Role of Omentin in Obesity Paradox in Lung Cancer

Simple Summary: Unlike other cancers, lung cancer risk is inversely associated with body mass index (BMI) with limited mechanistic understanding. Overweight and obese patients have been consistently found to respond better to therapy and show better survival. The adipose tissue-in addition to storing energy-secretes multiple unique cytokines or adipokines. Our in silico analysis reveals that a novel adipokine, omentin, is significantly and consistently downregulated in lung cancers compared to healthy lung tissue. Omentin was also found to be negatively correlated with important oncogenic transcription factors like ELK4, FOXA1 and FOXC1. Our study warrants further mechanistic studies on the role of omentin in lung cancers. Lung cancer remains the second-most-common cancer worldwide and is associated with the highest number of cancer-related mortality. While tobacco smoking is the most important risk factor for lung cancer, many other lifestyles and occupational factors significantly contribute. Obesity is a growing global health concern and contributes to similar to 30% cancer-related mortality, but unlike other lifestyle diseases, lung cancer is negatively associated with obesity. We meta-analyzed multiple case-control studies confirming increased survival and better outcomes in overweight and obese lung cancer patients. Tumor heterogeneity analysis showed significant enrichment of adipocytes and preadipocytes in normal lungs compared to lung cancers. Interestingly, one of the understudied adipokine, omentin, was significantly and consistently lower in lung neoplasms compared to normal lungs. Omentin has been examined in relation to osteoarthritis, inflammatory bowel disease, cardiovascular diseases, diabetes, chronic liver disease, psoriasis and some other cancers. Aberrant expression of omentin has been reported in solid tumors; however, little is known about its role in lung cancer. We found omentin to be consistently downregulated in lung cancers, and it exhibited a negative correlation with important transcription factors FOXA1, EN1, FOXC1 and ELK4. We, therefore, suggest that omentin may serve as a prognostic factor in lung cancer and explain the "obesity paradox" in lung cancer.