Recent Research Progress
CXCL8, also known as interleukin-8 (IL-8), belongs to the glutamate-leucine-arginine (ELR)+ CXC chemokine. It is usually produced by macrophages, epithelial cells, airway smooth muscle cells and endothelial cells. CXCL8 is rapidly induced by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β). Similar to other inflammatory factors, such as CXCL5 and IL-6, CXCL8 is responsible for the recruitment and activation of neutrophils and granulocytes to the site of inflammation. The inflammatory response with a large number of cytokines in the tumor microenvironment is more prominent in promoting tumor growth, progression and immunosuppression than exerting an effective anti-tumor response. In the context of cancer, CXCL8 acts as an important multifunctional cytokine to regulate tumor cell proliferation, invasion and migration by autocrine or paracrine means.
CXCL8 and OS
Osteosarcoma (OS) is a skeletal malignancy that spreads almost exclusively through the invasive metastasis to the lungs. Abnormal overexpression of ΔNp63 in OS cells directly drives the production of IL-6 and CXCL8 (Figure 1). All of these factors were expressed at higher levels in OS lung metastases than matched primary tumors from the same patient. Expression in cell lines correlated strongly with lung colonization efficiency in murine xenograft models. Lentiviral-mediated expression conferred increased metastatic potential to poorly metastatic OS cells. The use of genetic or drug inhibitors to disrupt IL-6 and CXCL8 signaling has minimal effect on tumor cell proliferation in vitro or in vivo, but combination therapy inhibits metastasis in multiple metastatic OS models. The strong interaction occurred between OS cells and primary bronchial epithelial cells and bronchial smooth muscle cells that drove feed-forward amplification of IL-6 and CXCL8 production. These results identify IL-6 and CXCL8 as the primary mediators of OS lung tropism and suggest that they may affect the pleiotropic and redundant mechanisms of metastasis.
Figure 1. ΔNp63 expression primes select tumor cells to respond to signals provided by lung cells with robust IL-6 and CXCL8 production. (Amy C, et al, JCI Insight, 2018)
CXCL8 and AML
Acute myeloid leukemia (AML) blasts release a variety of chemokines, of which CXCL8 has recently been considered important for tumor progression. The study found that patients with AML had a higher mean CXCL8 level. Among patients, high expression of CXCL8 is also a positive recurrence indicator, indicating the key role of CXCL8 in AML. Knockout of CXCL8 in leukemia cell lines resulted in a significant decrease in proliferation by induction of G0/G1 cell cycle arrest and apoptosis, which was accompanied by inactivation of extracellular signal-regulated kinase1/2 (ERK1/2). In addition, inhibition of ERK1/2 by specific chemical inhibitors reconstituted the CXCL8 knockdown phenomenon. In conclusion, it has been confirmed that the expression level of CXCL8 was positively correlated with the probability of recurrence in AML. And CXCL8 is closely related to AML cell growth by activating ERK1/2 signaling pathway.
CXCL8 and ADC
Lung adenocarcinoma (ADC) is a type of lung cancer and belongs to non-small cell carcinoma. The relationship between CXCL8 and the clinic-pathological parameters of ADC has been confirmed. CXCL8 may be an independent prognostic factor for overall survival (OS) and relapse free survival (RFS) in ADC patients. The human Dachshund homologue 1 (DACH1) was negatively correlated with CXCL8 and the recovery of DACH1 against CXCL8. Studies have shown that DACH1 was a key factor in the reverse regulation of CXCL8. Dual detection of DACH1 and CXCL8 can provide accurate information for predicting the prognosis of ADC patients.
CXCL8 and CRC
Colorectal cancer (CRC) is the most common malignant disease in the world, with an estimated 5-year survival rate ranging from 90% in patients with stage 1 to 10% in patients with metastatic disease. CXCL8 expression was inversely correlated with anoikis in CRC cells. CXCL8 treatment enhanced the resistance of CRC cells to apoptosis, accompanied by an increase in TLAK cell-originated protein kinase (TOPK), and activation of protein kinase B (AKT) and ERK. Furthermore, it was demonstrated that inhibition of ERK or AKT by specific chemical inhibitors attenuated CXCL8-mediated resistance to anoikis. Treatment with AKT inhibitor abolished the effect of CXCL8 on TOPK expression, indicating that TOPK was downstream of AKT during anoikis. In conclusion, CXCL8 is closely related to the resistance of CRC cells to anoikis, and that AKT, TOPK and ERK pathways may be potential therapeutic targets for CRC.
In summary, CXCL8 regulates many different cellular functions, including survival, growth and chemotaxis, as well as multiple effects on gene expression. It has also been shown that CXCL8 is involved in inflammation, immune response, and is an important biomarker for many diseases, including different types of cancer. Therefore, further study of the molecular pathogenesis of CXCL8 in various diseases is the key to providing new targeted therapies for various diseases.
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