Slc17a9, also known as VNUT (vesicular nucleotide transporter), is a transmembrane protein encoding a vesicular ATP transport protein [5,8]. It is involved in determining cell functions, playing a role in various biological processes, such as lysosomal function and cell viability by regulating Cathepsin D activity [5]. It also participates in pathways related to cancer progression, like the PI3K/Akt signaling pathway [7].

In cancer research, loss-of-function experiments have shown its significance. In clear cell renal cell carcinoma (ccRCC), SLC17A9 knockdown inhibited the proliferation, migration, and invasion of renal cancer cells. Mechanistically, it upregulates PTHLH to promote epithelial-mesenchymal transition (EMT) [1]. In HCC, HHEX-mediated ABI2 upregulates SLC17A9 to promote cancer stem cell-like properties and tumorigenesis [2]. In non-small cell lung cancer, SLC17A9 knockdown significantly inhibited cell proliferation and ATP levels in lung cancer cells [3]. In gastric carcinoma, high SLC17A9 expression was associated with poor survival [4]. In hepatocellular carcinoma, its high expression was related to poor prognosis [6,7]. In colorectal cancer, SLC17A9 overexpression was correlated with advanced stages and poor survival, and was an independent prognostic predictor [10]. In osteoblasts, knockdown of Slc17a9 in MC3T3-E1 cells increased osteoblast differentiation after compressive force [8]. In the context of pressure overload-induced cardiac inflammation and hypertrophy, depletion of ATP release from sympathetic efferent nerves by disrupting SLC17A9 inhibited NLRP3 inflammasome activation, IL-1β production, and adaptive cardiac hypertrophy [9].

In conclusion, Slc17a9 is crucial for multiple biological functions, especially in maintaining cell viability and lysosomal function. Its role in various cancers, including ccRCC, HCC, NSCLC, gastric, and colorectal cancer, as well as in osteoblast differentiation and cardiac inflammation and hypertrophy, has been revealed through model-based research. These findings from gene knockout or knockdown models contribute to understanding the mechanisms of these diseases and may provide potential targets for treatment.

References:

1. Li, Weiquan, Xu, Ning, Meng, Xiangui, Xiao, Wen, Zhang, Xiaoping. 2022. SLC17A9-PTHLH-EMT axis promotes proliferation and invasion of clear renal cell carcinoma. In iScience, 26, 105764. doi:10.1016/j.isci.2022.105764. https://pubmed.ncbi.nlm.nih.gov/36590170/

2. Li, Huizi, Liu, Jin, Lai, Jie, Zhang, Tong, Gu, Qiuping. 2024. The HHEX-ABI2/SLC17A9 axis induces cancer stem cell-like properties and tumorigenesis in HCC. In Journal of translational medicine, 22, 537. doi:10.1186/s12967-024-05324-2. https://pubmed.ncbi.nlm.nih.gov/38844969/

3. Gao, Yan, Chen, Yijia, Liu, Min, Ke, Changbin, Pei, Zhijun. 2023. SLC17A9 as a prognostic biomarker correlated with immune infiltrates in human non-small cell lung cancer. In American journal of cancer research, 13, 3963-3982. doi:. https://pubmed.ncbi.nlm.nih.gov/37818081/

4. Li, Junqing, Su, Taiqiang, Yang, Liang, Zhang, Changhua, He, Yulong. 2019. High SLC17A9 expression correlates with poor survival in gastric carcinoma. In Future oncology (London, England), 15, 4155-4166. doi:10.2217/fon-2019-0283. https://pubmed.ncbi.nlm.nih.gov/31799885/

5. Huang, Peng, Cao, Qi, Xu, Mengnan, Dong, Xian-Ping. 2022. Lysosomal ATP Transporter SLC17A9 Controls Cell Viability via Regulating Cathepsin D. In Cells, 11, . doi:10.3390/cells11050887. https://pubmed.ncbi.nlm.nih.gov/35269509/

6. Wu, Jingdong, Yang, Yongfei, Song, Jiansheng. 2020. Expression of SLC17A9 in hepatocellular carcinoma and its clinical significance. In Oncology letters, 20, 182. doi:10.3892/ol.2020.12043. https://pubmed.ncbi.nlm.nih.gov/32934749/

7. Kui, Xue-Yan, Gao, Yan, Liu, Xu-Sheng, Zhang, Yao-Hua, Pei, Zhi-Jun. 2022. Comprehensive Analysis of SLC17A9 and Its Prognostic Value in Hepatocellular Carcinoma. In Frontiers in oncology, 12, 809847. doi:10.3389/fonc.2022.809847. https://pubmed.ncbi.nlm.nih.gov/35957868/

8. Inoue, Asako, Nakao-Kuroishi, Kayoko, Kometani-Gunjigake, Kaori, Kokabu, Shoichiro, Kawamoto, Tatsuo. 2020. VNUT/SLC17A9, a vesicular nucleotide transporter, regulates osteoblast differentiation. In FEBS open bio, 10, 1612-1623. doi:10.1002/2211-5463.12918. https://pubmed.ncbi.nlm.nih.gov/32592329/

9. Higashikuni, Yasutomi, Liu, Wenhao, Numata, Genri, Komuro, Issei, Sata, Masataka. 2022. NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload. In Circulation, 147, 338-355. doi:10.1161/CIRCULATIONAHA.122.060860. https://pubmed.ncbi.nlm.nih.gov/36440584/

10. Yang, Liang, Chen, Zhihui, Xiong, Weixin, Song, Xinming, Liu, Jia. 2018. High expression of SLC17A9 correlates with poor prognosis in colorectal cancer. In Human pathology, 84, 62-70. doi:10.1016/j.humpath.2018.09.002. https://pubmed.ncbi.nlm.nih.gov/30236596/