ROR gamma t-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells
CANCER IMMUNOLOGY RESEARCH
Authors: Rizzo, Angelamaria; Di Giovangiulio, Martina; Stolfi, Carmine; Franze, Eleonora; Fehling, Hans-Joerg; Carsetti, Rita; Giorda, Ezio; Colantoni, Alfredo; Ortenzi, Angela; Rugge, Massimo; Mescoli, Claudia; Monteleone, Giovanni; Fantini, Massimo C.
Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3(+) regulatory T cells (Treg) coexpressing the Th17-related transcription factor ROR gamma t accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. ROR gamma t thorn FoxP3(+) cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate-mapping reporter and Treg-specific ROR gamma t conditional knockout mice. Tumor development and the intratumoral inflammatory milieu were characterized in these mice. The functional role of CTLA-4 expressed by Tregs and FoxO3 in dendritic cells (DC) was studied in vitro and in vivo by siRNA-silencing experiments. ROR gamma t expression identified a phenotypically stable population of tumor-infiltrating Tregs in humans and mice. Conditional RORgt knockout mice showed reduced tumor incidence, and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating DCs produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. ROR gamma t-deficient Tregs isolated from tumors overexpressed CTLA-4 and induced DCs to have elevated expression of the transcription factor FoxO3, thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of ROR gamma t-deficient mice restored IL6 expression and tumor growth. These data demonstrate that RORgt expressed by tumor-infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked. (C) 2018 AACR.
Peroxiredoxin I silencing inhibited the growth and promoted apoptosis of pancreatic cancer cells via targeting FOXO3 gene
CANCER MANAGEMENT AND RESEARCH
Authors: Sun, Xianchun; Kong, Lingting; Li, Bingshu; Zhang, Yan; Yang, Haiyan
Objective: Our study aimed to investigate the interaction between peroxiredoxin 1 (Prx1) and forkhead box O3 (FOXO3) and to explore the role of PI3K/AKT pathway in the development of pancreatic cancer. Material and methods: Human pancreatic normal cells HPDE6-C7 and pancreatic cancer cells PANC-1 were randomly divided into control group, Prx1-silencing (si-Prx1) group, Prx1/ FOXO3 dual-silencing (si-Prx1/FOXO3) group, and negative control group. Cell proliferation assay, clone formation assay, and cell apoptosis assay were performed to investigate the effects of Prx1 silencing and FOXO3 silencing on the proliferation and apoptosis ability of pancreatic cancer cells. qRT-PCR and Western blot were performed to study the Prx1 and FOXO3 mRNA in the two cells and FOXO3 protein expression in PANC-1 cells. Result: We found Prx1 silencing could inhibit growth and promote apoptosis of PANC-1 cells. And Prx1 silencing could decrease the Prx1 mRNA level and increase FOXO3 mRNA level. To further explore the role of Prx1 in PI3K/AKT, we study the cell proliferation and apoptosis ability after adding the PI3K inhibitor and PI3K activator. We observed that PI3K inhibitor could inhibit tumor cell growth and promote cell apoptosis. And PI3K inhibitor also downregulated Prx1 protein expression. Conclusion: We concluded that the Prx1 silencing inhibited the growth and promoted apoptosis of pancreatic cancer cells via modulation of PI3K/AKT pathway by targeting FOXO3 gene.