Insulin receptor plays a central role in skin carcinogenesis by regulating cytoskeleton assembly

Diabetes mellitus prevalence is increasing rapidly and is a major cause of mortality and morbidity worldwide. In addition to the known severe complications associated with the disease, in recent years diabetes has been recognized as amajor risk factor for cancer. Patients with diabetes experience significantly higher incidence of and higher mortality rates from many types of cancer. However, to date there are no conclusive data on the pathophysiology underlying the association between these two diseases. We previously reported that insulin regulates skin proliferation and differentiation, while IGF1 had different sometimes contrasting effects to those of insulin, suggesting direct involvement of insulin in transformation. To this end, we developed an epidermal skinspecific insulinreceptorknockout (SIRKO)mouse, inwhichthe insulinreceptor (IR) is inactivatedonly inskin,with no other metabolic consequences. We found that IR inactivation by itself resulted in a marked decrease in skin tumorigenesis. In the control group 100% of the mice developed tumors, but in the SIRKO group tumor incidence was over 60%lower, and 25%of the SIRKOmice did notdevelop tumors at all, and the tumors that diddevelopwere smaller and benign in their appearance. Furthermore, IR inactivation in vitro not onlyprevented cell transformation but also reversed the keratinocyte-transformed phenotype.We found that IR inactivation led to a striking abnormalityinthemajorkeratin cytoskeleton filaments structure in both in vivo andin vitro, a change thatwewere able to linkto thedecreasedtransformationpotential inIR-null cells. Insummary,we identifiedauniquepathwayinwhich IR regulates cytoskeletal assembly, thus affecting skin transformation, opening a new potential target for cancer treatmentandprevention.