PDGF-BB regulates the transformation of fibroblasts into cancer-associated fibroblasts via the IncRNA LURAP1L-AS1/LURAP1L/IKK/I[kappa]B/NF-[kappa]B signaling pathway

The most abundant cells in the tumor microenvironment are cancer-associated fibroblasts (CAFs). They play an important role in oral squamous cell carcinoma (OSCC) angiogenesis, invasion and metastasis. Platelet-derived growth factor (PDGF)-BB has an obvious regulating effect on the formation of CAFs through binding to PDGF receptor (PDGFR)-[beta], but the role of long non-coding (lnc) RNA in PDGF-BB-induced transformation of fibroblasts into CAFs remains poorly understood. Using an IncRNA ChIP, 370 IncRNA transcripts were identified to be significantly and differentially expressed between fibroblasts and PDGF-BB-induced fibroblasts, including 240 upregulated IncRNAs and 130 downregulated IncRNAs, indicating that IncRNAs are involved in the regulation of the transformation of CAFs. Previous studies have shown that the nuclear factor (NF)-KB signaling pathway plays an important role in the activation of CAFs. Dual-luciferase reporter assay and co-immunoprecipitation were conducted to confirm that the leucine-rich adaptor protein 1-like (LURAP1L), which is the target of IncRNA LURAP1L antisense RNA 1 (LURAP1L-AS1) had a positive regulatory effect on I-[kappa]B kinase (IKK)/NF-[kappa]B signaling. Therefore, LURAP1L-AS1 was selected and PDGF-BB was demonstrated to upregulate the expression of LURAP1L-AS1 and LURAP1L, which was reversed by a PDGFR-[beta] inhibitor. Subsequently, knocking down LURAP1L-AS1 suppressed the expression of PDGF-BB-induced fibroblast activation marker protein [alpha]-smooth muscle actin, fibroblast activation protein-[alpha], PDGFR-P and phosphorylated (p)-PDGFR-[beta]. IKK[alpha], p-1[kappa]B and p-NF-[kappa]B were downregulated by the knockdown of LURAP1L-AS1 and upregulated by over-expression of LURAP1L-AS1. The present study indicates that LURAP1L-AS1/LURAP1L/IKK/I[kappa]B/NF-[kappa]B plays an important regulatory role in PDGF-BB-induced fibroblast activation and may become a potential target for the treatment of OSCC. Key words: oral squamous cell carcinoma, nuclear factor-[kappa]B, long non-coding RNA, fibroblasts, cancer-associated fibroblasts, platelet-derived growth factor