Research progress of interleukin-8 in epithelial mesenchymal transition of oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC); Oral squamous cell carcinoma (OSCC) is one of the common malignant tumors, which often leads to facial, voice, eating and breathing dysfunction, and seriously affects the quality of life and prognosis of patients. In recent years, the 5-year survival rate of oral squamous cell carcinoma is only 50% - 60%, which is difficult to be further improved. Among many prognostic factors, tumor recurrence and metastasis are the most important causes of death.  

Many studies have shown that epithelial mesenchymal transition (EMT) plays an important role in this process. Epithelial mesenchymal transition (EMT) of tumor cells refers to the changes of cell morphology and secreted proteins of tumor cells under certain conditions, which is characterized by loss of cell polarity and transformation into long spindle shape; At the same time, the expression of cadherin and other adhesion proteins decreased, while the expression of vimentin and matrix metalloproteinase increased. These changes lead to the decrease of adhesion between tumor cells and basement membrane and the change of cytoskeleton; At the same time, the ability to degrade the matrix around tumor cells is significantly enhanced, which leads to the enhancement of tumor cell migration and invasion.

Recent studies have found that interleukin-8 (IL-8 / CXCL-8) is closely related to tumor growth, invasion and other biological behaviors. 

In 1987, Yoshimura et al. Isolated and purified IL-8 for the first time, and found that IL-8 had chemotactic effect on neutrophils. With the deepening of research, the function of IL-8 has been more fully understood. IL-8 gene is located on chromosome 4 q13-21, and its main active form contains 72 amino acids with a molecular weight of 8.4 KD. Besides tumor cells, monocytes, macrophages and epithelial cells can secrete it. CXCR1 and CXCR2, as two receptors of IL-8, mediate their biological effects. Among them, CXCR1 highly specifically binds to IL-8, while CXCR2 can also bind to chemokines such as CXCL1, cxcl2 and CXCL5 in addition to IL-8. CXCR1 is the main receptor on the surface of tumor cells. After IL-8 binds to the receptor, it regulates transcription factors, changes cell protein expression, affects cytoskeleton, and affects a series of cell biological behaviors.

It is generally believed that IL-8 is secreted by tumor cells, monocytes and epithelial cells. However, it is worth noting that the level of IL-8 is different in different patients, even in different parts of the same patient. Some studies suggest that the secretion of IL-8 may be related to the stress state of cells. For tumor cells, when they are exposed to hypoxia, acidic environment, or even attacked by immune cells or drugs, the secretion level of IL-8 increases.  

The existing data show that the tumor is often in a hypoxic and acidic environment, which plays a positive role in the secretion of IL-8, and promotes many malignant behaviors of tumor in disguised form. Interestingly, IL-8 can also promote the chemotaxis and killing of immune cells including T cells and NK cells. Meniailo et al. Found that IL-8 has a positive regulatory effect on the activation and growth of T cells; Montaldo et al. Have shown that IL-8 is indispensable for the differentiation of early NK cells. This may indicate that IL-8 is a double-edged sword for tumor tissue, which can not only promote the growth of tumor tissue, but also promote the aggregation of immune cells, so as to kill them. 

Studies have shown that the level of IL-8 in patients with oral squamous cell carcinoma is significantly higher than that in normal people, and its expression level is closely related to tumor stage and pathological status. The level of IL-8 in patients with advanced tumor, especially in patients with cervical lymph node metastasis, is significantly increased, indicating that IL-8 plays an important role in promoting the metastasis of oral squamous cell carcinoma. In vitro experiments also confirmed this result.

Matrix metalloproteinase (MMP) plays a key role in tumor invasion. MMP can degrade extracellular matrix (ECM) and provide conditions for tumor cell migration. In oral squamous cell carcinoma, the expression levels of MMP2 and MMP9 are closely related to the recurrence and prognosis of patients. A large number of studies have shown that IL-8 can increase the expression levels of MMP2 and MMP9 in tumor cells, which may be one of the key pathways for IL-8 to promote the invasion and metastasis of tumor cells. However, the intermediate pathway of IL-8 promoting MMP expression in oral squamous cell carcinoma is not clear. 

With the deepening of research, people have a more comprehensive understanding of the function of IL-8. In addition to promoting tumor invasion and migration, IL-8 plays an important role in regulating other behaviors of tumor tissue. New et al. Found that IL-8 can promote the regulation of cancer associated fibroblasts (CAF) on autophagy; 

 IL-8 is one of the important components in tumor microenvironment. Although the source of IL-8 is still controversial, the role of IL-8 in promoting epithelial mesenchymal transition of tumor tissue has been basically agreed. The mechanism of IL-8 promoting EMT process is also one of the hot spots of current research. It is worth noting that the current research on IL-8 mainly focuses on the exploration of its downstream pathway and further excavation of its function. There are few studies on the regulation of IL-8 upstream, and there is no unified conclusion. After IL-8 was taken up by tumor cells, PTEN (gene of phosphate and tension homology deleted on chromosometen) gene was phosphorylated.

PTEN as an important tumor suppressor gene, its allelic deletion, mutation and phosphorylation have been confirmed to be an important cause of cancer. PTEN phosphorylation eventually leads to the high expression of snail in the nucleus, which promotes the EMT behavior of tumor cells.  

In conclusion, IL-8 has been proved to be a tumor promoting agent for most solid tumors, but in the field of oral squamous cell carcinoma, the evidence for IL-8 is insufficient. The molecular mechanism of IL-8 in oral squamous cell carcinoma affecting tumorigenesis, development and prognosis needs to be further elucidated, so as to provide a reliable basis for providing new tumor treatment targets in the future.

 

 

Cindy