Kaci Orr

Introduction. Neuroblastoma (NB) is a neoplasm of the peripheral nervous system.^1,2 It is the most common and deadliest extracranial tumor of childhood, with approximately 650 cases diagnosed annually in the United States.¹ More than 50% of patients present with a metastasized tumor and are classified as high risk.³ The remission rate is less than 50% for these patients.³ Furthermore, up to 20% of high-risk neuroblastoma patients exhibit minimal residual disease, or neuroblastoma cells that are resistant to chemotherapeutic drugs and will increase the risk of relapse.³ The long-term survival rate for patients with relapsed neuroblastoma is less than 10%.³ Annexin A2 (ANXA2) is a protein that is overexpressed in many types of malignant tumors, including breast cancer and colorectal cancer.⁴ Methods. TMA-based IHC analysis of NB samples was utilized to quantify the expression levels of ANXA2.⁴ shRNA was used to knock down ANXA2 in a NB cell line, then a CCK-8 cell viability assay was employed to assess chemosensitivity.⁴ Immunoprecipitation and immunofluorescence staining were used to determine the relationship between ANXA2 and the p50 subunit of NF-κB.⁴ Results. Higher-intensity ANXA2 staining correlated with a more advanced stage, more cycles of chemotherapy, and less favorable survival.⁴ Knockdown of ANXA2 resulted in a lower IC50 for two chemotherapeutic drugs, doxorubicin and etoposide, and decreased the nuclear translocation of NF-κB p50.⁴ Immunoprecipitation confirmed the direct interaction between ANXA2 and NF-κB p50.⁴ Similar studies have demonstrated that up-regulation of ANXA4 decreases apoptosis of ovarian clear cell carcinoma cells and increases the transcriptional levels of Cyclin D1 and Bcl-2, which are targets of NF-κB.⁵ Other studies have established that ANXA2 activates JNK, which decreases the expression of p53 by stabilizing c-Jun.⁶ c-Jun binds to and represses the promoter of the p53 gene.⁶ Additionally, other studies have demonstrated that ANXA2 promotes the epithelial-to-mesenchymal transition in NSCLC cells, a process that is critical for tumor invasion and metastasis.⁷ Other studies have illustrated that treatment of hepatocellular carcinoma cells with (20S)-G-Rh2, a component of the medicinal herb ginseng, inhibits the interaction between and the nuclear translocation of ANXA2 and NF-κB p50.⁸ Conclusion. By demonstrating that knockdown of ANXA2 decreases the nuclear translocation of NF-κB p50 and the transcriptional levels of NF-κB target genes, multiple studies have established that ANXA2 is a coactivator of NF-κB p50.^4,5 ANXA2 also contributes to the chemoresistance and metastasis of cancer cells by activating JNK/c-Jun to downregulate p53 and promoting the epithelial-to-mesenchymal transition.^6,7

1. Mahapatra S, Challagundla KB. Neuroblastoma. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 17, 2020.
2. Johnsen JI, Dyberg C, Wickström M. Neuroblastoma-A Neural Crest Derived Embryonal Malignancy. Front Mol Neurosci. 2019;12:9. Published 2019 Jan 29. doi:10.3389/fnmol.2019.00009
3. Uemura S, Ishida T, Thwin KKM, et al. Dynamics of Minimal Residual Disease in Neuroblastoma Patients. Front Oncol. 2019;9:455. Published 2019 Jun 4. doi:10.3389/fonc.2019.00455
4. Wang Y, Chen K, Cai Y, et al. Annexin A2 could enhance multidrug resistance by regulating NF-κB signaling pathway in pediatric neuroblastoma. J Exp Clin Cancer Res. 2017;36(1):111. Published 2017 Aug 16. doi:10.1186/s13046-017-0581-6
5. Liu J, Wang H, Zheng M, Deng L, Zhang X, Lin B. p53 and ANXA4/NF‑κB p50 complexes regulate cell proliferation, apoptosis and tumor progression in ovarian clear cell carcinoma. Int J Mol Med. 2020;46(6):2102-2114. doi:10.3892/ijmm.2020.4757
6. Feng X, Liu H, Zhang Z, Gu Y, Qiu H, He Z. Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells. J Exp Clin Cancer Res. 2017;36(1):123. Published 2017 Sep 8.
7. Wu M, Sun Y, Xu F, Liang Y, Liu H, Yi Y. Annexin A2 silencing inhibits proliferation and epithelial-to-mesenchymal transition through p53-dependent pathway in NSCLCs.J Cancer. 2019;10(5):1077-1085. Published 2019 Jan 29. doi:10.7150/jca.29440
8. Wang YS, Lin Y, Li H, Li Y, Song Z, Jin YH. The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity. Sci Rep. 2017;7(1):12408. Published 2017 Sep 29. doi:10.1038/s41598-017-12572-4