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。

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.