Phlda3, encoding a 127-amino-acid protein with a pleckstrin homology (PH)-only domain, is a significant gene involved in multiple biological processes. It is closely associated with the PI3K/AKT, p53, and Wnt/β-catenin pathways. Phlda3 functions as a tumor suppressor in many cancers, regulating cell survival, proliferation, and invasion. Genetic models are valuable for studying its functions [1-10].

In pancreatic neuroendocrine tumors (PanNETs), loss-of-heterozygosity and methylation at the Phlda3 locus are frequent, inactivating the gene. PHLDA3-deficient mice show abnormal pancreatic islet cell proliferation and apoptosis resistance, indicating its role in PanNET tumorigenesis [1,4]. In squamous cell carcinomas (SCCs), loss of Phlda3 can complement p53 loss in metastatic tumor formation, and low Phlda3 expression in human patients is associated with a poorer prognosis [3]. In lung adenocarcinoma, Phlda3 promotes cell proliferation and invasion via the Wnt signaling pathway [2]. In esophageal squamous cell carcinoma, BARX2 transcriptionally activates Phlda3, which suppresses cancer development by down-regulating PI3K/AKT levels [5]. In prostate cancer, up-regulation of Phlda3 restrains cell proliferation, induces cell cycle arrest, and suppresses epithelial-mesenchymal transition by inhibiting Akt and the Wnt/β-catenin pathway [6]. In zebrafish, overexpression of phlda3 impairs hemangioblast specification and vascular development via the AKT signaling pathway [7].

In summary, Phlda3 is a crucial regulator in multiple biological processes, especially in cancer development. Gene knockout and other functional studies in mouse models and other organisms have revealed its roles in various disease areas, such as different types of cancers and vascular development. Understanding Phlda3 helps in elucidating disease mechanisms and may provide potential therapeutic targets.

References:

1. Chen, Yu, Ohki, Rieko. 2020. p53-PHLDA3-Akt Network: The Key Regulators of Neuroendocrine Tumorigenesis. In International journal of molecular sciences, 21, . doi:10.3390/ijms21114098. https://pubmed.ncbi.nlm.nih.gov/32521808/

2. Lei, Lei, Wang, Yuan, Li, Zhi-Han, Zou, Zi-Fang, Xu, Hong-Tao. 2021. PHLDA3 promotes lung adenocarcinoma cell proliferation and invasion via activation of the Wnt signaling pathway. In Laboratory investigation; a journal of technical methods and pathology, 101, 1130-1141. doi:10.1038/s41374-021-00608-3. https://pubmed.ncbi.nlm.nih.gov/34006890/

3. Saito, Megumi, Sada, Akane, Fukuyo, Masaki, Wakabayashi, Yuichi, Ohki, Rieko. 2021. PHLDA3 Is an Important Downstream Mediator of p53 in Squamous Cell Carcinogenesis. In The Journal of investigative dermatology, 142, 1040-1049.e8. doi:10.1016/j.jid.2021.09.007. https://pubmed.ncbi.nlm.nih.gov/34592332/

4. Takikawa, Masahiro, Ohki, Rieko. 2017. A vicious partnership between AKT and PHLDA3 to facilitate neuroendocrine tumors. In Cancer science, 108, 1101-1108. doi:10.1111/cas.13235. https://pubmed.ncbi.nlm.nih.gov/28295876/

5. Chen, Shaogeng, Lin, Xianzuan, He, Rongqi, Kang, Mingqiang, Xu, Rongyu. 2023. PHLDA3 activated by BARX2 transcription, suppresses the malignant development of esophageal squamous cell carcinoma by downregulating PI3K/AKT levels. In Experimental cell research, 426, 113567. doi:10.1016/j.yexcr.2023.113567. https://pubmed.ncbi.nlm.nih.gov/36965748/

6. Ma, Shuaijun, Quan, Penghe, Yu, Changjiang, Qin, Weijun, Yang, Xiaojian. 2021. PHLDA3 exerts an antitumor function in prostate cancer by down-regulating Wnt/β-catenin pathway via inhibition of Akt. In Biochemical and biophysical research communications, 571, 66-73. doi:10.1016/j.bbrc.2021.07.038. https://pubmed.ncbi.nlm.nih.gov/34303965/

7. Wang, Xiaojing, Li, Jia, Yang, Zhongcheng, Chen, Qiuyun, Wang, Qing K. 2018. phlda3 overexpression impairs specification of hemangioblasts and vascular development. In The FEBS journal, 285, 4071-4081. doi:10.1111/febs.14653. https://pubmed.ncbi.nlm.nih.gov/30188605/