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

Min Hong,1,2,* Zuoyang Zhang,3,* Qing Chen,4,* Yanxia Lu,1 Jianming Zhang,1,4 Chun Lin,1 Fan Zhang,1 Wenjuan Zhang,1 Xiaomin Li,1 Wei Zhang,1 Xuenong Li1 1Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; 2Department of Pathology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; 3Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China; 4Department of Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China *These authors contributed equally to this work Background: Interferon 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.Methods: Quantitative 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).Results: IRF1 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.Conclusion: Altogether, the results indicate that IRF1, which promotes RASSF5 expression, suppresses CRC metastasis and proliferation possibly through downregulation of the RAS-RAC1 pathway. Keywords: IRF1, RASSF5, Rac1, Ras, colorectal cance