Rnase4, a member of the pancreatic RNase superfamily, shares identical 5'-untranslated regions with angiogenin, suggesting co-regulation [3]. It has been implicated in multiple biological functions and disease-related processes. Its functions may involve host-defence mechanisms, and it is associated with pathways relevant to inflammation, tumorigenesis, and neurodegeneration.

In intestinal research, Rnase4-deficient mice experiments showed that Rnase4 kills Parasutterella, modulating the intestinal microbiome. This enhances indoleamine-2,3-dioxygenase 1 (IDO1) expression and the production of kynurenic and xanthurenic acid in intestinal epithelial cells, reducing colitis susceptibility. Decreased RNASE4 levels in IBD patients' intestinal tissues and stool correlate with increased stool Parasutterella, indicating its potential as a diagnostic biomarker and therapeutic target for IBD [1].

In glioblastoma, RNASE4 upregulation is associated with advanced pathological stages and poor survival. Functional assays in vitro and in vivo showed that it promotes cell proliferation, migration, invasion, stemness, and temozolomide resistance via activation of AXL/AKT and NF-κB/cIAPs signaling pathways [2].

In prostate cancer, plasma RNASE4 level is elevated, positively correlated with disease stage, grade, and Gleason score. An RNASE4-specific monoclonal antibody inhibits xenograft tumor growth in athymic mice, suggesting it as a biomarker and therapeutic target [4].

In conclusion, Rnase4 plays essential roles in maintaining gut microbiota and metabolite homeostasis, and is involved in the progression of glioblastoma and prostate cancer. Gene-knockout mouse models have been crucial in revealing these functions, providing insights into its potential as a biomarker and therapeutic target for related diseases.

References:

1. Sun, Jun, Chen, Muxiong, Hu, Zhen, Xu, Zhengping, Sheng, Jinghao. 2024. Ribonuclease 4 functions as an intestinal antimicrobial protein to maintain gut microbiota and metabolite homeostasis. In Nature communications, 15, 5778. doi:10.1038/s41467-024-50223-1. https://pubmed.ncbi.nlm.nih.gov/38987259/

2. Lee, Hsun-Hua, Chuang, Hao-Yu, Lin, Kent, Chi, Hsiang-Cheng, Lin, Kwang-Huei. 2024. RNASE4 promotes malignant progression and chemoresistance in hypoxic glioblastoma via activation of AXL/AKT and NF-κB/cIAPs signaling pathways. In American journal of cancer research, 14, 4320-4336. doi:10.62347/UDBJ5986. https://pubmed.ncbi.nlm.nih.gov/39417186/

3. Strydom, D J. . The angiogenins. In Cellular and molecular life sciences : CMLS, 54, 811-24. doi:. https://pubmed.ncbi.nlm.nih.gov/9760990/

4. Vanli, Nil, Sheng, Jinghao, Li, Shuping, Xu, Zhengping, Hu, Guo-Fu. 2022. Ribonuclease 4 is associated with aggressiveness and progression of prostate cancer. In Communications biology, 5, 625. doi:10.1038/s42003-022-03597-1. https://pubmed.ncbi.nlm.nih.gov/35752711/