Klhdc8a, the Kelch domain containing 8A gene, has emerged as a significant player in cancer-related processes. It is involved in pathways such as hedgehog signaling and has a role in ciliogenesis, which are crucial for cell growth, development, and differentiation [1]. In addition, its association with macrophage infiltration and oxidative stress indicates its importance in the tumor microenvironment [2].

In glioma, targeting Klhdc8a decreased glioblastoma stem cell (GSC) proliferation, self-renewal, induced apoptosis, and impaired in vivo tumor growth [1]. Knockdown of Klhdc8a in glioma cell lines led to reduced cell proliferation and colony formation, associated with down-regulation of key proteins in the Wnt/β-catenin pathway [4]. In papillary thyroid cancer, Klhdc8a knockdown hindered cell viability, invasion, and migration, inhibited M2 macrophage polarization while promoting M1 polarization, and suppressed tumor growth in xenograft models [3]. In normal ovarian epithelial cells, Klhdc8a knockdown promoted the polarization of pro-tumoral macrophages via the C5a/C5aR/p65 NFκB signaling pathway [5].

In conclusion, Klhdc8a plays a vital role in cancer development, influencing cell proliferation, macrophage polarization, and tumor growth. Loss-of-function experiments in cell lines and animal models, though not specifically KO/CKO mouse models in the provided references, have been crucial in revealing its functions in glioma, papillary thyroid cancer, and ovarian cancer-related processes, highlighting its potential as a therapeutic target in these diseases.

References:

1. Lee, Derrick, Gimple, Ryan C, Wu, Xujia, Raleigh, David R, Rich, Jeremy N. 2023. Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling. In The Journal of clinical investigation, 133, . doi:10.1172/JCI163592. https://pubmed.ncbi.nlm.nih.gov/36394953/

2. Cheng, Tong, Xu, Manyu, Zhang, Hui, Wang, Ziheng, Huang, Jianfei. 2022. KLHDC8A Expression in Association with Macrophage Infiltration and Oxidative Stress Predicts Unfavorable Prognosis for Glioma. In Oxidative medicine and cellular longevity, 2022, 2694377. doi:10.1155/2022/2694377. https://pubmed.ncbi.nlm.nih.gov/36199422/

3. Peng, Yun, Wen, Meiling, Yu, Jianping, He, Chun, Yu, Jichun. . KLHDC8A Regulates M1/M2 Macrophage Polarization Through the PD-1/STAT3 Pathway to Promote Papillary Thyroid Cancer Development. In Discovery medicine, 36, 1858-1868. doi:10.24976/Discov.Med.202436188.172. https://pubmed.ncbi.nlm.nih.gov/39327249/

4. Tian, Yu, Hu, Xiaofei, Wang, Xiaoling, Zhu, Chao, Tu, Yanyang. 2024. Evaluating KLHDC8A as a biomarker for glioma: impact on survival and proliferation through the Wnt/β-catenin pathway. In Discover oncology, 15, 732. doi:10.1007/s12672-024-01625-6. https://pubmed.ncbi.nlm.nih.gov/39614999/

5. Fang, Jie, Wang, Jin, Zhao, Xinyue, Yang, Yaping, Xiao, Yujia. 2024. KLHDC8A knockdown in normal ovarian epithelial cells promoted the polarization of pro-tumoral macrophages via the C5a/C5aR/p65 NFκB signaling pathway. In Cellular immunology, 409-410, 104913. doi:10.1016/j.cellimm.2024.104913. https://pubmed.ncbi.nlm.nih.gov/39805213/