Lab Links Gene To Aged Skin Problems, Cancer

The discovery by the laboratory of Xiao-Jing Wang, M.D., Ph.D., professor of otolaryngology/head and neck surgery, OHSU School of Medicine, and member of the OHSU Cancer Institute, points to a new pathway that could some day be used as a therapeutic target for not only treating hair loss and oily skin, but prevent and treat cancer.

The study's results are published in the current issue of the journal Developmental Cell.

Epidermal stem cells give rise to the outer layer of the skin that serves as a barrier for the body, as well as follicles that produce hairs and sebaceous glands that produce lipid oil to lubricate the skin. In aged skin, a protein called Smad7 is overproduced, which triggers hair loss and sebaceous gland growth.

The Developmental Cell study is the first to definitively link Smad7 over-expression and the pathological changes that occur in aged skin.

"In humans, scientists and medical doctors documented the aging skin phenotype a long time ago, and the Smad7 over-expression in aged skin was reported a few years ago, but nobody knew whether these two events had any link," said Wang, who also serves in the OHSU departments of Cell and Developmental Biology, and Dermatology. "We found the mechanism that links these two together."

For their study, the researchers created genetically engineered mice in which Smad7 is expressed in the skin, including epidermal stem cells, with the expression level comparable to aged skin. They found that Smad7 over-expression shifts the epidermal stem cell differentiation program from forming hair follicles to sebaceous glands, causing the mice to exhibit balding and oily skin.

Surprising to the researchers was that, independent of its normal role in blocking signaling from a group of genes called Smad, Smad7 shuts down signaling of another group of genes called Wnt, by binding to a Wnt signaling protein known as Beta-catenin and degrading it with an enzyme called Smurf2. Wnt signaling is critical for organ development, but if Wnt signaling is too active, it also causes cancer.

"Our study identifies a new Beta-catenin degradation pathway," the scientists said in the study. "This finding has a significant impact not only on skin development and diseases, but also on diseases and cancers in other organs."

For example, enhanced Beta-catenin signaling contributes to many cancer types, including those of the colon, lung and brain. The researchers believe inducing over-expression of Smad7 or delivery of Smad7 directly to tumor cells would provide a therapeutic approach because of the boost in Beta-catenin degradation.

However, impaired Beta-catenin signaling contributes to neurodegeneration, such as that caused by Alzheimer's disease, retina degeneration, bone density defect and aging. For these diseases, blocking Smad7-mediated Beta-catenin degradation may offer a therapeutic approach.

The Developmental Cell study was supported by grants from the National Institutes of Health.