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ARTN is a subtype of the glial cell-derived neurotrophic factor (GDNF) family of ligands (GFL). It mainly mediates the survival, differentiation, and migration of various types of neurons. GFRα3, one of ARTN and its receptor, is highly expressed in malignant tumors and plays a role in the development of various malignant tumors. Studying the mechanism of action of ARTN in malignant tumors can help early diagnosis, treatment and prognosis of tumors, and may be a powerful theoretical basis for guiding targeted therapy of malignant tumors.
The glial cell line-derived neurotrophic factor (GDNF) belongs to the TFGβ superfamily, and its ligand includes four members. ARTN is the last member of the GDNF family. The primary structure of ARTN is similar to GDNF, NTN, and PSP. It has a full length of 3.9 kb and the encoded protein consists of 220 amino acids. Members of the GDNF family need to bind to their respective high-affinity receptors and then bind to a common signaling molecule, RET. Then, phosphorylation of RET is activated to activate different intracellular pathways that regulate physiological processes such as cell growth, differentiation, proliferation, and migration.
Fig 1. GDNF family of ligands and their receptors. (Kramer, et al. 2015)
The Role of ARTN in the Development of Neural Tissue
ARTN plays different roles in the different stages of differentiation, survival and growth of sympathetic neurons. Studies have observed the effect of ARTN on the passage, survival and growth of the cervical and thoracic paraspinal ganglia in the embryonic and postnatal rats. The study found that ARTN can promote the differentiation of sympathetic neural stem cells and increase the passage of new neurons. ARTN supports the survival of dopaminergic neurons. An in vitro experiment injected NBN/ARTN or GDNF chronic viral vector cDNA into the nigrostriatal and ventral midbrain. After 3 weeks, only 20% of the nigrostria in the control group survived, while NBN/ARTN and GDNF group have 80% to 90% survive. It can be seen that NBN/ARTN is similar to GDNF and is a powerful neuroprotective factor for nigrostriatal dopaminergic neurons. In addition, ARTN is a strong inducer of intestinal hematopoietic cells. The ARTN receptor pathway promotes the formation of Peyre’s Patch, a major component of the gut-associated lymphoid tissue.
ARTN and Cancer
ARTN is an oncogene for breast cancer, and ARTN is expressed in a variety of breast cancer cell lines and breast cancer tissues. As the degree of malignancy increases, ARTN expression increases. Cell experiments confirmed that up-regulation of ARTN expression levels can increase the non-adherent growth of breast cancer cells and increase the number of cell population formation. Moreover, it can promote the formation of tumor cell phenotype and increase the invasion and metastasis of breast cancer tumor cells. ARTN promotes tumor growth by activating Twist1-VEGF-A channel partially mediated VEGF-A to promote neovascularization. Ding et al. found that ARTN mediates the acquired resistance to trastuzumab in HER2-positive breast cancer and reduces the sensitivity of trastuzumab in the treatment of breast cancer.
Liver cancer is one of the top ten malignant tumors in the world. ARTN is highly expressed in hepatocellular carcinoma cell lines. In vitro, ARTN can promote the growth, migration, and inhibition of hepatoma cells. In the mouse tumor formation experiment, the ARTN overexpressing cell line not only formed a larger tumor but also more invasive. In pathological studies, ARTN is associated with prognosis in patients with liver cancer. ARTN is expected to be a target for the diagnosis and treatment of liver cancer, providing new ideas and methods for the treatment of liver cancer. Zhang et al. identified a novel HIF-1α/ARTN axis that promotes CSC (hypoxia-regulated cancer stem cell)-like behavior in an anoxic environment, suggesting that ARTN is a valuable therapeutic target for HCC.
Pancreatic cancer is a highly malignant tumor with a very poor prognosis. Gao et al found that ARTN can promote the aggressiveness and neurotrophic function of pancreatic cancer in vivo and in vitro. Therefore, Artemin can be used as a new therapeutic target for pancreatic cancer. In the study, the expression of ARTN and its receptor GFRα3 /RET in pancreatic ductal adenocarcinoma and normal tissues were analyzed by Western blot. The expression of ARTN mRNA in pancreatic and cancer cell lines was detected by QRT-PCR. The results suggest that ARTN and receptor GFRα3 /RET can be detected in pancreatic cancer tissues and cell lines, and distributed along the nerve and blood vessel walls to promote cancer cell infiltration.
The tumorigenicity of ARTN is also manifested in endometrial cancer. Studies have shown that the expression of ARTN protein in endometrial cancer tissues is significantly higher than that in normal endometrial tissues, which is positively correlated with tumor stage and infiltration. In the allograft model, up-regulation of ARTN expression can increase tumor size, promote tumor invasion, hyperproliferation, and low differentiation. These effects of ARTN are mediated by AKT1, and small interfering RNA (siRNA) can inhibit the tumorigenic effects of ARTN. Wang et al. examined the differential expression of ARTN and matrix metalloproteinase protein 9 (MMP-9) in endometrial carcinoma (EC), indicating that ARTN and MMP-9 are involved in the development, progression, invasion, and metastasis of EC.