Digital gene expression profiling of mouse skin gene expression after cyclophosphamide (CYP) treatment

Chemotherapy often causes adverse effects including hair loss, however, the molecular basis remains unclear. A common assumption is that by targeting actively dividing cancer cells, chemo-drugs would inevitably damage normal proliferating cells as a “side effect”. Using both mouse hair and avian feather as models, here we show that down-regulation of sonic hedgehog (Shh) signaling is a critical event mediating chemo-drug induced tissue damage. Reduced expression of Shh is also apparent in human patients who experience hair loss after receiving chemotherapy, and in animal models treated with several frontline chemo-drugs. Supplementation of Shh protein or steroid hormones that activate Shh signaling prevented hair loss, but interestingly, not the damage to the pigment system. Together, our results have elucidated a molecular mechanism underlying chemotherapy-induced tissue damage, and suggested novel concepts and methodologies for future clinical interventions and drug development. Overall design: Cyclophosphamide (CYP) was i.p. administered to 2-month-old male C57B/6 mice at 150mg/kg, which were depilated 9 days earlier to induce active hair growth. Total RNAs were extracted from whole skin at designated times, quality monitored by Agilent 2100 analysis, and proceeded for sequencing by Illumina Genome Analyzer in Beijing Genome Institute (BGI), Shenzhen, China. The sequencing results were annotated according to a reference mouse gene database provided by BGI.