Plek2, also known as pleckstrin-2, is a cytoskeleton-associated protein mainly involved in cytoskeletal protein recombination and cell stretch migration regulation [6]. It is closely related to the epithelial-mesenchymal transition (EMT) process, which is crucial in cancer metastasis. Plek2 has been implicated in multiple signaling pathways such as EGFR/CCL2, PI3K/AKT, and is associated with the development of various cancers [1,2,3].

In gallbladder cancer (GBC), knockdown of Plek2 in mouse models suppressed GBC cells migration, invasion and liver metastasis, indicating its role in promoting GBC invasion and metastasis via the EGFR/CCL2 pathway [1]. In osteosarcoma (OS), Plek2 knockdown significantly suppressed OS growth in vivo, and in vitro experiments showed it promoted OS cell proliferation and invasion through the activation of the PI3K/AKT signaling pathway [2]. Similar findings were observed in lung adenocarcinoma (LUAD), where Plek2-silenced LUAD cells had impaired tumor growth in mice, and Plek2 knockdown led to suppressed cell proliferation and migration [3]. In head and neck squamous cell carcinoma (HNSCC), Plek2 was important for maintaining the malignant behaviors of HNSCC cells both in vitro and in vivo [4]. In non-small cell lung cancer (NSCLC), Plek2 promoted cell proliferation and migration, and bromodomain containing protein 4 (BRD4) was found to regulate the transcription of Plek2 gene [5]. In nicotine-induced lung adenocarcinoma, α5-nicotinic acetylcholine receptor (α5-nAChR) mediated nicotine-induced Plek2 expression, and α5-nAChR/PLEK2 signaling was involved in LUAD cell migration, invasion and stemness, which was confirmed in mouse xenograft tissues [6]. In uveal melanoma (UVM), Plek2 was upregulated and correlated with poor patient prognosis, likely influencing the calcium signaling pathway [7]. In pancreatic ductal adenocarcinoma (PDAC), Plek2 knockdown suppressed tumor growth in a xenograft tumor model, and Plek2 promoted PDAC cell migration and invasion potentially through the activation of the EMT process [8].

In conclusion, Plek2 plays a tumor-promoting role in multiple cancers, including GBC, OS, LUAD, HNSCC, NSCLC, nicotine-induced LUAD, UVM, and PDAC. Gene knockout or knockdown in mouse models has been crucial in revealing its role in cancer cell proliferation, migration, invasion, and metastasis, providing potential therapeutic targets for these diseases.