State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
Int J Oral Sci. 2021 Mar 10;13(1):8. doi: 10.1038/s41368-021-00112-w.
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.
口腔鳞状细胞癌（OSCC）具有较高的转移率。针对 PD-L1 或 PD-1 的肿瘤免疫疗法具有革命性意义；然而，只有少数 OSCC 患者对这种治疗有反应。因此，深入了解 OSCC 生长和转移的分子机制至关重要。在这项研究中，我们分析了蛋白激酶 D3（PKD3）和 PD-L1 的表达水平及其与间质和上皮标志物表达的相关性。我们发现，OSCC 细胞和组织中 PKD3 和 PD-L1 的表达显著增加，与间充质标志物的表达呈正相关，与上皮标志物的表达呈负相关。沉默 PKD3 显著抑制了 OSCC 细胞的生长、转移和侵袭，而过表达则促进了这些过程。我们的进一步分析表明，PKD3 和 PD-L1 之间存在正反馈调节，可通过 ERK/STAT1/3 通路驱动 OSCC 细胞的 EMT，从而促进肿瘤生长和转移。此外，沉默 PKD3 显著抑制了 PD-L1 的表达，我们还通过小鼠足垫异种移植模型研究了 OSCC 的淋巴结转移。因此，我们的研究结果为靶向 PKD3 提供了理论依据，可作为阻断 EMT 以调节 PD-L1 表达和抑制 OSCC 生长和转移的替代方法。
