Jab1 promotes gastric cancer tumorigenesis via non-ubiquitin proteasomal degradation of p14ARF.

Jab1 has been reported to regulate various proteins in signal transduction pathways and be implicated in carcinogenesis or tumor progression. However, the precise role and molecular mechanism of Jab1 in gastric tumorigenesis have not yet been fully elucidated. Jab1 staining in gastric cancer tissues and paired non-cancerous tissues was measured using tissue microarray (TMA) technology. The impact of Jab1 on tumor growth in vivo was analyzed using xenotransplantation experiments in Balb/c mice. The expression of Jab1 and p14ARF in gastric cancer cells was analyzed by western blot and confocal immunofluorescence. CCK-8 and cell cycle experiment were used to evaluate the cell proliferation. Ubiquitination assay was performed to validate whether ubiquitination is involved in Jab1-mediated p14ARF degradation. The expression level of protein p14ARF was inversely correlated with the protein level of Jab1. Then, we investigated the mechanism that how Jab1 induced p14ARF depletion. Mechanistic studies showed that Jab1 induced ubiquitin-independent proteasomal p14ARF degradation in gastric cancer cells. Our data demonstrated that Jab1 protein was a vital upstream negative modulation factor of p14ARF, and Jab1 could promote cell proliferation and tumor growth via inhibiting the expression of p14ARF in vivo and in vitro. Moreover, silencing Jab1 protein expression declined tumor growth and further increased the apoptosis rate of gastric cancer cells. In further studies of gastric cancer specimens, we found the increased level of Jab1 protein shortened the overall survival. Jab1 is upstream of p14ARF and promote gastric cancer cell proliferation in vitro and in vivo. Furthermore, Jab1 decreased the expression of p14ARF though ubiquitination independent proteasomal degradation. Therefore, the connection of Jab1 and p14ARF may provide new methods for the treatment of gastric cancer.