Serum Response Factor-Regulated IDO1/Kyn-Ahr Pathway Promotes Tumorigenesis of Oral Squamous Cell Carcinoma

SIMPLE SUMMARY: Oral squamous cell carcinoma (OSCC) is the most widespread malignancy of the head and neck and is characterized by a high potential for local invasion and lymph node metastasis. Serum response factor (SRF) regulates pro-carcinogenic genes in various cancers, but its role in OSCC remains unclear. The present study is the first to elucidate the role of SRF in OSCC development to our knowledge. We revealed that SRF is overexpressed in patients with OSCC, which is correlated with the depth of invasion and lymph node metastasis. Tumorigenicity assays in nude mice further proved that SRF promoted OSCC tumorigenesis in vivo. In addition, overexpressed SRF regulated the novel IDO1/Kyn-AhR signaling pathway to enhance OSCC cell migration and invasion by modulating EMT. In conclusion, we revealed a novel molecular mechanism by which SRF modulates OSCC metastasis. Our study could provide potential targets or biomarkers for OSCC diagnosis and treatment. ABSTRACT: Serum response factor (SRF) regulates pro-carcinogenic genes in various cancers, but its role in oral squamous cell carcinoma (OSCC) remains unclear. SRF expression in 70 OSCC samples was detected via immunohistochemistry. Abundant SRF expressed in OSCC tissues was closely associated with tumor metastasis. SRF-overexpressing OSCC cells were constructed to evaluate how SRF affects OSCC cell tumorigenesis and epithelial-to-mesenchymal transition (EMT) in vitro and in vivo. Overexpressed SRF increased OSCC cell migration and invasion in vitro and tumor growth and invasion in vivo. This promoted EMT, characterized by decreased and increased expression of E- and N-cadherin, respectively. Furthermore, an analysis of RNA sequences of transcriptional targets of SRF showed that SRF transactivated the indoleamine 2, 3-dioxygenase 1 (IDO1)/kynurenine-aryl hydrocarbon receptor (Kyn-AhR) signaling pathway in OSCC cell lines. Direct SRF binding to the IDO1 gene promoter upregulated transcription, which was detected through chromatin immunoprecipitation and dual luciferase reporter assays. Inhibiting IDO1 or AhR impaired SRF-induced migration and invasion and prevented EMT in OSCC cells. Our results demonstrated that SRF is a critical regulator of the IDO1/Kyn-AhR signaling pathway. This in turn increases OSCC cell migration and invasion by modulating EMT, which, consequently, favors OSCC cell growth and metastasis. We revealed a novel molecular mechanism through which SRF modulates OSCC metastasis. This should provide potential targets or biomarkers for OSCC diagnosis and treatment.