Klotho通过调控肺癌干细胞PI3K/AKT/Wnt/β-catenin等信号在肺癌治疗及预后中的作用研究

Cancer is closely associated with aging, with the increase of age, the incidence of cancer increased significantly, the age factor of lung cancer is particularly evident. Recently published studies suggest that klotho,an anti-aging gene, in addition to its anti-aging effects, can also serve as a potential tumor suppressor in a variety of tumor cells. We firstly studied and showed that klotho can also works as a tumor suppressor in lung cancer. It can inhibit growth and promote apoptosis in lung cancer cells by regulating signaling pathways of IGF-1/insulin、Wnt/β-catenin and Bax/bcl-2. It can also sensitize lung cancer cells to cisplatin via PI3k/Akt pathway. However, after radiotherapy and chemotherapy, there are great risks of cancer recurrence, and the reason is that cancer stem cells(CSCs) survive after the therapy. The cells have the strong antagonistic effects of radiotherapy and chemotherapy. Combined with our previous research results, we found that klotho affected the signaling pathways of PI3K/AKT/ Wnt/β-catenin which play an important role in cancer stem cells occurrence and development. We hypothesized that in lung cancer, klotho could inhibit lung cancer stem cells growth and sensitize them to cisplatin by regulating PI3K/AKT/ Wnt/β-catenin signaling pathways and affecting ABCG2 expression. The anti-cancer effect would be more effective and thoroughly.

癌症与老化密切相关，随着年龄增长，癌症发病率显著增加，其中肺癌的年龄因素尤其明显。新近发现，新的抗衰老基因klotho除了具有抗衰老作用外，在多种肿瘤中还发挥着抑癌基因作用。本实验室首次提出klotho在肺癌中也发挥抑癌作用。它通过调节IGF-1/insulin、Wnt/β-catenin、Bax/bcl-2等信号抑制肺癌细胞生长并促进其凋亡；调节PI3K/AKT通路改善耐药细胞株对化疗药顺铂敏感性。然而，癌症经传统放化疗等治疗后都有巨大复发风险，原因主要是放化疗后残存的细胞主要为癌症干细胞的缘故，其对放化疗具有显著对抗性。深入分析发现，klotho影响的Wnt/β-catenin、PI3K/AKT等信号，在癌症干细胞发生、发展中具有重要作用。我们推测：在肺癌细胞中，klotho通过调节PI3K/AKT/ Wnt/β-catenin等信号抑制肺癌干细胞生长并改善其耐药性，抑癌作用更彻底。

肺癌发病率及死亡率均居恶性肿瘤首位，肺癌与老化密切相关，随着人口老龄化的加速，肺癌形势将日益严峻。新近发现，抗衰老基因klotho除了具有抗衰老作用外，在多种肿瘤中还发挥着抑癌基因作用。本课题组对Klotho在肺癌中的作用进行了系列研究，结果发现：（1）非小细胞肺癌（NSCLC）中，Klotho可通过调节IGF-1/insulin、Bax/Bcl-2、Wnt/β-catenin、PI3K/AKT等信号通路，抑制肺癌细胞生长、迁移，促进其凋亡，改善其对化疗药敏感性。（2）衰老成纤维细胞可通过分泌IL-6、IL-8等细胞因子及趋化因子，改变肿瘤微环境，从而促进肺癌细胞增殖、迁移；而Klotho可以通过调节衰老成纤维细胞SASP，抑制IL-6、IL-8等分泌，从而间接发挥抑制肺癌增殖、迁移作用。其可能机制是通过调节STAT3、P53、A-sma、E-cadherin等信号实现的。（3）囊泡运输相关蛋白Rab8与Klotho存在物理性的结合，并且在不影响Klotho表达量的基础上，Rab8可能通过提高Klotho膜表面分布水平，参与调节NSCLC细胞的生物学行为变化。（4）BDNF在NSCLC中高表达，通过与受体TrkB结合，刺激STAT3的激活，从而促进NSCLC增殖。有趣的是，激活的STAT3反过来促进BDNF的合成，从而延长激活TrkB信号。因此，BDNF/TrkB与STAT3信号通路之间存在一个自分泌环，具有正反馈作用，参与了肺癌的调控。（5）我们预实验数据还发现：BDNF/TrkB激活STAT3，活化的STAT3可能通过与Klotho转录子E2F竞争结合Klotho启动子结合位点，导致Klotho低表达，促进NSCLC细胞增殖、迁移；此外，BDNF/TrkB还可能通过PLC-γ通路诱导Rab8生成，促进肺癌细胞增殖、迁移。本课题的顺利完成将为今后充分认识Klotho在肺癌中的作用奠定了基础。