Macrophages-induced IL-18-mediated eosinophilia promotes characteristics of pancreatic malignancy. Kandikattu Hemanth Kumar,Manohar Murli,Verma Alok Kumar,Kumar Sandeep,Yadavalli Chandra Sekhar,Upparahalli Venkateshaiah Sathisha,Mishra Anil Life science alliance Reports indicate that accumulated macrophages in the pancreas are responsible for promoting the pathogenesis of chronic pancreatitis (CP). Recently, macrophage-secreted cytokines have been implicated in promoting pancreatic acinar-to-ductal metaplasia (ADM). This study aims to establish the role of accumulated macrophage-activated NLRP3-IL-18-eosinophil mechanistic pathway in promoting several characteristics of pancreatic malignancy in CP. We report that in a murine model of pancreatic cancer (PC), accumulated macrophages are the source of NLRP3-regulated IL-18, which promotes eosinophilic inflammation-mediated accumulation to periductal mucin and collagen, including the formation of ADM, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasm. Most importantly, we show improved malignant characteristics with reduced levels of oncogenes in an anti-IL-18 neutralized and IL-18 gene deficient murine model of CP. Last, human biopsies validated that NLRP3-IL-18-induced eosinophils accumulate near the ducts, showing PanINs formation in PC. Taken together, we present the evidence on the role of IL-18-induced eosinophilia in the development of PC phenotype like ADM, PanINs, and ductal cell differentiation in inflammation-induced CP. 10.26508/lsa.202000979

ISG12a and its interaction partner NR4A1 are involved in TRAIL-induced apoptosis in hepatoma cells. Liu Nianli,Wu Zhiyuan,Chen Aoxing,Chai Dafei,Li Liantao,Zhang Longzhen,Zheng Junnian Journal of cellular and molecular medicine Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells while sparing normal cells, thereby leading to the development of TRAIL receptor agonists for cancer treatment. However, these agonist-based therapeutics exhibit little clinical benefits due to the lack of biomarkers to predict whether patients are responsive to the treatment, as well as determine the resistance of cancer cells to TRAIL-based agonists. Our previous study has demonstrated that ISG12a enhances TRAIL-induced apoptosis and might serve as a biomarker to predict the TRAIL response. The downstream mechanism by which ISG12a augments TRAIL-induced apoptosis remains to be elucidated. In this study, we found that ISG12a was localized in the mitochondria and nucleus and augmented TRAIL-induced apoptosis through intrinsic apoptotic pathway. In addition, ISG12a interacted with NR4A1 and promoted its nuclear-to-cytoplasm translocation. Upon translocate to cytoplasm, NR4A1 targeted mitochondria and induced Bcl2 conformational change, thereby exposing its BH3 domain. Moreover, TRAIL treatment can induce NR4A1 expression through the activation of NF-κB in TRAIL-resistant Huh7 hepatoma cells. Knockdown of NR4A1 could overcome TRAIL resistance. However, in TRAIL-sensitive LH86 liver cancer cells, TRAIL activated the Jun N-terminal kinases signalling pathway. Overall, these results showed that both ISG12a and its interaction partner NR4A1 are involved in TRAIL-mediated apoptosis in hepatoma cells. 10.1111/jcmm.14251

Knockdown of IFI27 inhibits cell proliferation and invasion in oral squamous cell carcinoma. Wang Hong,Qiu Xunding,Lin Shigeng,Chen Xubin,Wang Tao,Liao Tianan World journal of surgical oncology BACKGROUND:The development of oral squamous cell carcinoma (OSCC) involves genetic mutations, epigenetic gene expression modification, and other processes. It has been reported that IFI27 is upregulated in OSCC, but its function is unknown. The aim of this study was to investigate the role of IFI27 on OSCC cell proliferation and invasion. METHODS:The protein level of IFI27 in OSCC tissues and adjacent tissues was detected by immunohistochemistry. In the OSCC cell model, we designed the IFI27 siRNA to downregulate the expression of IFI27; gene and protein of IFI27 in those models were then detected by Q-PCR and Western blot. MTT assay was used to detect the effect of -IFI27 knockdown on cell proliferation; Annexin V-PI staining flow cytometry was used to detect the effect of IFI27 downregulation on apoptosis of cancer cells. The effect of IFI27 downregulation on oral cancer cell invasion was detected using Transwell assay. RESULTS:IFI27 was highly expressed in OSCC tissues by immunohistochemical assay. In the OSCC cell model, IFI27 siRNA could downregulate the mRNA and protein expression level of IFI27. As showed in MTT assay, Annexin V-PI assay, and Transwell assay, through the downregulation of IFI27, TSCCA and TCA8113 cell proliferation were inhibited, OSCC cell apoptosis was promoted, and its migration and invasion were inhibited. CONCLUSION:IFI27 is involved in the development and progression of OSCC. Its high expression promotes cell proliferation and invasion and reduces apoptosis. These findings may provide new biomarkers and therapeutic targets for OSCC diagnosis and clinical treatment. 10.1186/s12957-018-1371-0

IFI27/ISG12 Downregulates Estrogen Receptor α Transactivation by Facilitating Its Interaction With CRM1/XPO1 in Breast Cancer Cells. Frontiers in endocrinology The estrogen receptor alpha (ERα) is a ligand-activated transcription factor whose activity is modulated by its interaction with multiple protein complexes. In this work, we have identified the protein interferon alpha inducible protein 27 (IFI27/ISG12) as a novel ERα-associated protein. IFI27/ISG12 transcription is regulated by interferon and estradiol and its overexpression is associated to reduced overall survival in ER+ breast cancer patients but its function in mammary gland tissue remains elusive. In this study we showed that overexpression of IFI27/ISG12 in breast cancer cells attenuates ERα transactivation activity and the expression of ERα-dependent genes. Our results demonstrated that IFI27/ISG12 overexpression in MCF-7 cells reduced their proliferation rate in 2-D and 3-D cell culture assays and impaired their ability to migrate in a wound-healing assay. We show that IFI27/ISG12 downregulation of ERα transactivation activity is mediated by its ability to facilitate the interaction between ERα and CRM1/XPO1 that mediates the nuclear export of large macromolecules to the cytoplasm. IFI27/ISG12 overexpression was shown to impair the estradiol-dependent proliferation and tamoxifen-induced apoptosis in breast cancer cells. Our results suggest that IFI27/ISG12 may be an important factor in regulating ERα activity in breast cancer cells by modifying its nuclear versus cytoplasmic protein levels. We propose that IFI27/ISG12 may be a potential target of future strategies to control the growth and proliferation of ERα-positive breast cancer tumors. 10.3389/fendo.2020.568375