Novel obesity-associated adipokine modulates the malignant phenotype of endometrial cancer cells

Endometrioid Endometrial Cancer (EEC) is the most common gynecologic malignancy in the United States. Around 60% of women with EEC are believed to be associated with being overweight or obese. This fraction of patients is likely to increase as the obesity epidemic continues in the United States. Omentin (ITLN1) is a novel adipokine that is expressed in mesothelial cells covering the omental adipose tissue. The serum omentin level is inversely correlated with Body Mass Index and it increases with weight loss. We demonstrated that serum omentin level is significantly lower in patients with EEC compared to healthy women. Besides, immunocompetent mice fed with high-fat diet demonstrated a significantly higher tumor burden and lower circulating omentin level than those fed with low-fat diet, suggesting that obesity suppresses circulating omentin level and promotes EEC progression. To determine the roles of omentin in EEC pathogenesis, both human and mouse EEC cell lines were treated with recombinant omentin to evaluate cell growth and cell motility. We found that EEC cells treated with recombinant omentin have a significantly lower cell proliferation rate compared to control cells treated with PBS. Omentin-treated EEC cells also resulted in a significantly reduced migration rate compared to control cells. Since omentin was previously reported to bind to alpha-v-beta-3 (alphavbeta3) integrin to exert biological functions, we treated the EEC cells with alphavbeta3 blocking antibody to see if the effects of omentin on cell growth and motility would be abrogated. We found that alphavbeta3 blocking antibody abrogated the suppressive effect of omentin on cell growth compared to normal mouse IgG control. Similarly, alphavbeta3 blocking antibody counteracted the effect of omentin on cell migration. These suggest that omentin binding to the alphavbeta3 integrin inhibited cell proliferation and motility. In addition, Western blot analysis showed that omentin downregulated key alphavbeta3 downstream signaling molecules, such as p-ERK and p-CREB. Addition of alphavbeta3 blocking antibody in omentin-treated cells reversed the suppressive effect of omentin on p-ERK, further suggesting that omentin/alphavbeta3 integrin axis may play an important role in mediating the tumor suppressive effect of omentin.In conclusion, the above findings suggest that omentin suppresses EEC cell growth and migration potentially through binding to alphavbeta3 integrin. Further study is needed to characterize the specific pathways involved in omentin-mediated suppression on EEC cells and to develop omentin as a low toxicity chemopreventive and therapeutic agent for EEC patients