Tspan9, also known as NET-5 and PP1057, is a member of the tetraspanin family of four-transmembrane proteins. Tetraspanins are involved in regulating the trafficking, lateral diffusion and clustering of transmembrane proteins they interact with. Tspan9 is associated with pathways such as integrin-mediated downstream FAK/Ras/ERK1/2 signaling, PI3K/AKT/mTOR-mediated autophagy, and may play a role in cell adhesion, migration, and metastasis [1,2].

In osteosarcoma, knockdown of Tspan9 suppressed the migration, invasion, and epithelial-mesenchymal transition (EMT) activity in OS cells, while overexpression had opposite effects. Mice implanted with HOS cells in which Tspan9 was downregulated had significantly impaired tumor lung metastasis, suggesting Tspan9 promotes osteosarcoma metastasis via the FAK-Ras-ERK1/2 pathway [1].

In gastric cancer, TSPAN9 overexpression in 5-FU-resistant cells compared to parental cells was found. Increasing TSPAN9 expression restored 5-FU-mediated inhibition of cell proliferation, and inhibiting it in drug-resistant cells restored their sensitivity to 5-FU. TSPAN9 also promoted autophagy in gastric cancer cells, downregulated PI3K and related proteins, and interacted with PI3K to inhibit its catalytic activity [2]. In contrast, overexpression of Tspan9 in human gastric cancer SGC7901 cells inhibited their proliferation, migration and invasion through downregulating the phosphorylation of ERK1/2 and the secretion levels of metastasis-related proteins [5].

In hepatocellular carcinoma, TSPAN9 was downregulated in tissues and its downregulation was associated with poor prognosis, immune-related signaling pathway, and tumor immune infiltration [4].

In conclusion, Tspan9 plays diverse roles in different cancers. Its functions in promoting metastasis in osteosarcoma, affecting chemosensitivity and autophagy in gastric cancer, and its association with prognosis in hepatocellular carcinoma highlight its significance in cancer research. Gene-targeted mouse models, such as Tspan9-deficient mice in platelet studies [3], can further help in understanding its in-vivo functions, potentially providing new therapeutic targets for these diseases.

References:

1. Shao, Shijie, Piao, Lianhua, Wang, Jiangsong, Zhu, Junke, Wang, Yimin. 2022. Tspan9 Induces EMT and Promotes Osteosarcoma Metastasis via Activating FAK-Ras-ERK1/2 Pathway. In Frontiers in oncology, 12, 774988. doi:10.3389/fonc.2022.774988. https://pubmed.ncbi.nlm.nih.gov/35280793/

2. Qi, Yaoyue, Qi, Weiwei, Liu, Shihai, Qiu, Wensheng, Lv, Jing. 2020. TSPAN9 suppresses the chemosensitivity of gastric cancer to 5-fluorouracil by promoting autophagy. In Cancer cell international, 20, 4. doi:10.1186/s12935-019-1089-2. https://pubmed.ncbi.nlm.nih.gov/31911756/

3. Haining, Elizabeth J, Matthews, Alexandra L, Noy, Peter J, Watson, Steve P, Tomlinson, Michael G. 2016. Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation. In Platelets, 28, 629-642. doi:10.1080/09537104.2016.1254175. https://pubmed.ncbi.nlm.nih.gov/28032533/

4. Tan, Shengkui, Song, Xin, Zhang, Chenchen, Zhu, Xiaonian, Tan, Hongzhuan. 2022. hsa-miR-9-5p-Mediated TSPAN9 Downregulation Is Positively Related to Both Poor Hepatocellular Carcinoma Prognosis and the Tumor Immune Infiltration. In Journal of immunology research, 2022, 9051229. doi:10.1155/2022/9051229. https://pubmed.ncbi.nlm.nih.gov/35600044/

5. Li, Pai-Yun, Lv, Jing, Qi, Wei-Wei, Sheng, Jie, Qiu, Wen-Sheng. 2016. Tspan9 inhibits the proliferation, migration and invasion of human gastric cancer SGC7901 cells via the ERK1/2 pathway. In Oncology reports, 36, 448-54. doi:10.3892/or.2016.4805. https://pubmed.ncbi.nlm.nih.gov/27177197/