Abstract
BackgroundLipopolysaccharide (LPS) from Helicobacter pylori (HP) plays an important role in gastric cancer occurrence and development. Toll-like receptor 4 (TLR4) and myeloid differential protein-2 (MD-2) are also reported to be involved in gastric cancer cell proliferation and invasion. CXC chemokine receptor 7 (CXCR7), a second receptor for CXCL12, has been detected in multiple types of tumor tissues. Nevertheless, the biological function and regulation of CXCR7 and its relationship with TLR4 and MD-2 in gastric cancer are not completely understood and therefore warrant further study.MethodsCXCR7 expression was examined in 150 gastric cancer tissues using immunohistochemistry (IHC). RT-PCR and western blotting were used to detect CXCR7 expression in several gastric cancer cell lines (SGC7901, AGS, MGC-803, MKN-45 and BGC823). shRNAs were designed using a pGPU6/GFP/Neo vector. A CCK-8 assay was used to assess cell proliferation, and transwell assays were performed to assess cell migration. In addition, a gastric cancer xenograft model was generated.ResultsThe LPS-TLR4-MD-2 pathway elevates CXCR7 expression in SGC7901 cells, and TLR4/MD-2-mediated increases in CXCR7 levels modulate the proliferation and migration of tumor cells. Knockdown of TLR4 and MD-2 demonstrated that both are essential for LPS-induced CXCR7 expression, which in turn is responsible for LPS-induced SGC7901 cell proliferation and migration. Moreover, higher TLR4, MD-2 and CXCR7 expression was detected in gastric cancer tissues than in paracancerous normal control tissues. The expression levels of TLR4, MD-2 and CXCR7 were closely related to gastric cancer TNM stage and lymph node metastasis. In an animal model, significant differences in CXCR7 expression in tumor masses were observed between the control group and experimental group.ConclusionsThe results of this study indicate that CXCR7 plays an important role in gastric cancer progression via inflammatory mechanisms, suggesting that CXCR7 could provide a basis for the development and clinical application of a targeted drug for gastric cancer.
Highlights
Lipopolysaccharide (LPS) from Helicobacter pylori (HP) plays an important role in gastric cancer occurrence and development
Expression of Toll-like receptor 4 (TLR4), myeloid differential protein-2 (MD-2) and CXC chemokine receptor 7 (CXCR7) in gastric cancer cell lines We investigated the mRNA and protein expression levels of TLR4 and MD-2 in human gastric cancer cell lines (SGC-7901, AGS, MGC-803, BGC-823 and MKN-45) and normal gastric epithelial GES-1 cells using RT-PCR and western blotting
The results showed that the mRNA and protein expression of both TLR4 and MD-2 was higher in gastric cancer lines than in normal gastric epithelial GES-1 cells (Fig. 1a-d)
Summary
Lipopolysaccharide (LPS) from Helicobacter pylori (HP) plays an important role in gastric cancer occurrence and development. CXC chemokine receptor 7 (CXCR7), a second receptor for CXCL12, has been detected in multiple types of tumor tissues. Chronic inflammation is correlated with many malignant tumors [2, 3], and chronic atrophic gastritis with intestinal metaplasia is associated with an Transmembrane Toll-like receptors (TLRs) are a class of signal transduction proteins referred to as pattern (2019) 14:3 recognition receptors that can recognize pathogen-related molecular patterns (PAMPs). LPS can induce the formation of an LPS-TLR4-MD-2 multimer by complexing with TLR4 and myeloid differential protein-2 (MD-2), which can further activate proinflammatory signaling pathways and facilitate the expression of corresponding cytokines and receptors [15, 16]. CXC chemokine receptor 7 (CXCR7), a second receptor for CXCL12, has been detected on the surface of multiple types of tumor tissues [17, 18]. The biological function and regulation of CXCR7 and its relationship with TLR4 and MD-2 in gastric cancer are still not completely understood and are worthy of study
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