However, other studies suggested that GKN1 may be secreted from epithelial cells, and have functions in both paracrine and autocrine systems [6] in control of normal cell growth, differentiation, and apoptosis. In addition, this study demonstrated that GKN1 was able to increase the sensitivity of gastric cancer cells to 5-FU treatment. This finding suggested that p38 MAPK inhibitor GKN1 may be useful as an adjuvant target in combination with other chemotherapeutical agents in the treatment of gastric cancer. 5-FU has been a widely used as a chemotherapeutic agent in treating
patients with gastric cancer. It is a pyrimidine analogue and can incorporate into DNA or RNA for the induction of cell cycle arrest and apoptosis through inhibition of DNA duplication in tumor cells. In this regard, GKN1 could induce cell apoptosis, thus GKN1 could enhance 5-FU antitumor activity in gastric cancer cells. This result may
partially explain the reason that patients who have lost GKN1 expression have shorter overall survival [20]. However, it remains to be determined how GKN1 is able to induce apoptosis in gastric cancer cells. Our preliminary data revealed that GKN1 expression was able to modulate expression of several apoptosis-related genes using a cDNA microarray click here analysis. Of the 112 genes covered by the Oligo GEArrays Human Apoptosis Microarray, the expression of 19 genes may directly affect by GKN1. However, some of these screening genes (such as BAX and BCL2A1) may be indirectly or even not affected or regulated by GKN1 protein [14, 21]. Considering limitations of the microarray analysis, these screening genes need to be verified by qRT-PCR or western blot analyses in the further study. Conclusions In summary, expression of GKN1 mRNA and protein was progressively downregulated from the
normal mucosa, precancerous to cancerous gastric tissues. Restoration of GKN1 expression Farnesyltransferase induced gastric cancer cells to undergo apoptosis, and enhanced sensitivity to 5-FU-induced apoptosis. These data indicate that GKN1 plays a role in regulation of gastric epithelial homeostasis and that lost GKN1 expression could contribute to gastric cancer development. Acknowledgements This study was supported in part by grants from The National Natural Science Foundation of China (No. 81072048 and No. 30871145), from the Natural Science Foundation of Guangdong Province (No. 7001641), from the Junior Teacher Cultivation Project of Sun Yat-sen University (No. 09ykpy22), and (No. 10ykjc23). References 1. Talamonti MS, Kim SP, Yao KA, Wayne JD, Feinglass J, Bennett CL, Rao S: Surgical outcomes of patients with gastric carcinoma: the importance of primary tumor location and microvessel invasion. Surgery 2003, 134:720–727. discussion 727–729PubMedCrossRef 2. Jemal A, Thomas A, Murray T, Thun M: Cancer statistics, 2002. CA Cancer J Clin 2002, 52:23–47.PubMedCrossRef 3. Krejs GJ: Gastric cancer: epidemiology and risk factors. Dig Dis 2010, 28:600–603.