Clinicopathological significance of p38β, p38γ, and p38δ and its biological roles in esophageal squamous cell carcinoma

P38 beta, p38 gamma, and p38 delta have been sporadically and scarcely reported to be involved in the carcinogenesis of cancers, compared with p38 alpha isoform. However, little has been known regarding their clinicopathological significance and biological roles in esophageal squamous cell carcinoma (ESCC). Expression status of p38 beta, p38 gamma, and p38 delta was assayed using immunohistochemistry with ESCC tissue microarray; ensuing clinicopathological significance was statistically analyzed. To define its biological roles on proliferation, migration and invasion of ESCC cell line Eca109 in vitro, MTT, wound healing, and Transwell assays were employed, respectively. As confirmation, athymic nude mice were taken to verify the effect over proliferation in vivo. It was found that both p38 beta and p38 delta expression, other than p38 gamma, were significantly higher in ESCC tissues compared with paired normal controls. In terms of prognosis, only p38 beta expression was observed to be significantly associated with overall prognosis. Clinicopathologically, there was significant association between p38 gamma expression and clinical stage, lymph nodes metastases, and tumor volume. No significant association was found for p38 beta and p38 delta between its expression and other clinicopathological parameters other than significant difference of expression between ESCC versus normal control. In Eca109, it was observed that p38 beta, p38 gamma, and p38 delta can promote the cell growth and motility. As verification, over-expression of p38 delta can promote, whereas knockdown of p38 gamma can prevent, the tumorigenesis in nude mice model xenografted with Eca109 cells whose basal level of p38 delta was stably over-expressed and p38 gamma was stably knocked down. Together, our results demonstrate that p38 beta, p38 gamma, and p38 delta played oncogenic roles in ESCC.