Nid2, also known as Nidogen-2, is a ubiquitous component in the basement membrane. It plays crucial roles in multiple biological processes. It is involved in maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs) via the Jagged1-Notch3 signaling pathway, which is essential for vascular homeostasis [9]. It also serves as an endogenous ligand of LGR4, biasing the activation of Gαq-PKCα-AMPKα1 signaling to inhibit vascular calcification [3].

In disease-related studies, Nid2 has diverse impacts. In lung cancer, DNA hypermethylation of NID2 reduces its expression level, promoting cancer development. After NID2 demethylation or overexpression in cancer cells, cell viability, proliferation, migration, and invasion ability decrease, and the apoptosis rate increases. Overexpressing NID2 or demethylation in lung cancer cells inhibits tumorigenesis in nude mice [1]. In gastric cancer, NID2 is over-expressed, positively associated with TNM stage, and promotes the invasion and migration of cancer cells. Bioinformatics prediction shows it might regulate the progression of gastric cancer via protein digestion and absorption, amoebiasis, PI3K-AKt-signaling pathway, focal adhesion, and ECM-receptor interaction pathways [2]. In pancreatic cancer, reducing NID2 in cancer-associated fibroblasts (CAFs) by CRISPR interference reduces stiffness and matrix remodeling, impairs cancer cell invasion, improves vascular patency, and enhances response to gemcitabine/Abraxane [4]. In melanoma, NID2 is a key factor in collagen, involved in fibroblast activation, and forms a barrier to limit the proximity of CD8+ T cells to tumor cells, leading to a poor response to immunotherapy [5]. In oral squamous cell carcinoma (OSCC), specific methylation at cg22881914 of NID2 could be a potential marker for detection [6]. Also, NID2 promoter hypermethylation can be used as a biomarker for prevention and early detection in OSCC tissues and saliva [8]. In glioma, certain single-nucleotide polymorphisms (SNPs) of NID2 are associated with an increased risk of glioma and poor prognosis in Chinese patients [7].

In conclusion, Nid2 is essential for maintaining normal physiological functions in the body, especially in vascular-related processes. Through gene-knockout or other loss-of-function models, its roles in promoting or inhibiting tumor development in various cancers, as well as its potential as a biomarker in cancer diagnosis, have been revealed. These findings provide important insights into understanding disease mechanisms and developing new therapeutic strategies.

References:

1. Wang, Jianfeng, Zhao, Yan, Xu, Hongyan, Zou, Qingxu, Lin, Fengwu. 2019. Silencing NID2 by DNA Hypermethylation Promotes Lung Cancer. In Pathology oncology research : POR, 26, 801-811. doi:10.1007/s12253-019-00609-0. https://pubmed.ncbi.nlm.nih.gov/30826972/

2. Yu, Zhi-Hao, Wang, Yue-Mei, Jiang, Yu-Zhang, Wan, Yi-Yuan, Wang, Xiao-Wei. 2019. NID2 can serve as a potential prognosis prediction biomarker and promotes the invasion and migration of gastric cancer. In Pathology, research and practice, 215, 152553. doi:10.1016/j.prp.2019.152553. https://pubmed.ncbi.nlm.nih.gov/31362888/

3. Chen, Yufei, Mao, Chenfeng, Gu, Rui, Sun, Jinpeng, Kong, Wei. 2022. Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification. In Circulation research, 131, 1037-1054. doi:10.1161/CIRCRESAHA.122.321614. https://pubmed.ncbi.nlm.nih.gov/36354004/

4. Pereira, Brooke A, Ritchie, Shona, Chambers, Cecilia R, Cox, Thomas R, Timpson, Paul. 2024. Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response. In Science advances, 10, eadl1197. doi:10.1126/sciadv.adl1197. https://pubmed.ncbi.nlm.nih.gov/38959305/

5. Sha, Yan, Mao, An-Qi, Liu, Yuan-Jie, Wu, Mu-Yao, Shen, Hui. 2023. Nidogen-2 (NID2) is a Key Factor in Collagen Causing Poor Response to Immunotherapy in Melanoma. In Pharmacogenomics and personalized medicine, 16, 153-172. doi:10.2147/PGPM.S399886. https://pubmed.ncbi.nlm.nih.gov/36908806/

6. Srisuttee, Ratakorn, Arayataweegool, Areeya, Mahattanasakul, Patnarin, Mutirangura, Apiwat, Kitkumthorn, Nakarin. 2020. Evaluation of NID2 promoter methylation for screening of Oral squamous cell carcinoma. In BMC cancer, 20, 218. doi:10.1186/s12885-020-6692-z. https://pubmed.ncbi.nlm.nih.gov/32171289/

7. Hao, Jie, Huang, Congmei, Zhao, Weiwei, Jin, Tianbo, Hu, Mingjun. 2024. Association of NID2 SNPs with Glioma Risk and Prognosis in the Chinese Population. In Neuromolecular medicine, 26, 27. doi:10.1007/s12017-024-08795-0. https://pubmed.ncbi.nlm.nih.gov/38935278/

8. Guerrero-Preston, R, Soudry, E, Acero, J, Califano, J, Sidransky, D. 2011. NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva. In Cancer prevention research (Philadelphia, Pa.), 4, 1061-72. doi:10.1158/1940-6207.CAPR-11-0006. https://pubmed.ncbi.nlm.nih.gov/21558411/

9. Mao, Chenfeng, Ma, Zihan, Jia, Yiting, Fu, Yi, Kong, Wei. 2021. Nidogen-2 Maintains the Contractile Phenotype of Vascular Smooth Muscle Cells and Prevents Neointima Formation via Bridging Jagged1-Notch3 Signaling. In Circulation, 144, 1244-1261. doi:10.1161/CIRCULATIONAHA.120.053361. https://pubmed.ncbi.nlm.nih.gov/34315224/