Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education of Beijing, Beijing, People's Republic of China.
PLoS One. 2012;7(11):e50313. doi: 10.1371/journal.pone.0050313. Epub 2012 Nov 29.
Lung cancer is highly heterogenous and is composed of various subtypes that are in diverse differential stages. The newly identified integrin-interacting proteins Kindlin-1 and Kindlin-2 are the activators of transmembrane receptor integrins that play important roles in cancer progression. In this report we present the expression profiles of Kindlin-1 and Kindlin-2 in lung cancers using patient specimens and established their correlation with lung cancer progression. We found that Kindlin-1 was expressed in epithelia-derived non-small-cell lung cancer, especially in squamous cell lung cancer but expressed at low levels in poorly differentiated large cell lung cancer. However, Kindlin-2 was highly expressed in large cell lung cancer. Both Kindlin-1 and Kindlin-2 were found not expressed or expressed at very low levels in neuroendocrine-derived small cell lung cancer. Importantly, the Kindlin-1 expression level was positively correlated with the differentiation of squamous cell lung cancer. Surprisingly, we found that the very homologous Kindlin family proteins, Kindlin-1 and Kindlin-2, displayed counteracting functional roles in lung cancer cells. Ectopic expression of Kindlin-1 in non-small-cell lung cancer cells inhibited in vitro cell migration and in vivo tumor growth, while Kindlin-2 promoted these functions. Mechanistically, Kindlin-1 prohibited epithelail to mesenchymal transition in non-small-cell lung cancer cells, while Kindlin-2 enhanced epithelail to mesenchymal transition in these cells. Taken together, we demonstrated that Kindlin-1 and Kindlin-2 differentially regulate lung cancer cell progression. Further, the expression levels of Kindlin-1 might be potentially used as a marker for lung cancer differentiation and targeting Kindlin-2 might block the invasive growth of large cell lung cancer.
肺癌高度异质，由处于不同分化阶段的各种亚型组成。新鉴定的整合素相互作用蛋白 Kindlin-1 和 Kindlin-2 是跨膜受体整合素的激活剂，在癌症进展中发挥重要作用。在本报告中，我们使用患者标本研究了 Kindlin-1 和 Kindlin-2 在肺癌中的表达谱，并确定了它们与肺癌进展的相关性。我们发现 Kindlin-1 在上皮源性非小细胞肺癌中表达，特别是在鳞状细胞肺癌中，但在低分化大细胞肺癌中表达水平较低。然而，Kindlin-2 在大细胞肺癌中高度表达。Kindlin-1 和 Kindlin-2 在神经内分泌源性小细胞肺癌中均未表达或表达水平非常低。重要的是，Kindlin-1 的表达水平与鳞状细胞肺癌的分化呈正相关。令人惊讶的是，我们发现非常同源的 Kindlin 家族蛋白 Kindlin-1 和 Kindlin-2 在肺癌细胞中表现出相反的功能作用。非小细胞肺癌细胞中 Kindlin-1 的异位表达抑制了体外细胞迁移和体内肿瘤生长，而 Kindlin-2 则促进了这些功能。机制上，Kindlin-1 阻止非小细胞肺癌细胞上皮向间充质转化，而 Kindlin-2 增强了这些细胞的上皮向间充质转化。总之，我们证明了 Kindlin-1 和 Kindlin-2 差异调节肺癌细胞的进展。此外，Kindlin-1 的表达水平可能潜在地用作肺癌分化的标志物，而靶向 Kindlin-2 可能会阻止大细胞肺癌的侵袭性生长。
