| Lung cancer is the leading cause of cancer related morality in China, the United States and many other areas in worldwide. Though there are some improvements in early prevention and treatment, lung cancer often has a poor prognosis and five-year survival rate for all stages remains unsatisfactory. Therefore, to prevent and conquer this disease, we could further explore the pathogenesis and development of lung cancer and identify more novel molecular target and drugs.In non-transformed lung epithelial cells, cellular division is an ordered, regulated and highly conserved process that controls cell growth, cell mitosis and DNA integrity. Disruption of normal cell cycle regulation is a prominent abnormality in malignant tumors, including lung cancer. Cyclin Dl, an oncoprotein encoded by the CCND1gene is a key indicator in cell cycle. During G1phase, complexes of the cyclin-dependent kinase (CDK4/6) and cyclins (Cyclin D1) phosphorylate pRb, trigger Rb hyperphosphorylation and dissociation, leading to G1to S phase cell cycle transit. Abnormalities of Cyclin D1are detected in lung cancer cases and Cyclin D1over-expression is reported to be an indicator of poor prognosis. Therefore, Cyclin D1can serve as potential drug target for lung cancer. Basing on above, we tried to screen inhibitors of Cyclin D1and find a natural compound, gambogenic acid (GEA), which was extracted from gamboges, could markedly inhibit lung cancer cells, however, human embryonic lung fibroblasts and bronchial epithelial cell lines were less sensitive to this compound. Furthermore, GEA may trigger the degradation of Cyclin D1and inhibition of CDK2, leading to arrest of cell cycle at G1phase. We then explored the degradation mechanisms of Cyclin D1, and found that GSK3β inhibitor LiC1or GSK3β specific siRNA suppressed GEA-induced degradation of this protein. In addition, proteasome inhibitors abrogated GEA-induced Cyclin D1turnover. Intriguingly, GEA induced autophagy through inactivation of PTEN/AKT/mTOR signal pathway in lung cancer cells. All of these data had documented GEA’s anti-cancer activity via degradation Cyclin D1and inducing autophagy in lung cancer cells, suggesting its potential in cancer control.In addition to identify small-molecular compound that target lung cancer, we further studied the pathogenesis of environmental exposure-associated lung cancer via next generation sequencing. Xuanwei County locates in the northeastern of Yunnan Province and is rich in coal, iron, copper and other mines, especially the smoky coal. Unfortunately, the lung cancer mortality rates in this region are among the China’s highest, with a clear upward trend from the mid-1970s to today. The major factor associated with the rate of lung cancer incidence in Xuanwei was indicated to be indoor air pollution caused by the indoor burning of smoky coal. Taken together, lung cancer in this region is a unique model for environmental factor-related human cancer analysis. We screened14no small cell lung cancers (NSCLC) samples from Xuanwei and applied whole genome sequencing to discover the most comprehensive mutation profiles of cancer genomes, including somatic point mutations, small insertions and deletions, chromosomal rearrangements and copy number variations. We had validated some interest genes in150primary patients from Xuanwei and no-exposure smoky coal regions and found some mutations are frequently in Xuanwei areas. For example, silengcing the gene of CACNA1E by siRNA inhibited growth and clonogenic activity of lung cancer cells, and suppress EGFR/AKT signal pathway.In conclusion, GEA could induce G1arrest via GSK3β-dependent Cyclin D1degradation and trigger autophagy, leading to inhibition of proliferation and inactivation of PTEN/AKT/mTOR signal pathway. More importantly, though whole genome sequencing of cancers, we found and validated the recurrence of interest genes, providing novel strategies for preventive and therapeutic in lung cancer. |
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