Activation of the RAS/ERK signaling pathway by RASAL1 and its clinical significance in squamous cell carcinomas of the tongue

Abstract

ObjectiveThis study aimed to identify specific RAS-GAPs involved in RAS activation squamous cell carcinomas (SCCs) of the tongue, and to investigate the role of RAS signaling in tongue SCC progression. Subjects and methodsWe analyzed mutations in K-RAS, H-RAS, and N-RAS genes by PCR-single strand conformational polymorphism (PCR-SSCP), and relative levels of mRNA of three genes encoding RAS-GAPs (RASAL1, NF1, and DAB2IP) by real-time reverse transcriptional-PCR (RT-PCR) in 20 cases of tongue SCCs. To examine if the interaction between RAS-GAPs and phosphorylated ERK1/2 (p-ERK1/2) activated the RAS signaling pathway, we evaluated the expression of p-ERK1/2, a kinase located downstream of RAS, by immunohistochemistry. Finally, the association between p-ERK1/2 overexpression and clinicopathological factors was examined in 45 cases of tongue SCCs. ResultsNo mutations were detected in K-RAS, H-RAS, and N-RAS genes in 20 cases of tongue SCC. The levels of mRNA of RASAL1, NF1 and DAB2IP were downregulated in 80.0 %, 31.6 % and 25.0 %, respectively. There was a statistically significant relationship between RASAL1 downregulation and p-ERK1/2 overexpression (p = 0.014), suggesting that RAS/ERK signaling pathway was controlled by RASAL1 in tongue SCC. Furthermore, we showed that p-ERK1/2 was overexpressed more frequently in advanced-staged tumors than in early-staged ones. ConclusionsThe findings of the present study suggest that activation of the RAS/ERK signaling pathway, which is triggered by RASAL1 downregulation, is involved in the progression of tongue SCC.