Kindlin-1和Kindlin-2调控肺癌细胞可塑性的分子机制及其作为肺癌分化和预后标志物的研究

Lung cancer has become the number one killer among cancer-caused patient deaths in both men and women in China and the incidence of lung cancer increases rapidly. Unfortunately, little is known for the molecular mechanism accounting for lung cancer invasion and metastasis especially for the mechanism of lung cancer cell plasticity. Our previous investigations identified that Kindlin-1 promotes poorly differentiated lung cancer cells to differentiate towards well differentiated epithelial-like lung cancer cells. However, Kindlin-2 is mainly expressed in the tumor stroma and promotes lung cancer cell dedifferentiation. Our pilot studies suggest that the Kindlin-1 and Kindlin-2 are involved in lung cancer progression and regulate lung cancer cell plasticity. Importantly, both Kindlin-1 and Kindlin-2 were found to be involved in the regulation of TGF-β signalings. However, nothing is known for the role of Kindlin-1 and Kindlin-2 in lung cancer differentiation as well as the underlying mechanisms. In this grant proposal, we will investigate the regulatory role of Kindlin-1 and Kindlin-2 in lung cancer cell plasticity induced by TGF-β signaling pathway with emphasis on the interaction for Kindlin-1 and Kindlin-2 with TGF-β signaling pathway which regulates the differentiation and dedifferentiation of lung cancer cells. In particular, we will elucidate the molecular mechanisms accounting for differential roles of Kindlin-1 and Kindlin-2 in the regulation of lung cancer cell differentiation and dedifferentiation. Furthermore, in the current study we will also examine the possibility for Kindlin-1 and Kindlin-2 to be differential as well as prognostic markers for lung cancer patients. We anticipate to uncover the inter-relationship between the differentiations of lung cancer with the patient prognosis, which is finally beneficial to lung cancer patients.

肺癌目前已成为我国男女性别中癌症死亡最高的恶性肿瘤，且有加速上升之势。对肺癌侵袭和转移的分子机制尤其是肺癌细胞的可塑性知之甚少。我们的研究表明，Kindlin-1促使肺癌细胞向上皮方向分化，而Kindlin-2驱使肺癌细胞去分化，提示Kindlin-1 和Kindlin-2以不同方式共同参与肺癌细胞可塑性的调节。重要的是，二者均参与TGF-β信号通路的调控。然而, Kindlin-1 和Kindlin-2在肺癌的分化、侵袭和转移中的差异调控作用及其分子机制不详。本申请中，我们将研究Kindlin-1 和Kindlin-2在TGF-β信号通路诱导肺癌细胞可塑性的过程中所发挥的作用；研究二者与TGF-β信号通路相互作用调控肺癌细胞的分化与去分化及其分子机制；探讨Kindlin-1 和Kindlin-2作为肺癌分化和预后标志物的可能性。本研究预期将揭示肺癌分化状态和预后之间的关系并惠及肺癌病人。

已经有报道发现Kindlin-1/2基因与发育和肿瘤均密切相关，然而其如何调节肺癌分化与进程尚不清楚，其在发育过程中及人体器官中的表达规律也还没有报道。本研究发现Kindlin-1和Kindlin-2在非小细胞肺癌中差异表达，而在小细胞肺癌中低表达或不表达，提示Kindlin-1和Kindlin-2在非小细胞肺癌的进程中起作用。Kindlin-1在鳞癌和腺癌中高表达，尤其是在中、高分化鳞癌中表达更高。而在分化较低的小细胞肺癌和未分化大细胞肺癌中表达较低或不表达。Kindlin-2主要高表达于肺癌间质，而在肺癌本身组织当中表达有很大差异：在鳞癌表达低，在腺癌中有少量表达，小细胞肺癌无Kindlin-2表达，而部分未分化大细胞肺癌中Kindlin-2表达高。Kindlin-2促进而Kindlin-1抑制肺癌细胞系H1299细胞的EMT、运动与迁移和体内成瘤能力。提示，Kindlin-1表达与肺癌高分化相关，抑制进程，Kindlin-2表达与肺癌低分化相关，促进进程；二者调节肺癌可塑性。本研究还发现Kindlin-1/2在人胚、鼠胚、成人器官中的表达规律，Kindlin-1在内外胚层及其来源器官高表达而Kindlin-2在中胚层及其来源器官高表达。并发现Kindlin-1/2在肺癌、食管癌中差异表达，并且在肺癌、食管癌进展过程中发挥相反作用。机制上，Kindlin-2通过调节转录了因子HOXB9表达水平促进肺癌分期分级并预示肺腺癌不良预后，HOXB9在被PCAF乙酰化和SIRT1去乙酰化中维持平衡，切换对JMJD6的转录调节，从而实现其对肺癌进程的调控。总之，同一家做中的两个分子在发育及肿瘤中均发挥差异表达及相反作用，而Kindlin-2通过Kindlin-2--HOXB9--JMJD6分子机制实现对肺癌的调节。