Chronic pulmonary inflammation is an important risk factor for lung cancer. Accumulating data have shown that smokers with chronic pulmonary inflammation have a higher risk of developing lung cancer as compared to smokers without pulmonary inflammation. Molecular links between pulmonary inflammation and lung cancer are microRNAs (miRs) and pro-inflammatory signaling pathways such as Akt, NF-?B and STAT3. Therefore, targeting of miRs and pro-inflammatory signaling pathways by chemo preventive agents could suppress lung tumor genesis. The main goal of this project is to assess the efficacy of combinations of indole- 3-carbinol (I3C) and silibinin (SB), two widely consumed naturally occurring phytochemicals, to inhibit chronic inflammation-related lung cancer and determine the mechanisms involved. In preliminary studies, we developed a novel and facile mouse model for inflammation-driven lung cancer and showed in in vitro studies with lung cancer cell lines that the ant proliferative and apoptotic effects of I3C plus SB were paralleled b decreased activation of the pro-inflammatory proteins Akt, NF-?B and STAT3, down-regulation of miR-21 and miR-155, but up-regulation of PTEN and SHIP1, targets for miR-21 and miR-155, respectively. Therefore, we hypothesized that inflammation-driven lung tumor genesis could be inhibited by I3C plus SB, at least in part, via modulation of miR-21 and miR-155 levels in association with inhibition of Akt, NF-kB and STAT3 signaling. This hypothesis will be tested by the following three Aims:
Specific Aim 1 : Evaluate the efficacy of I3C plus SB against NNK plus LPS-induced mouse lung adenocarcinoma, inflammatory milieu and dysregulation of miRs.
Specific Aim 2 : Determine the efficacy of anti-miR-21 and anti-miR-155, alone or in combination, to inhibit inflammation-driven lung tumor genesis in A/J mice.
Specific Aim 3 : Elucidate how I3C plus SB interrupts the inflammatory positive feedback loop involving Akt, NF-kB/STAT3, and miR-21/miR155 and thus inhibits cell proliferation and survival. Impact/Significance: The results of this study could establish the basis for future clinical trials of I3C plus SB for lung cancer chemoprevention and provide a better understanding of the molecular events underlying inflammation-driven lung tumor genesis.
Lung cancer is the leading cause of cancer-related mortality. Chronic pulmonary inflammation is linked to an increased risk for lung cancer since proinflammatory molecules stimulate the growth and survival of lung cancer cells. Here, we propose that suppression of these pro-inflammatory molecules by combinations of indole-3-carbinol (I3C) and silibinin (SB), two widely consumed plant constituents, inhibits inflammation-driven lung cancer. The results from these studies should allow further development of this mixture for clinical trials.
|Fujioka, Naomi; Fritz, Vincent; Upadhyaya, Pramod et al. (2016) Research on cruciferous vegetables, indole-3-carbinol, and cancer prevention: A tribute to Lee W. Wattenberg. Mol Nutr Food Res 60:1228-38|
|Song, Jung Min; Qian, Xuemin; Molla, Kalkidan et al. (2015) Combinations of indole-3-carbinol and silibinin suppress inflammation-driven mouse lung tumorigenesis by modulating critical cell cycle regulators. Carcinogenesis 36:666-75|
|Qian, Xuemin; Khammanivong, Ali; Song, Jung Min et al. (2015) RNA-sequencing studies identify genes differentially regulated during inflammation-driven lung tumorigenesis and targeted by chemopreventive agents. Inflamm Res 64:343-61|
|Melkamu, T; Qian, X; Upadhyaya, P et al. (2013) Lipopolysaccharide enhances mouse lung tumorigenesis: a model for inflammation-driven lung cancer. Vet Pathol 50:895-902|