Btnl9, or butyrophilin-like protein 9, is a member of the immunoglobulin families. It is involved in immune-related and cancer-related pathways, playing an important role in biological processes [1]. Its function can be further explored through genetic models like gene knockout (KO) or conditional knockout (CKO) mouse models.

In multiple cancers, research has revealed significant roles of Btnl9. In thyroid cancer, its expression was down-regulated in tumor samples compared to normal tissues, associated with tumor stages, immune cell infiltrations, and prognosis. Lower Btnl9 expression was linked to a poorer progression-free interval [1]. In breast cancer, Btnl9 expression was declined, and its low expression was related to early T-stage progression, relapse-free survival, and overall survival. Ectopic expression of Btnl9 inhibited cell proliferation, colony formation, and metastasis, and induced apoptosis, blocking cells in the G2/M phase via the P53/CDC25C and P53/GADD45 pathways [2]. In non-small-cell lung cancer, lncRNA CALML3-AS1 was found to inhibit Btnl9 transcription and expression through the recruitment of EZH2, driving cancer progression [3]. In uveal melanoma, Btnl9 mRNA was lower in tumor tissues, and high expression was associated with a favorable prognosis, and it could suppress invasion [4]. In lung adenocarcinoma, Btnl9 expression was downregulated and associated with poor overall survival, and was positively correlated with immune cell infiltration levels [5]. In pancreatic cancer, decreased expression of Btnl9 was associated with a reduced survival rate [6]. In BRAF-mutated peritoneal metastasis from colorectal cancer, increased expression of Btnl9 was observed [7]. In addition, in a Mendelian randomization study of plasma proteomics for amyotrophic lateral sclerosis (ALS), Btnl9 showed a negative correlation with ALS risk [8]. Also, in breast cancer, the expression pattern of Btnl9 as an immune checkpoint gene was investigated among others [9].

In conclusion, Btnl9 is involved in immune-related and cancer-related pathways, and its dysregulation is associated with various cancers and other diseases like ALS. The findings from different disease-based research, though not from KO/CKO mouse models in these references, show its potential as a prognostic biomarker and therapeutic target in cancer, and its significance in understanding disease mechanisms in multiple disease areas.

References:

1. Zhang, Luyao, Yu, Shuang, Hong, Shubin, Li, Yanbing, Xiao, Haipeng. 2023. Comprehensive analysis of BTNL9 as a prognostic biomarker correlated with immune infiltrations in thyroid cancer. In BMC medical genomics, 16, 234. doi:10.1186/s12920-023-01676-8. https://pubmed.ncbi.nlm.nih.gov/37798795/

2. Mo, Qingfan, Xu, Ke, Luo, Chenghao, Wang, Long, Ren, Guosheng. 2021. BTNL9 is frequently downregulated and inhibits proliferation and metastasis via the P53/CDC25C and P53/GADD45 pathways in breast cancer. In Biochemical and biophysical research communications, 553, 17-24. doi:10.1016/j.bbrc.2021.03.022. https://pubmed.ncbi.nlm.nih.gov/33756341/

3. Zhang, Heng, Wang, Shao-Qiang, Zhu, Jie-Bo, Duan, Chao-Jun, Zhang, Chun-Fang. 2023. LncRNA CALML3-AS1 modulated by m6A modification induces BTNL9 methylation to drive non-small-cell lung cancer progression. In Cancer gene therapy, 30, 1649-1662. doi:10.1038/s41417-023-00670-7. https://pubmed.ncbi.nlm.nih.gov/37884580/

4. Jiang, Zhongming, Liu, Fei. 2019. Butyrophilin-Like 9 (BTNL9) Suppresses Invasion and Correlates with Favorable Prognosis of Uveal Melanoma. In Medical science monitor : international medical journal of experimental and clinical research, 25, 3190-3198. doi:10.12659/MSM.914074. https://pubmed.ncbi.nlm.nih.gov/31039142/

5. Ma, Weishuang, Liang, Jiaming, Mo, Junjian, Tian, Dongbo, Chen, Zisheng. 2021. Butyrophilin-like 9 expression is associated with outcome in lung adenocarcinoma. In BMC cancer, 21, 1096. doi:10.1186/s12885-021-08790-9. https://pubmed.ncbi.nlm.nih.gov/34635082/

6. Khojasteh-Leylakoohi, Fatemeh, Mohit, Reza, Khalili-Tanha, Nima, Batra, Jyotsna, Avan, Amir. 2023. Down regulation of Cathepsin W is associated with poor prognosis in pancreatic cancer. In Scientific reports, 13, 16678. doi:10.1038/s41598-023-42928-y. https://pubmed.ncbi.nlm.nih.gov/37794108/

7. Lund-Andersen, Christin, Torgunrud, Annette, Kanduri, Chakravarthi, Larsen, Stein G, Flatmark, Kjersti. 2024. Novel drug resistance mechanisms and drug targets in BRAF-mutated peritoneal metastasis from colorectal cancer. In Journal of translational medicine, 22, 646. doi:10.1186/s12967-024-05467-2. https://pubmed.ncbi.nlm.nih.gov/38982444/

8. Lu, Chuan, Huang, Xiao-Xiao, Huang, Ming, Liu, Chaoning, Xu, Jianwen. 2025. Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses. In BMC neurology, 25, 82. doi:10.1186/s12883-025-04091-x. https://pubmed.ncbi.nlm.nih.gov/40033250/

9. Fang, Jun, Chen, Feng, Liu, Dong, Chen, Zhigang, Wang, Yuezhen. . Prognostic value of immune checkpoint molecules in breast cancer. In Bioscience reports, 40, . doi:10.1042/BSR20201054. https://pubmed.ncbi.nlm.nih.gov/32602545/