The Molecular Mechanism Of Hair Follicle Tissue Damage Caused By Chemotherapy

At present, the major methods of treatment for cancer are surgical, radiotherapy and chemotherapy. Although chemo-drugs (such as cyclophosphamide, paclitaxel,5-fluorouracil) can kill and inhibit the growth of tumor, at the same time, chemo-drugs also can cause some damage to normal tissue and other side effects, the most obvious is hair loss. However, the molecular mechanism of chemotherapy-induced alopecia has not been well documented. Previous work has suggested that p53 is essential for the development of chemotherapy induced hair loss in mouse, chemo-drugs stimulate apoptosis in the hair follicles and cause hair loss through p53-dependent Fas pathway. Using mouse skin, we compared the differences of the genomic expression profile after injecting cyclophosphamide and found that sonic hedgehog (Shh) signaling is markedly depressed at the first day after treatment, but p53 and its downstream p21 and Fas genes have no change. What’s more, shh signaling is important to the development of follicle, so we next used the avian feather as research model, because shh dose not express in the feather shaft, but is essential in the marginal plate. Our results showed that the barbs lost instead of the whole feather post-treatment. Furthermore, chemotherapy-induced mouse alopecia can be rescued by exogenous shh protein to a certain degree. Western blot results show that cyclins associated with p53 also have no change post-chemotherapy, at the same time, p53-/-mouse also have alopecia. These all demonstrated that Shh signaling is the major target of chemo-drug that caused hair loss. Using BrdU staining, we find only shh-dependent growth is perturbed. Combined previous research results and expression profile analysis show cell-cycle regulatory protein N-myc and CDC25 may be regulated by shh. We used AGS cells in vitro drug experiments confirmed shh decreased rapidly after treatment, down-regulation of shh reduced N-myc and CDC25 and induced cell cycle arrest, resulting in tissue damage at last. We also found some other chemo-drugs that cause hair loss have the similar effect to CYP. In summary, our works discovered the target of chemo-drugs and revealed the molecular mechanism of hair follicle tissue damage caused by chemotherapy. This provides new research ideas and methods for us in cancer treatment and drug development.