PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK-STAT1/3-EMT signalling.
Bomiao CuiJiao ChenMin LuoYiying LiuHongli ChenDie LüLiwei WangYingzhu KangYun FengLibin HuangPing ZhangPublished in: International journal of oral science (2021)
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.
Keyphrases
- polycystic kidney disease
- poor prognosis
- induced apoptosis
- signaling pathway
- cell cycle arrest
- lymph node metastasis
- cell proliferation
- epithelial mesenchymal transition
- stem cells
- squamous cell carcinoma
- bone marrow
- pi k akt
- binding protein
- cell death
- gene expression
- long non coding rna
- drug delivery
- mass spectrometry
- risk factors
- cancer therapy
- single molecule
- combination therapy