Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Abstract

We sought to elucidate the role of Rho guanine nucleotide exchange factor 5 (ARHGEF5) in tumorigenesis of lung adenocarcinoma cells. ARHGEF5 protein levels were assessed in 91 human lung adenocarcinoma specimens, and A549 and NCI-H1650 cells, by IHC and Western blotting. In addition, ARHGEF5 mRNA expression was evaluated by quantitative reverse transcriptase-PCR. Furthermore, ARHGEF5 long and short isoform coexpression was detected by immunofluorescence. Finally, flow cytometry; CCK8 and wound-healing assays; cell invasion, migration and adhesion; and xenografts were used to evaluate the biologic significance of ARHGEF5. ARHGEF5 was significantly increased in lung adenocarcinoma tissues and cell lines. Interestingly, ARHGEF5 levels were significantly associated with tumor grade and pathologic stage, but not age, gender, T stage, or lymph node metastasis status. ARHGEF5 knockdown by RNAi resulted in dramatically reduced proliferation, adhesion, invasion, and migratory capability of A549 and NCI-H1650 cells. Likewise, protein levels of p-Src, p-Akt, and NF-kB were significantly decreased after ARHGEF5 knockdown. In parallel, increased S-phase population and MMP-2/cyclin D1 expression were observed in the cancer cells, which were not apoptotic. In addition, ARHGEF5 knockdown A549 and NCI-H1650 cells injected s.c. and i.v. into nude mice exhibited decreased xenograft volume and overtly reduced metastasis. Conversely, ARH-GEF5 overexpression in A549 and NCI-H1650 cells increased their tumorigenicity in vitro. ARHGEF5 acts as a proto-oncogene in human lung adenocarcinoma cell tumorigenesis.

ARHGEF19 interacts with BRAF to activate MAPK signaling during the tumorigenesis of non‐small cell lung cancer

“…Aberrant expression of RhoGEFs is a major mechanism driving the abnormal activation of their target proteins and signaling pathways, which are associated with certain types of cancer , . RhoA, potentiating ERK/MAPK through a ROCK‐dependent pathway, is overexpressed in several tumor types, such as colon, breast, and lung cancers .…”

Emerging Roles of Ephexins in Physiology and Disease

“…In addition, Ephexin3 is highly linked to cancer progression. Higher levels of Ephexin3 are observed in cervical, colorectal, and lung-derived cancers and patients with a high level of Ephexin3 and Src show shorter survival time [41,42,43,45,46]. Moreover, mutations in Ephexin3 is also correlated with cancer.…”

“…For example, it has been reported that they regulate angiogenesis [34], efferocytosis, a type of phagocytosis to clear apoptotic cells in the body [35,36,37], and vascular muscle contractility [18]. Moreover, aberrant expression or function of Ephexins are related to various types of cancer [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. Thus, the roles of Ephexins are not limited to the nervous system.…”

The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes

“…53 It is well established that proteins of the same family with FGD3 organize such formations on plasma membranes to release MMPs and in turn induce degradation of the surrounding stroma. 54,55 Remarkably, blockade of filopodia formation by flavoinoids has been shown to decrease the release of MMP-2 in cancer. 56 Electron microscopy studies could help investigate filopodial formations on cells in PPROM.…”