Abstract
Oral squamous cell carcinoma (OSCC) has a high incidence of metastasis. Tumour immunotherapy targeting PD-L1 or PD-1 has been revolutionary; however, only a few patients with OSCC respond to this treatment. Therefore, it is essential to gain insights into the molecular mechanisms underlying the growth and metastasis of OSCC. In this study, we analysed the expression levels of protein kinase D3 (PKD3) and PD-L1 and their correlation with the expression of mesenchymal and epithelial markers. We found that the expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, which correlated positively with that of mesenchymal markers but negatively with that of epithelial markers. Silencing PKD3 significantly inhibited the growth, metastasis and invasion of OSCC cells, while its overexpression promoted these processes. Our further analyses revealed that there was positive feedback regulation between PKD3 and PD-L1, which could drive EMT of OSCC cells via the ERK/STAT1/3 pathway, thereby promoting tumour growth and metastasis. Furthermore, silencing PKD3 significantly inhibited the expression of PD-L1, and lymph node metastasis of OSCC was investigated with a mouse footpad xenograft model. Thus, our findings provide a theoretical basis for targeting PKD3 as an alternative method to block EMT for regulating PD-L1 expression and inhibiting OSCC growth and metastasis.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumour of the head and neck
These data suggest that the binding of these data demonstrate that protein kinase D3 (PKD3) contributes to regulating the PD-1 fusion protein to Programmed death ligand-1 (PD-L1) promotes Epithelial–mesenchymal transition (EMT) in Oral squamous cell carcinoma (OSCC)
Our research revealed that PKD3 regulates EMT and PD-L1 expression in OSCC through the extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 1/3 (STAT1/3) pathways and establishes a positive feedback loop with PD-L1 to promote tumour growth and metastasis
Summary
Bomiao Cui[1], Jiao Chen[1], Min Luo 1, Yiying Liu[1], Hongli Chen[1], Die Lü1, Liwei Wang[1], Yingzhu Kang[1], Yun Feng[1], Libin Huang[2] and Ping Zhang[1]. We found that the expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, which correlated positively with that of mesenchymal markers but negatively with that of epithelial markers. Our further analyses revealed that there was positive feedback regulation between PKD3 and PD-L1, which could drive EMT of OSCC cells via the ERK/STAT1/3 pathway, thereby promoting tumour growth and metastasis. Our previous studies determined that PKD3 can regulate PD-L1 expression.[14] PD-L1 is closely related to EMT in HNSCC.[25] To verify whether PKD3 is involved in the regulation database and obtained the gene expression data of 564 HNSCC specimens to analyse the correlation of PKD3, PD-L1, and EMTrelated markers In this large dataset, the expression of PKD3 of EMT in OSCC, we first analysed the protein levels of PKD3, and PD-L1 was positively correlated with that of mesenchymal. The levels of PKD3, PD-L1 development of OSCC and is closely related to its EMT
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