Int J Biol Sci 2022; 18(15):5963-5977. doi:10.7150/ijbs.72982 This issue Cite

Research Paper

Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways

Zhangshuo Yang1,#, Hao Zhang1,#, Maohui Yin1, Zhixiang Cheng1, Ping Jiang1, Maohui Feng2✉, Bo Liao1✉, Zhisu Liu1✉

1. Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, People's Republic of China.
2. Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, People's Republic of China.
#These authors contributed equally to this work.

Citation:
Yang Z, Zhang H, Yin M, Cheng Z, Jiang P, Feng M, Liao B, Liu Z. Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways. Int J Biol Sci 2022; 18(15):5963-5977. doi:10.7150/ijbs.72982. https://www.ijbs.com/v18p5963.htm
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Abstract

Graphic abstract

Although liver cancer is a malignant tumor with the highest mortality across the world, its pathogenesis and therapeutic targets remain unclear. Apoptosis, a natural cell death mechanism, is an important target of anticancer therapy. The discovery of effective apoptotic regulators can lead to the identification of novel therapeutic targets for treating cancer. Neurotrophin 3 (NTF3) is a member of the nerve growth factor (NGF) family that is involved in the progression of various cancers, including medulloblastoma, primitive neuroectodermal brain tumors, and breast cancer. NTF3 is under-expressed in human hepatocellular carcinoma (HCC), albeit its specific effects and the action mechanism have not been elucidated. Here, we confirmed that NTF3 expression was significantly low in HCC with reference to the GSEA database. By collecting patient data from our center and performing qRT-PCR analysis, we found that NTF3 expression was significantly downregulated in 74 patients with HCC. Low NTF3 expression was associated with a shorter overall survival (OS), recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). Both in vivo and in vitro experiments revealed that NTF3 considerably inhibited the progression of HCC cells. We found that the ligand NTF3 is regulated by c-Jun and binds to the p75 neurotrophin receptor (p75NTR) and then activates the JNK and P38 MAPK pathways to induce apoptosis. Entinostat (the target of HDAC1/HDAC3) can activate the NTF3/p75NTR pathway. These results indicate that NTF3 is a tumor suppressor, and that its low expression can help in predict poor clinical outcomes in HCC. Therefore, NTF3 can be used as a potential treatment molecule for HCC.

Keywords: Hepatocellular carcinoma, Neurotrophin 3, p75NTR, Tumor suppress


Citation styles

APA
Yang, Z., Zhang, H., Yin, M., Cheng, Z., Jiang, P., Feng, M., Liao, B., Liu, Z. (2022). Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways. International Journal of Biological Sciences, 18(15), 5963-5977. https://doi.org/10.7150/ijbs.72982.

ACS
Yang, Z.; Zhang, H.; Yin, M.; Cheng, Z.; Jiang, P.; Feng, M.; Liao, B.; Liu, Z. Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways. Int. J. Biol. Sci. 2022, 18 (15), 5963-5977. DOI: 10.7150/ijbs.72982.

NLM
Yang Z, Zhang H, Yin M, Cheng Z, Jiang P, Feng M, Liao B, Liu Z. Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways. Int J Biol Sci 2022; 18(15):5963-5977. doi:10.7150/ijbs.72982. https://www.ijbs.com/v18p5963.htm

CSE
Yang Z, Zhang H, Yin M, Cheng Z, Jiang P, Feng M, Liao B, Liu Z. 2022. Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways. Int J Biol Sci. 18(15):5963-5977.

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