cancer. Critical Reviews in Oncology/Hematology. 2021; 157: 103178.

[13] Ohtani-Kaneko R. Crmp4-KO mice as an animal model for investigating certain phenotypes of autism spectrum disorders. International Journal of Molecular Sciences. 2019; 20: 2485.

[14] Chi C, Hou W, Zhang Y, Chen J, Shen Z, Chen Y, et al. PDHB-AS suppresses cervical cancer progression and cisplatin resistance via inhibition on Wnt/b-catenin pathway. Cell Death & Disease. 2023; 14: 90.

[15] Guangzhen Zhao JJ. HOMER1A restores sevoflurane-stimulated cognitive dysfunction by regulating microglia’s activation through activating the AMPK/TXNIP axis. Signa Vitae. 2023; 19: 202–212.

[16] Zhang C, Liu L, Li W, Li M, Zhang X, Zhang C, et al. Upregulation of FAM83F by c-Myc promotes cervical cancer growth and aerobic glycolysis via Wnt/b-catenin signaling activation. Cell Death & Disease. 2023; 14: 837.

[17] Wang D, Wu S, He J, Sun L, Zhu H, Zhang Y, et al. FAT4 overexpression promotes antitumor immunity by regulating the b-catenin/STT3/PD-L1 axis in cervical cancer. Journal of Experimental & Clinical Cancer Research. 2023; 42: 222.

[18] Matsunuma R, Chan DW, Kim BJ, Singh P, Han A, Saltzman AB, et al. DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer. Proceedings of the National Academy of Sciences of the United States of America. 2018; 115: E11978–E11987.