小分子化合物抗肺癌作用以及肺癌全基因组测序研究
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摘要
肺癌是最常见恶性肿瘤,并逐渐成为包括中国、美国等世界其他国家死亡率最高的癌症。目前对早期肺癌的预防和治疗虽然已经取得很大进展,但治疗效果与预后仍欠佳,为预防和攻克肺癌,需要进一步探索肿瘤发病机理和找寻更多新药物进行靶向治疗。
正常的肺上皮细胞通过有序的细胞周期来调控细胞生长、分裂和DNA合成,一旦这种正常调控紊乱,细胞将向恶性程度演化,最终诱发肿瘤产生。Cyclin Dl (CCND1编码)为细胞周期G1期的关键调控蛋白,通过与CDK4/6激酶形成复合物使Rb的Ser/Thr残基磷酸化,使细胞周期从G1期向S期转换。Cyclin D1在肺癌样本中表达异常且其过表达与预后差相关联,因此Cyclin D1可以作为肺癌靶向治疗的一个靶点。在此基础上,我们寻找并发现中药来源的小分子化合物GEA能够抑制多种肺癌细胞系增殖而对正常肺成纤维细胞和上皮细胞敏感性较差,且GEA可以促进Cyclin D1降解,抑制CDK2激酶活性,最终导致周期阻滞于G1期。通过GSK3β抑制剂或者siRNA可以抑制GEA引起的Cyclin D1降解,运用蛋白酶体抑制剂进一步发现GEA是通过泛素-蛋白酶体途径降解CyclinDl。有趣的是,我们还发现GEA可以促进肺癌细胞自噬,并抑制PTEN/AKT/mTOR信号通路。这些都说明GEA能够下调Cyclin Dl和诱导自噬,具有潜在的肺癌治疗应用前景。
除小分子化合物的肺癌靶向治疗外,我们还进一步研究了环境因素相关肺癌的发病机制。位于我国云南省东北部的宣威地区是当地主要产煤区(特别是烟煤),其肺癌发病率居全国最高并呈逐年增高趋势,室内燃煤空气污染是其主要致病因素,因此该地区肺癌病人样本可以作为研究环境诱发肺癌机制的良好对象。通过对14对非小细胞肺癌病人组织DNA以及匹配癌旁组织DNA进行高通量全基因组测序分析,发现大量与肺癌发生相关的突变、插入／缺失、染色体重排和拷贝数变化等。通过扩大样本验证,我们发现了一些该地区特有的突变基因,其中,通过siRNA干扰的方法沉默CACNA1E基因表达,能够显著抑制肺癌细胞系的增殖和克隆形成能力,并且抑制EGFR/AKT信号通路,说明这些基因可能参与了肺癌的形成过程。
综上所述,GEA通过降解原癌蛋白Cyclin D1引起G1期阻滞和促进细胞自噬来抑制肺癌细胞增殖。通过全基因组测序,发现新的与肿瘤发生发展相关的致病基因,并通过外显子测序扩大样本验证,为治疗肺癌提供新的策略。
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.
正常的肺上皮细胞通过有序的细胞周期来调控细胞生长、分裂和DNA合成,一旦这种正常调控紊乱,细胞将向恶性程度演化,最终诱发肿瘤产生。Cyclin Dl (CCND1编码)为细胞周期G1期的关键调控蛋白,通过与CDK4/6激酶形成复合物使Rb的Ser/Thr残基磷酸化,使细胞周期从G1期向S期转换。Cyclin D1在肺癌样本中表达异常且其过表达与预后差相关联,因此Cyclin D1可以作为肺癌靶向治疗的一个靶点。在此基础上,我们寻找并发现中药来源的小分子化合物GEA能够抑制多种肺癌细胞系增殖而对正常肺成纤维细胞和上皮细胞敏感性较差,且GEA可以促进Cyclin D1降解,抑制CDK2激酶活性,最终导致周期阻滞于G1期。通过GSK3β抑制剂或者siRNA可以抑制GEA引起的Cyclin D1降解,运用蛋白酶体抑制剂进一步发现GEA是通过泛素-蛋白酶体途径降解CyclinDl。有趣的是,我们还发现GEA可以促进肺癌细胞自噬,并抑制PTEN/AKT/mTOR信号通路。这些都说明GEA能够下调Cyclin Dl和诱导自噬,具有潜在的肺癌治疗应用前景。
除小分子化合物的肺癌靶向治疗外,我们还进一步研究了环境因素相关肺癌的发病机制。位于我国云南省东北部的宣威地区是当地主要产煤区(特别是烟煤),其肺癌发病率居全国最高并呈逐年增高趋势,室内燃煤空气污染是其主要致病因素,因此该地区肺癌病人样本可以作为研究环境诱发肺癌机制的良好对象。通过对14对非小细胞肺癌病人组织DNA以及匹配癌旁组织DNA进行高通量全基因组测序分析,发现大量与肺癌发生相关的突变、插入／缺失、染色体重排和拷贝数变化等。通过扩大样本验证,我们发现了一些该地区特有的突变基因,其中,通过siRNA干扰的方法沉默CACNA1E基因表达,能够显著抑制肺癌细胞系的增殖和克隆形成能力,并且抑制EGFR/AKT信号通路,说明这些基因可能参与了肺癌的形成过程。
综上所述,GEA通过降解原癌蛋白Cyclin D1引起G1期阻滞和促进细胞自噬来抑制肺癌细胞增殖。通过全基因组测序,发现新的与肿瘤发生发展相关的致病基因,并通过外显子测序扩大样本验证,为治疗肺癌提供新的策略。
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.
引文
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