CCR7 pathway induces epithelial–mesenchymal transition through up-regulation of Snail signaling in gastric cancer

Abstract

The chemokine receptor 7 (CCR7) and Snail signaling have been linked to various types of cancers. The associations between these signalings and the epithelial-mesenchymal transition (EMT) are not clear in gastric cancer. Here, the expression of CCR7 and Snail was detected in gastric cancer by immunohistochemistry and Western blot. Meanwhile, gastric cancer cells were subjected to CCL19, si-control, and si-Snail treatment. Cell cycle, migration, and invasion were also analyzed. The expression patterns of CCR7 and Snail were similar in either gastric cancer tissues or cells. The increased expression of CCR7 was closely associated with the increased Snail expression, which both were closely correlated with metastasis, stage and differentiation, and poor prognosis. The increased p-ERK, p-AKT, Snail, and MMP9 expression and the decreased E-cadherin were confirmed in MGC803 cells in a dose-dependent manner in response to CCL19 treatment. However, the blockade of Snail abrogated the up-regulation of MMP9 and down-regulation of E-cadherin. CCR7-induced ERK and PI3K pathway regulated Snail signaling. Besides si-Snail treatment led to MGC803 cell cycle arrest and affected the migration and invasion. In conclusion, our study suggested that CCR7 promotes Snail expression to induce the EMT, resulting in cell cycle progression, migration, and invasion in gastric cancer. CCR7-Snail pathway provided more potential regimens for cancer therapy.

Molecular background of the regional lymph node metastasis of gastric cancer (Review)

“…A meta-analysis which included 1,697 participants with GC indicated that increased CCR7 expression was associated with negative clinicopathological prognostic factors including deeper tumor invasion and predicted a worse long-term survival outcome (46). The possible underlying molecular mechanism is that CCR7 contributes to TGF-β1-induced epithelial-mesenchymal transition (EMT), facilitating lymph node metastasis in patients with gastric cancer (47,48). Therefore CCR7 may potentially serve as a novel prognostic indicator and a potential target for gastric cancer therapy.…”

C‑C motif chemokine receptors in gastric cancer (Review)

“…In addition, signaling via CCR7 induced chemotactic and invasive responses in CCR7-positive gastric cancer cells, suggesting that functional CCR7 in gastric cancer cells may exert an important role in migration and invasion of gastric cancer. Recently, two groups demonstrated that CCR7 is involved in the epithelial-mesenchymal transition in gastric cancer (44,45). Zhang et al (44) reported that CCR7 induced the epithelial-mesenchymal transition by upregulating Snail, and that Snail signaling was regulated by the ERK and PI3K pathways instead of the Rho pathway, resulting in G 1 /S cell cycle progression, migration and invasion of gastric tumor cells.…”

“…Recently, two groups demonstrated that CCR7 is involved in the epithelial-mesenchymal transition in gastric cancer (44,45). Zhang et al (44) reported that CCR7 induced the epithelial-mesenchymal transition by upregulating Snail, and that Snail signaling was regulated by the ERK and PI3K pathways instead of the Rho pathway, resulting in G 1 /S cell cycle progression, migration and invasion of gastric tumor cells. Ma et al (45) investigated a CCR7-associated mechanism involved in gastric cancer progression, which was predicted on the basis of a bioinformatics analysis and verified in gastric cancer cells and primary tumor tissues.…”

Expression of chemokine receptor CCR7 is a negative prognostic factor for patients with gastric cancer: a meta-analysis

“…After excluding irrelevant articles by reviewing the titles and abstracts of those studies, two investigators (P. Du and Y. Liu) reviewed the full text version of the remaining 30 articles independently in accordance with the inclusion and exclusion criteria. Finally, 15 articles [7][8][9][10][13][14][15][16][17][18][19][20][21][22][23] comprising data on 1697 participants met the requirement of the analysis. The detailed search steps are described in Fig.…”

“…Many studies have been conducted to understand the relationship between CCR7 expression and clinicopathological features and 5-year overall survival (OS) rate, but a unanimous conclusion has yet to be reached. The prognosis of CCR7 expression in gastric cancer reported by different researchers was contradictory [7][8][9][10].…”