Identifying a Novel Signaling Pathway in Skin Cancer

A multi-center study led by Cleveland Clinic researchers discovered a novel signaling pathway that directly impacts keratinocyte proliferation and tumor formation in skin cancer.

IL-17 is emerging as an important cell signaling protein in cancer promotion and progression. It plays an essential role in host defense against bacterial and fungal infections. Chronic overproduction of IL-17 contributes to inflammatory conditions like psoriasis, multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease. This is important because chronic inflammation is known to pose a potential risk for cancer development.

The study provided a novel mechanism for IL-17-dependent tumorigenesis via a direct IL-17-TRAF4-ERK5 axis in stimulating cell proliferation and tumor formation, according to lead author Xiaoxia Li, PhD, The Paul L. Fox, PhD, Endowed Chair in Molecular Medicine at Cleveland Clinic Lerner Research Institute. The IL-17-TRAF4-ERK5 axis and its regulated genes form a positive feedback loop for keratinocytes proliferation and tumor formation.

A direct impact

While IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlying molecular mechanism was not fully understood. In this study, Dr. Li says, researchers found the direct impact of IL-17-TRAF4-ERK5 axis on keratinocytes proliferation and tumorigenesis.

“Given the TRAF4 overexpression in a wide range of human malignancies, this study suggests that TRAF4 might be an important feature of the tumor cells, and the IL-17 signaling cascade might be an important therapeutic target for cancers with high TRAF4 expression,” says Dr. Li.

Next steps

Researchers are now looking into whether blocking this IL-17 signaling cascade in different cancers with high levels of TRAF4 will lead to reduced tumor growth, thus confirming the clinical relevance of this pathway in other types of cancer.

“We are also developing peptides and screening small molecules that could block this novel cascade,” says Dr. Li. “This might further lead to new cancer therapeutics.”