Abstract
Epidemiological studies have recently shown that obesity increases lung cancer risk, but the underlying biological connection is unclear. To determine whether high-fat diet (HFD)-induced obesity influences the susceptibility to chemical-induced lung tumorigenesis, a HFD feeding condition was combined with a multi-dose urethane-induced lung tumorigenesis model using C57BL/6J mice. In cell culture models, lung cancer cell lines A549 and H460 were used to investigate the effect of leptin on cell viability and its underlying mechanism of action. The results showed that obesity was induced with a 60 kcal% HFD feeding. Serum leptin levels increased with HFD feeding and further increased in urethane-administered and HFD-fed mice. Compared to the control diet-fed mice, the HFD-fed mice exhibited increased lung tumor burden and typical pro-tumorigenic STAT3 pathway activation in lung tissues after urethane administration. In vitro, leptin significantly increased the viability of lung cancer cell lines A549 and H460 in a dose-dependent manner by activation of STAT3, Bcl-2, and cyclin D1. These effects were significantly attenuated when PI3K or mTOR were inhibited by LY294002 or rapamycin, respectively. These results suggested that HFD-induced obesity could promote the development of lung tumorigenesis in C57BL/6J mice, and leptin-mediated activation of the PI3K/Akt/mTOR/STAT3 pathway was likely involved in this mechanism.
Highlights
Lung cancer is the most common malignant tumor and the leading cause of cancer-related deaths worldwide
The results showed that high-fat diet (HFD)-related obesity could promote the development of urethane-induced lung cancer in C57BL/6J mice, and the leptin-mediated activation of PI3K/Akt/mammalian target of rapamycin (mTOR)/STAT3 pathway was involved in the mechanism
Nitroquinoline 1-oxide-induced pulmonary tumorigenesis in ICR male mice was reported as early as in 1989 [11], the underlying mechanisms related to obesity and lung cancer risk have not been investigated in animal models largely because the majority of studies published indicated that high body mass index (BMI) had an inverse relationship with lung cancer risk in humans [6]
Summary
Lung cancer is the most common malignant tumor and the leading cause of cancer-related deaths worldwide. Obesity Promote Lung Cancer Risk is the leading risk factor for lung cancer, there are other lifestyle-related risk factors involved as well. Obesity can contribute to the morbidity and etiology of many diseases, including cardiovascular diseases, diabetes, steatohepatitis, and cancer, through chronic systematic inflammation and an unbalanced energy metabolism [3]. A comprehensive systematic review conducted by the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) found that obesity was the risk factor for several cancer types, including postmenopausal breast cancer, colorectal cancer, and prostate cancer [4]. In 2016, the International Agency for Research on Cancer (IARC)-working group reported that the risk of 13 types of cancer was positively related to obesity [2]
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