Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.
Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.
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DOI：
10.1371/journal.pone.0134842
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Jeong Y
中科院分区：
文献类型：
--
作者：
Kim J;Sato M;Choi JW;Kim HW;Yeh BI;Larsen JE;Minna JD;Cha JH;Jeong Y
肺癌是由多种基因突变的组合引起的。为了了解核受体（NR）在癌基因相关肺癌发病机制中的相关性，我们通过在一组人支气管上皮细胞（HBEC）中使用QPCR分析研究了整个48个NR成员的表达谱，其中包括癌前和肿瘤发生HBEC，其携带致癌K-rasV 12和/或p53改变。分析的配置文件显示，致癌的改变伴随着转录的变化，在癌前HBEC和15个NR的表达根据HBEC的恶性进展。其中，过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ），一种被选为原理验证研究的NR，在癌前HBEC中显示出表达增加，当这些HBEC获得完全体内致瘤性时，这种表达令人惊讶地逆转。值得注意的是，噻唑烷二酮（TZD）处理的PPARγ激活逆转了癌前HBEC中促炎性环氧合酶2（COX 2）表达的增加。在具有可诱导表达的PPARγ的完全致瘤性HBEC中，TZD处理以PPARγ-sumoylation依赖性方式抑制肿瘤细胞生长、克隆形成和细胞迁移。从机制上讲，配体-PPAR γ的类小泛素化降低了COX 2的表达，增加了15-羟基前列腺素脱氢酶的表达。这表明配体介导的PPARγ类小泛素化通过调节前列腺素代谢在肺癌发病中起重要作用。
Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.