Knockdown of CRAD suppresses the growth and promotes the apoptosis of human lung cancer cells via Claudin 4

Abstract

Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer-related mortality globally. However, the mechanism underlying NSCLC is not fully understood. Here we investigated the role of cancer-related regulator of actin dynamics (CRAD) in NSCLC. We showed that CRAD was up-regulated in human NSCLC tissues and lung cancer cell lines. Lentivirus-mediated knockdown of CRAD repressed the proliferation and colony growth of A549 and H1299 cells. Apoptosis was enhanced by CRAD silencing in both cells, implicating that CRAD might maintain the survival of lung cancer cells. Microarray and bioinformatic assay revealed that CRAD directly or indirectly regulated diverse genes, including those involved in cell cycle and DNA damage repair. qRT-PCR and Western blot results confirmed the dysregulated genes as shown in microarray analysis. Claudin 4 was up-regulated in CRAD silenced A549 cells. The knockdown of Claudin 4 blocked the effects of CRAD on the expression of cell cycle and apoptosis effectors and enhanced the viability of A549 cells with CRAD down-regulation. Taken together, our findings demonstrate that CRAD acts as an oncogene in NSCLC at least partly through repressing Claudin 4.

Claudin-4: A New Molecular Target for Epithelial Cancer Therapy

“…In contrast, there are also reports suggesting that the expression of CLDN4 suppresses carcinogenesis. CLDN4 knockout mice exhibit a hyperproliferation of the urothelium [ 77 ], while activation of the tumor suppressor gene cancer-related regulator of actin dynamics (CRAD) is associated with CLDN4 upregulation [ 78 ]. CLDN4 inhibits EphA2 oncogenic signaling by inactivating the β-catenin and PI3K-AKT pathways [ 79 ].…”