Artn, also known as Enovin or Neublastin, is a member of the glial cell line-derived neurotrophic factor (GDNF) family ligands. It binds preferentially to receptor GFRα3, coupled with receptor tyrosine kinase RET, forming a signaling complex that activates standard cascades such as phosphorylation of mitogen-activated protein kinase (p-ERK, p-p38 and p-JNK), PI3K-AKT and Src, regulating intracellular pathways crucial for nervous system development and homeostasis. It also has roles in non-neuron tissues, like in the formation of Peyer's patch-like structures in gut lymphoid tissue [4].

In cancer research, Artn has been implicated in various processes. Tumor-induced erythroid progenitor cells secrete Artn, which promotes tumor progression by activating RET signaling. Blockade of Artn or depletion of these cells augmented the antitumor effects of radiotherapy and anti-PD-L1 therapies in mice, and in human patients, reduction of Artn was associated with tumor regression [1]. In gastric cancer, the Artn-GFRA3 axis induces epithelial-mesenchymal transition phenotypes, migration, and invasion via KRAS signaling [2]. In breast cancer, the lncRNA JHDM1D-AS1 can up-regulate Artn by inhibiting miR-940, enhancing tumorigenesis and metastasis [3]. In endometrial carcinoma, the expression of Artn increases during the disease's development, invasion, and metastasis, and is positively correlated with MMP-9 expression [5].

In conclusion, Artn plays essential roles in nervous system development and homeostasis. Its dysregulation is strongly associated with cancer progression in multiple cancer types. Studies using models, such as in mouse experiments related to radiotherapy and immunotherapy, have revealed its significance in tumor-promoting mechanisms, highlighting its potential as a therapeutic target in cancer treatment.

References:

1. Hou, Yuzhu, Liang, Hua L, Yu, Xinshuang, Fu, Yang-Xin, Weichselbaum, Ralph R. . Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity. In Science translational medicine, 13, . doi:10.1126/scitranslmed.abb0130. https://pubmed.ncbi.nlm.nih.gov/33627484/

2. Wang, Xiao-Long, Jin, Gui-Xiu, Dong, Xiao-Qiang. . ARTN-GFRA3 axis induces epithelial-mesenchymal transition phenotypes, migration, and invasion of gastric cancer cells via KRAS signaling. In Neoplasma, 71, 266-278. doi:10.4149/neo_2024_231006N524. https://pubmed.ncbi.nlm.nih.gov/38958711/

3. Zuo, Yonggang, Ma, Mingde, Wen, Yuqing, Chang, Liang, Qu, Changping. 2023. JHDM1D-AS1-driven inhibition of miR-940 releases ARTN expression to induce breast carcinogenesis. In Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 25, 2192-2203. doi:10.1007/s12094-023-03102-y. https://pubmed.ncbi.nlm.nih.gov/36862282/

4. Zhu, Sipin, Li, Yihe, Bennett, Samuel, Xu, Huazi, Xu, Jiake. 2020. The role of glial cell line-derived neurotrophic factor family member artemin in neurological disorders and cancers. In Cell proliferation, 53, e12860. doi:10.1111/cpr.12860. https://pubmed.ncbi.nlm.nih.gov/32573073/

5. Wang, X H, Liu, Y N, Tian, K, Zheng, Y Q, Shi, Z M. . Expression and clinical significance of ARTN and MMP-9 in endometrial carcinoma. In Journal of biological regulators and homeostatic agents, 31, 879-887. doi:. https://pubmed.ncbi.nlm.nih.gov/29254290/