PLAU, also known as plasminogen activator urokinase, is a selected serine protease that converts plasminogen to plasmin. This conversion is involved in various physiological and pathological processes, such as the proteolytic degradation of the extracellular matrix (ECM) [8]. It has been implicated in multiple signaling pathways including NF-κB, STAT3, and PI3K-Akt, which are crucial for cell proliferation, migration, and invasion, thus playing an important role in tumor development [3,4,8]. Genetic models like gene knockout (KO) or conditional knockout (CKO) mouse models could potentially be used to further study its functions.

In multiple cancer types, PLAU shows significant overexpression. In bladder urothelial carcinoma (BLCA), high PLAU expression is associated with poor prognosis, abundant methylated sites, and positive correlation with neutrophil infiltration. Knockdown of PLAU in bladder cancer cell lines inhibits invasive, proliferative, and aggressive phenotypes [1]. In lung squamous carcinoma, PLAU promotes cell proliferation and migration, and its expression is transcriptionally negatively regulated by GATA6 [2]. In cholangiocarcinoma, high PLAU expression is linked to poor patient survival, and PLAU knockdown suppresses cell proliferation, migration, and enhances apoptosis, with the activation of NF-κB signaling being required for its malignant effects [3]. In head and neck cancer, PLAU promotes cell proliferation and migration via the STAT3 signaling pathway, and its elevated expression is associated with lower overall and disease-free survival [4]. In cervical cancer, PLAU knockdown significantly suppresses cell migration and invasion, and the transcription factor YinYang 1 (YY1) regulates its mRNA expression [5]. In ARID1A-depleted non-small cell lung cancer, PLAU promotes growth and attenuates cisplatin chemosensitivity through interaction with TM4SF1 [6]. In head and neck squamous cell carcinoma (HNSCC), PLAU promotes cell proliferation and epithelial-mesenchymal transition (EMT), and its inhibition suppresses tumor growth in vivo [7]. Also in HNSCC, PLAU is an independent prognostic biomarker, and its expression is associated with HPV positivity, neck node status, and immune cell proportions [8]. In differentiated thyroid carcinoma, PLAU is an independent risk factor for recurrence, and its methylation levels are associated with clinicopathological features [9]. In HNSCC, PLAU is associated with a poor prognosis and is positively correlated with LAMC2 expression [10].

In conclusion, PLAU plays a significant role in promoting tumor cell proliferation, migration, invasion, and in some cases, is associated with poor prognosis across multiple cancer types. The use of KO or CKO mouse models, as suggested, could potentially further elucidate its functions in these disease conditions, providing more insights into cancer development mechanisms and potential therapeutic targets.

References:

1. Shi, Ke, Zhou, Jianda, Li, Man, Zhang, Xiulan, Jiang, Li. 2023. Pan-cancer analysis of PLAU indicates its potential prognostic value and correlation with neutrophil infiltration in BLCA. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 166965. doi:10.1016/j.bbadis.2023.166965. https://pubmed.ncbi.nlm.nih.gov/38000776/

2. Guo, Jiankun, Wang, Hailong, Huang, Changhua, Luo, Shiwen, Chen, Limin. 2024. PLAU, transcriptionally negatively regulated by GATA6, promotes lung squamous carcinoma cell proliferation and migration. In Biochimica et biophysica acta. Molecular cell research, 1871, 119744. doi:10.1016/j.bbamcr.2024.119744. https://pubmed.ncbi.nlm.nih.gov/38702016/

3. Hu, Mei-Di, Jia, Ling-Hua, Wang, Ming-Long. 2023. PLAU contributes to the development of cholangiocarcinoma via activating NF-κB signaling pathway. In Cell biology international, 47, 1381-1391. doi:10.1002/cbin.12025. https://pubmed.ncbi.nlm.nih.gov/37067236/

4. Cui, Xiaobo, Sun, Hongyang, Liu, Xiaoqing, Zhang, Shu, Li, Xin. 2024. PLAU promotes cell proliferation and migration of head and neck cancer via STAT3 signaling pathway. In Experimental cell research, 438, 114056. doi:10.1016/j.yexcr.2024.114056. https://pubmed.ncbi.nlm.nih.gov/38663475/

5. Gao, Yanjun, Ma, Xinmei, Lu, Huanxi, Xu, Pan, Xu, Chengling. 2022. PLAU is associated with cell migration and invasion and is regulated by transcription factor YY1 in cervical cancer. In Oncology reports, 49, . doi:10.3892/or.2022.8462. https://pubmed.ncbi.nlm.nih.gov/36524374/

6. Zheng, Yuanliang, Zhang, Lixiang, Zhang, Kangliang, Huang, Risheng, Liao, Hongli. 2024. PLAU promotes growth and attenuates cisplatin chemosensitivity in ARID1A-depleted non-small cell lung cancer through interaction with TM4SF1. In Biology direct, 19, 7. doi:10.1186/s13062-024-00452-7. https://pubmed.ncbi.nlm.nih.gov/38229120/

7. Chen, Guangjin, Sun, Jiwei, Xie, Mengru, Tang, Qingming, Chen, Lili. 2021. PLAU Promotes Cell Proliferation and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma. In Frontiers in genetics, 12, 651882. doi:10.3389/fgene.2021.651882. https://pubmed.ncbi.nlm.nih.gov/34093649/

8. Li, Zhexuan, Chen, Changhan, Wang, Juncheng, Zhu, Gangcai, Zhang, Xin. 2021. Overexpressed PLAU and its potential prognostic value in head and neck squamous cell carcinoma. In PeerJ, 9, e10746. doi:10.7717/peerj.10746. https://pubmed.ncbi.nlm.nih.gov/33520474/

9. Wu, Min, Wei, Bo, Duan, Sai-Li, Huang, Peng, Chang, Shi. 2022. Methylation-Driven Gene PLAU as a Potential Prognostic Marker for Differential Thyroid Carcinoma. In Frontiers in cell and developmental biology, 10, 819484. doi:10.3389/fcell.2022.819484. https://pubmed.ncbi.nlm.nih.gov/35141223/

10. Guo, Zhi-Chen, Jing, Si-Li, Cui, Hao, Na, Si-Jia, Tu, Jun-Bo. 2023. PLAU and LAMC2 can predict a poor prognosis in patients with HNSCC. In Journal of Cancer, 14, 1660-1672. doi:10.7150/jca.84407. https://pubmed.ncbi.nlm.nih.gov/37325056/