PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK -STAT1/3-EMT signaling [post]

Bomiao Cui, Jiao Chen, Min Luo, Yiying Liu, Hongli Chen, Die Lv, Liwei Wang, Yingzhu Kang, Yun Feng, Libin Huang, Ping Zhang
2020 unpublished
Background: Oral squamous cell carcinoma (OSCC) has a high incidence of metastasis. Tumor immunotherapy targeting programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) is revolutionary; however, only a few patients with OSCC respond to this treatment. Therefore, it is necessary to understand the molecular mechanisms of OSCC growth and metastasis to identify new therapeutic targets. Methods: In this study, we first analyzed the expression level of protein kinase D3 (PKD3)
more » ... kinase D3 (PKD3) and PD-L1, and their correlation with mesenchymal and epithelial markers through UALCAN database, UCSC Xena, western blot, and immunostaining of human OSCC tissue sections. We knocked down and overexpressed PKD3 in OSCC cell lines and analyzed cell growth, migration, and invasion using western blot, cell proliferation assays, wound healing assays, and Transwell assays. A mouse footpad xenograft model was used to study the effects of PKD3 on tumor growth and lymph node metastasis in vivo. Results: The expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, and correlated positively with mesenchymal markers but negatively with epithelial markers. Silencing PKD3 significantly inhibited the growth, metastasis, and invasion of OSCC cells, while its overexpression promoted these processes. PKD3 regulated PD-L1 expression through the ERK/STAT1/3 signaling pathway, forming a positive feedback regulatory loop with PD-L1 to induce epithelial-mesenchymal transition (EMT) in OSCC. Conclusions: There is a positive feedback regulation between PKD3 and PD-L1, which can drive the EMT of OSCC cells through the ERK/STAT1/3 pathway, thereby promoting tumor growth and metastasis. 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 . Keywords: OSCC, PKD3, PD-L1, EMT, tumor growth, metastasis
doi:10.21203/rs.3.rs-28178/v1 fatcat:s5oioe47rjfhxe5m6aognzkepm