PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway

Abstract

Cancer-associated fibroblasts (CAFs) plays an important role in the tumor microenvironment. The heterogeneity of CAFs affects the effect of CAFs on promoting or inhibiting tumors, which can be regulated by other cells in the tumor microenvironment through paracrine methods. The urokinase-type plasminogen activator (PLAU) system mediates cell proliferation, migration, adhesion, and other functions through the proteolytic system, intracellular signal transduction, and chemokine activation. PLAU promotes tumor progression in many tumors. We explored the function of PLAU in ESCC and the influence of PLAU secreted by tumor cells on the heterogeneity of CAFs. We found that PLAU is highly expressed in ESCC, which is related to poor prognosis and can be used as a prognostic marker for ESCC. Through loss-of function and gain-of function experiments, we found that PLAU promoted ESCC proliferation and clone formation via MAPK pathway, and promotes migration by upregulating Slug and MMP9, which can be reversed by the MEK 1/2 inhibitor U0126. At the same time, through sequencing, cytokine detection, and RT-qPCR verification, we found that tumor cells secreted PLAU promoted the conversion of fibroblasts to inflammatory CAFs, which upregulated expression and secretion of IL8 via the uPAR/Akt/NF-κB pathway. The IL8 secreted by CAFs in turn promotes the high expression of PLAU in tumor cells and further promoted the progression of ESCC. In summary, PLAU was not only a prognostic marker of ESCC, which promoted tumor cell proliferation and migration, but also promoted the formation of inflammatory CAFs by the PLAU secreted by tumor cells.

Identification of key genes associated with esophageal adenocarcinoma based on bioinformatics analysis

“…Remarkably, a recent study performed by Fang et al has revealed that PLAU could promote progression of ESCC tumor cell and that tumor cell-secreted PLAU could expedite the conversion of fibroblasts to inflammatory cancer-associated fibroblasts, accelerating the proliferation and migration of ESCC cells (69). Our study demonstrated that PLAU may serve as a prognostic biomarker of EAC, which warrants further exploration in future studies.…”

A Novel Immune-Related Prognostic Signature in Head and Neck Squamous Cell Carcinoma

“…Previous studies have established the involvement of these six immune-related genes in invasion and metastasis of HNSCC tumor cells. More recently, both PLAU and STC2 were identified as oncogenes in HNSCC tumors, associated with immunosuppression and inflammation (Chang et al, 2003;Ieta et al, 2009;Na et al, 2015;Yang et al, 2017Yang et al, , 2020Joshi, 2020;Fang et al, 2021;Li et al, 2021). TNFRSF4 (also known as CD134/ OX40) is one of the representative targets of second-generation immune checkpoints, and its clinical efficacy has been observed by anti-TNFRSF4 (MEDI6469) therapy in HNSCC patients through regulating antigen-specific tumorinfiltrating T cells (Duhen et al, 2021).…”

HNF1A POU Domain Mutations Found in Japanese Liver Cancer Patients Cause Downregulation of HNF4A Promoter Activity with Possible Disruption in Transcription Networks

“…However, the contribution of IYD in relation to HNF-family genes to tumorigenesis in the liver has not been investigated yet, and further studies are needed. HPR, PKLR and PLAU have been reported to be overexpressed in breast cancers and esophageal squamous cell carcinoma [ 69 , 70 , 71 ]. Conversely, our study showed the downregulation of those genes.…”