Association of CXCR1 and 2 expressions with gastric cancer metastasis in ex vivo and tumor cell invasion in vitro

- There is a strong link between CXCR1, CXCR2 and MMP9 and stage of gastric cancer.
- Receptors CXCR1 and CXCR2 associated with gastric cancer cell motility.
- CXCR1 or CXCR2 regulated gastric cancer cells migration and invasion, respectively.
- JNK and Erk pathways may mediate the effects of CXCR1 and 2 in gastric cancer.

BackgroundCXCR1 and CXCR2, cell surface receptors of interleukin-8, regulate cell migration and alteration of their expression has been associated with poor prognosis of various cancers. The aim of this study was to detect their expression in gastric cancer to identify associations with another cell adhesion molecule, matrix metalloproteinase-9 (MMP9), and with clinicopathological data ex vivo, and then explore their potential role in gastric cancer cells in vitro.Materials and methodsA total of 172 cases of gastric cancer tissue specimens were collected for immunohistochemical analysis of CXCR1, CXCR2, and MMP9 expression. Expression of CXCR1 and CXCR2 proteins was knocked in or down using their cDNA and shRNA, respectively, in gastric cancer cell lines to assess the changed cell phenotypes and gene expression.ResultsCXCR1, CXCR2, and MMP9 were expressed in 61.0%, 77.9%, and 75.6% of gastric cancer tissues, respectively. Moreover, CXCR1 and CXCR2 expression was associated with tumor differentiations, advanced clinical stages, lymph node, and distant metastasis of gastric cancer. Similarly, MMP9 expression was associated with CXCR1 and CXCR2. Expression of these three proteins was interrelated. In vitro study showed that levels of CXCR1 and CXCR2 proteins were associated with the capacity of gastric cancer cell migration, while knockdown of their expression inhibited gastric cancer cell migration and invasion abilities in vitro. In contrast, overexpression of CXCR1 and CXCR2 proteins promoted tumor cell migration and invasion. At the gene levels, knockdown of CXCR1 or CXCR2 expression suppressed expression of Ets-1, SRC-1, and JNK proteins and phosphorylated c-Jun and Erk1/2. Conversely, upregulation of CXCR1 or CXCR2 promoted expression of Ets-1, SRC-1, JNK, and c-Jun proteins and phosphorylated JNK, c-Jun and Erk1/2.ConclusionsThese findings suggest that CXCR1 and CXCR2 play an important role in gastric cancer progression. Further study will be performed to investigate whether target of their expression can be used as a novel strategy in clinical control of gastric cancer metastasis.

Expression of CXCR1, CXCR2 and MMP9 proteins associated with stage and metastasis in gastric cancer patients and CXCR1 and 2 proteins regulated gastric cancer cells migration and invasion, respectively. JNK/c-Jun and Erk/Ets-1 pathways may mediate the effects of CXCR1 and 2 in gastric cancer.