Department of Anatomy-Histology-Embryology, Medical School, University of Patras, 26500, Patras, Greece.
Department of General Biology, Medical School, University of Patras, 26504, Patras, Greece.
J Mol Histol. 2020 Aug;51(4):385-400. doi: 10.1007/s10735-020-09888-3. Epub 2020 Jun 22.
Integrin-linked kinase (ILK) forms a heterotrimeric protein complex with PINCH and PARVIN (IPP) in Focal Adhesions (FAs) that acts as a signaling platform between the cell and its microenvironment regulating important cancer-related functions. We aimed to elucidate the role of ILK in lung adenocarcinoma (LUADC) focusing on a possible link with KRAS oncogene. We used immunohistochemistry on human tissue samples and KRAS-driven LUADC in mice, analysis of large scale publicly available RNA sequencing data, ILK overexpression and pharmacological inhibition as well as knockdown of KRAS in lung cancer cells. ILK, PINCH1 and PARVB (IPP) proteins are overexpressed in human LUADC and KRAS-driven LUADC in mice representing poor prognostic indicators. Genes implicated in ILK signaling are significantly enriched in KRAS-driven LUADC. Silencing of KRAS, as well as, overexpression and pharmacological inhibition of ILK in lung cancer cells provide evidence of a two-way association between ILK and KRAS. Upregulation of PINCH, PARVB and Ras suppressor-1 (RSU1) expression was demonstrated in ILK overexpressing lung cancer cells in addition to a significant positive correlation between these factors in tissue samples, while KRAS silencing downregulates IPP and RSU1. Pharmacological inhibition of ILK in KRAS mutant lung cancer cells suppresses cell growth, migration, EMT and increases sensitivity to platinum-based chemotherapy. ILK promotes an aggressive lung cancer phenotype with prognostic and therapeutic value through functions that involve KRAS, IPP complex and RSU1, rendering ILK a promising biomarker and therapeutic target in lung adenocarcinoma.
整合素连接激酶（ILK）在黏着斑（FAs）中与 PINCH 和 PARVIN（IPP）形成异三聚体蛋白复合物，作为细胞与其微环境之间的信号平台，调节重要的与癌症相关的功能。我们旨在阐明 ILK 在肺腺癌（LUADC）中的作用，重点研究其与 KRAS 癌基因之间可能的联系。我们使用免疫组织化学方法对人类组织样本和 KRAS 驱动的 LUADC 进行分析，对大规模公开可用的 RNA 测序数据进行分析，对肺癌细胞进行 ILK 过表达和药理学抑制以及 KRAS 敲低。ILK、PINCH1 和 PARVB（IPP）蛋白在人 LUADC 和 KRAS 驱动的 LUADC 中过度表达，代表预后不良的指标。与 ILK 信号相关的基因在 KRAS 驱动的 LUADC 中显著富集。KRAS 沉默以及 ILK 在肺癌细胞中的过表达和药理学抑制为 ILK 和 KRAS 之间的双向关联提供了证据。在 ILK 过表达的肺癌细胞中，上调了 PINCH、PARVB 和 Ras 抑制剂-1（RSU1）的表达，此外，在组织样本中这些因素之间存在显著的正相关，而 KRAS 沉默下调了 IPP 和 RSU1。在 KRAS 突变型肺癌细胞中，ILK 的药理学抑制可抑制细胞生长、迁移、EMT 并增加对铂类化疗的敏感性。ILK 通过涉及 KRAS、IPP 复合物和 RSU1 的功能促进具有预后和治疗价值的侵袭性肺癌表型，使 ILK 成为肺腺癌有前途的生物标志物和治疗靶点。
