IRF1 inhibits the proliferation and metastasis of colorectal cancer by suppressing the Ras-Rac1 pathway

Abstract

BackgroundInterferon regulatory factor 1 (IRF1) plays a role in the immune response, cellular necrosis, DNA damage, and DNA repair, offering an attractive target for anticancer treatment. However, little is known about the role of IRF1 in the regulation of CRC progression.MethodsQuantitative reverse transcription-PCR, Western blot, and immunohistochemistry were used to examine the expression level of IRF1; Cell Counting Kit-8, migration assay, and xenograft mouse models were used to examine the function of IRF1 in CRC cell lines; a ChIP assay was used to examine the binding between IRF1 and Ras association domain-containing protein 5 (RASSF5).ResultsIRF1 expression was lower in colorectal cancer (CRC) than in normal mucosa and the IRF1 expression level was inversely associated with CRC metastasis. In addition, IRF1 could inhibit CRC cell proliferation, migration, and metastasis in vivo and in vitro; IRF1 also induced cell cycle arrest but had no effect on cell apoptosis. IRF1 enhanced the expression of RASSF5 by increasing its promoter activity. Moreover, this study revealed a novel mechanism for inhibiting the RAS-RAC1 pathway by overexpression of RASSF5.ConclusionAltogether, the results indicate that IRF1, which promotes RASSF5 expression, suppresses CRC metastasis and proliferation possibly through downregulation of the RAS-RAC1 pathway.

IRF1 association with tumor immune microenvironment and use as a diagnostic biomarker for colorectal cancer recurrence

“…IRF1, which belongs to the IRF family (34), is weakly expressed in resting dendritic cells and macrophages, but is induced by interferon-γ (IFN-γ) in M1 polarized macrophages (35,36). Previous studies have revealed that IRF1 inhibited the proliferation and metastasis of CRC (37,38). UBE2L6, which is also known as UBCH8, promotes apoptosis in cervical cancer cells (39).…”

Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

“…Taking advantage of in vivo experiments, it was shown that thiopurines treatments (TG) inhibited CAC in the AOM/DSS mouse model, via decreased β-catenin in a RAC1-dependent mechanism [ 144 ]. In the context of epithelial cell targeting, EMT and metastatic potential might be inhibited upon activation of RAC1; for instance, upon CSRP2 treatment (Hippo-ERK-PAK/LIMK/cortactin) [ 145 ], miR-142-3p transfection [ 146 ], upregulation of SSH3 (LIMK) [ 147 ] or PLS1 (ERK1/2) [ 148 ], downregulation of DMTN [ 149 ], or IRF1 suppression [ 150 ]. Recent work from An et al revealed the different behavior of RAC1 inhibition in combination with irradiation on cell cycle.…”

Coordination between Rac1 and Rab Proteins: Functional Implications in Health and Disease

“…Cancer is a complex group of diseases characterized by uncontrolled cell growth. Excess of Rac1 activity has been linked to several cancer types such as breast cancer, colorectal cancer, gastric cancer, prostate cancer, and cervical cancer [60,61,62,63,64,65]. In particular, Rac1 is involved in several phases of cancer development, as it can promote cancer initiation, cancer progression, and metastases through its role in gene transcription, cell cycle progression, neovascularization, cell adhesion, migration, and invasion [56,66,67,68,69].…”