ARHGAP9, a Rho GTPase activating protein, inactivates Rho GTPases by hydrolyzing GTP into GDP. It regulates cancer-related cellular events like proliferation, differentiation, apoptosis, migration, and invasion mainly through inhibiting JNK/ERK/p38, PI3K/AKT, and Wnt/β-catenin signaling pathways [1]. Genetic/epigenetic variations and abnormal expression of ARHGAP9 are associated with various diseases, especially cancers, making it a potential target for personalized cancer-targeted drug development [1].

In lung adenocarcinoma, ARHGAP9 knockdown promotes metastasis by activating the Wnt/β-catenin signaling pathway via suppressing DKK2 [2]. In colorectal cancer, over-expression of ARHGAP9 inhibits cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) by blocking the PI3K/AKT/mTOR signaling pathway [3]. In hepatocellular carcinoma, ARHGAP9 overexpression can inhibit cell proliferation, migration, invasion, and lung metastases through up-regulating FOXJ2/E-cadherin [4]. In gastric cancer, ARHGAP9 siRNA inhibits cell viability, migration, invasion, and EMT by inactivating Akt and p38 signaling and inhibiting MMP2 and MMP9 [5]. In bladder cancer, lower expressions of ARHGAP9 correlate with a poor prognosis, indicating its potential as a prognostic biomarker [6]. In breast cancer, knockdown of ARHGAP9 reduces cell proliferation, migration, and invasive ability, and induces cell cycle arrest and apoptosis [7].

In conclusion, ARHGAP9 plays a crucial role in regulating cancer-related cellular processes. Studies on ARHGAP9 in various cancers, such as lung, colorectal, hepatocellular, gastric, bladder, and breast cancers, through functional experiments like knockdown or over-expression, have revealed its potential as a prognostic biomarker and a therapeutic target. Understanding the function of ARHGAP9 in these disease conditions can provide new strategies for cancer treatment.

References:

1. Song, Wenping, Chen, Jinhua, Li, Shuolei, Zhang, Wenzhou, Li, Liang. . Rho GTPase Activating Protein 9 (ARHGAP9) in Human Cancers. In Recent patents on anti-cancer drug discovery, 17, 55-65. doi:10.2174/1574892816666210806155754. https://pubmed.ncbi.nlm.nih.gov/34365932/

2. Song, Wenping, Wu, Xuan, Cheng, Cheng, Chen, Jinhua, Zhang, Wenzhou. 2023. ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2. In Genomics, 115, 110684. doi:10.1016/j.ygeno.2023.110684. https://pubmed.ncbi.nlm.nih.gov/37454937/

3. Sun, Jufeng, Zhao, Xiaoguang, Jiang, Huamao, Ma, Yinda, Qian, Zhiyu. 2022. ARHGAP9 inhibits colorectal cancer cell proliferation, invasion and EMT via targeting PI3K/AKT/mTOR signaling pathway. In Tissue & cell, 77, 101817. doi:10.1016/j.tice.2022.101817. https://pubmed.ncbi.nlm.nih.gov/35679685/

4. Zhang, Hong, Tang, Qing-Feng, Sun, Meng-Yao, Zhang, Li-Jun, Zhang, Hong. 2018. ARHGAP9 suppresses the migration and invasion of hepatocellular carcinoma cells through up-regulating FOXJ2/E-cadherin. In Cell death & disease, 9, 916. doi:10.1038/s41419-018-0976-0. https://pubmed.ncbi.nlm.nih.gov/30206221/

5. Sun, Lingjia, Zhang, Youping, Lou, Jie. 2017. ARHGAP9 siRNA inhibits gastric cancer cell proliferation and EMT via inactivating Akt, p38 signaling and inhibiting MMP2 and MMP9. In International journal of clinical and experimental pathology, 10, 11979-11985. doi:. https://pubmed.ncbi.nlm.nih.gov/31966562/

6. Piao, Xuan-Mei, Jeong, Pildu, Yan, Chunri, Yun, Seok Joong, Kim, Wun-Jae. 2019. A novel tumor suppressing gene, ARHGAP9, is an independent prognostic biomarker for bladder cancer. In Oncology letters, 19, 476-486. doi:10.3892/ol.2019.11123. https://pubmed.ncbi.nlm.nih.gov/31897161/

7. Wang, Tianyi, Ha, Minwen. 2018. Silencing ARHGAP9 correlates with the risk of breast cancer and inhibits the proliferation, migration, and invasion of breast cancer. In Journal of cellular biochemistry, 119, 7747-7756. doi:10.1002/jcb.27127. https://pubmed.ncbi.nlm.nih.gov/29905031/