ABSTRACT
RNA binding proteins, including IMP1/IGF2BP1, are essential regulators of intestinal development and cancer. Imp1 hypomorphic mice exhibit gastrointestinal growth defects, yet the specific role for IMP1 in colon epithelial repair is unclear. Our prior work revealed that intestinal epithelial cell-specific Imp1 deletion (Imp1ΔIEC ) was associated with better regeneration in mice after irradiation. Here, we report increased IMP1 expression in patients with Crohn's disease and ulcerative colitis. We demonstrate that Imp1ΔIEC mice exhibit enhanced recovery following dextran sodium sulfate (DSS)-mediated colonic injury. Imp1ΔIEC mice exhibit Paneth cell granule changes, increased autophagy flux, and upregulation of Atg5. In silico and biochemical analyses revealed direct binding of IMP1 to MAP1LC3B, ATG3, and ATG5 transcripts. Genetic deletion of essential autophagy gene Atg7 in Imp1ΔIEC mice revealed increased sensitivity of double-mutant mice to colonic injury compared to control or Atg7 single mutant mice, suggesting a compensatory relationship between Imp1 and the autophagy pathway. The present study defines a novel interplay between IMP1 and autophagy, where IMP1 may be transiently induced during damage to modulate colonic epithelial cell responses to damage.
Subject(s)
Intestinal Mucosa/metabolism , RNA-Binding Proteins/genetics , Wound Healing/genetics , Adult , Aged , Animals , Autophagy/genetics , Autophagy-Related Protein 7/genetics , Autophagy-Related Protein 7/metabolism , Biomarkers , Case-Control Studies , Cell Line , Colitis, Ulcerative/genetics , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/pathology , Colon , Crohn Disease/genetics , Crohn Disease/metabolism , Crohn Disease/pathology , Disease Models, Animal , Female , Gene Deletion , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Intestinal Mucosa/pathology , Male , Mice , Middle Aged , Paneth Cells/metabolism , Paneth Cells/pathology , Protein Binding , Protein Biosynthesis , RNA Processing, Post-Transcriptional , RNA, Messenger/genetics , RNA-Binding Proteins/metabolism , Young AdultABSTRACT
Colorectal cancer (CRC) is the fourth most common cancer in both men and women in the United States, resulting in over 55,000 deaths annually. Environmental and genetic factors influence the development of CRC, and inflammation is a critical hallmark of cancer that may arise from a variety of factors. PURPOSE OF REVIEW: While patients with inflammatory bowel disease (IBD) have a higher risk of developing CRC, sporadic CRCs may engender or be potentiated by inflammation as well. In this review, we focus on recent advances in basic and translational research utilizing murine models to understand the contribution of inflammatory signaling pathways to CRC. RECENT FINDINGS: We discuss advances in the utility of three-dimensional enteroid/colonoid/tumoroid cultures to understand immune-epithelial interactions in CRC, as well as the potential for utilizing patient-derived tumoroids for personalized therapies. SUMMARY: This review underscores the importance of understanding the complex molecular mechanisms underlying inflammation in sporadic CRC and highlights up-and-coming or new avenues for CRC biomarkers or therapies.
ABSTRACT
UNLABELLED: The colon tumor microenvironment is becoming increasingly recognized as a complex but central player in the development of many cancers. Previously, we identified an oncogenic role for the mRNA-binding protein IMP1 (IGF2BP1) in the epithelium during colon tumorigenesis. In the current study, we reveal the contribution of stromal IMP1 in the context of colitis-associated colon tumorigenesis. Interestingly, stromal deletion of Imp1 (Dermo1Cre;Imp1(LoxP/LoxP), or Imp1(ΔMes)) in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated cancer resulted in increased tumor numbers of larger size and more advanced histologic grade than controls. In addition, Imp1(ΔMes) mice exhibited a global increase in protumorigenic microenvironment factors, including enhanced inflammation and stromal components. Evaluation of purified mesenchyme from AOM/DSS-treated Imp1(ΔMes) mice demonstrated an increase in hepatocyte growth factor (HGF), which has not been associated with regulation via IMP1. Genetic knockdown of Imp1 in human primary fibroblasts confirmed an increase in HGF with Imp1 loss, demonstrating a specific, cell-autonomous role for Imp1 loss to increase HGF expression. Taken together, these data demonstrate a novel tumor-suppressive role for IMP1 in colon stromal cells and underscore an exquisite, context-specific function for mRNA-binding proteins, such as IMP1, in disease states. IMPLICATIONS: The tumor-suppressive role of stromal IMP1 and its ability to modulate protumorigenic factors suggest that IMP1 status is important for the initiation and growth of epithelial tumors.
Subject(s)
RNA-Binding Proteins/metabolism , Tumor Microenvironment , Animals , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Gene Deletion , Hepatocyte Growth Factor/metabolism , Humans , Mesoderm/metabolism , Mice , RNA-Binding Proteins/genetics , Stromal Cells/metabolismABSTRACT
Igf2 mRNA binding protein 1 (IMP1, CRD-BP, ZBP-1) is a messenger RNA binding protein that we have shown previously to regulate colorectal cancer (CRC) cell growth in vitro. Furthermore, increased IMP1 expression correlates with enhanced metastasis and poor prognosis in CRC patients. In the current study, we sought to elucidate IMP1-mediated functions in CRC pathogenesis in vivo. Using CRC cell xenografts, we demonstrate that IMP1 overexpression promotes xenograft tumor growth and dissemination into the blood. Furthermore, intestine-specific knockdown of Imp1 dramatically reduces tumor number in the Apc (Min/+) mouse model of intestinal tumorigenesis. In addition, IMP1 knockdown xenografts exhibit a reduced number of tumor cells entering the circulation, suggesting that IMP1 may directly modulate this early metastatic event. We further demonstrate that IMP1 overexpression decreases E-cadherin expression, promotes survival of single tumor cell-derived colonospheres and promotes enrichment and maintenance of a population of CD24+CD44+ cells, signifying that IMP1 overexpressing cells display evidence of loss of epithelial identity and enhancement of a tumor-initiating cell phenotype. Taken together, these findings implicate IMP1 as a modulator of tumor growth and provide evidence for a novel role of IMP1 in early events in CRC metastasis.
Subject(s)
Adenomatous Polyposis Coli Protein/physiology , Cell Transformation, Neoplastic/pathology , Colorectal Neoplasms/pathology , Intestines/pathology , Neoplastic Stem Cells/pathology , RNA-Binding Proteins/physiology , Animals , Apoptosis , Blotting, Western , Cell Adhesion , Cell Differentiation , Cell Movement , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , Colorectal Neoplasms/metabolism , Embryo, Mammalian/metabolism , Embryo, Mammalian/pathology , Epithelial-Mesenchymal Transition , Fibroblasts/metabolism , Fibroblasts/pathology , Heterografts , Humans , Immunoenzyme Techniques , Integrases/metabolism , Intestinal Mucosa/metabolism , Mice , Mice, Nude , Neoplasm Metastasis , Neoplastic Cells, Circulating/metabolism , Neoplastic Cells, Circulating/pathology , Neoplastic Stem Cells/metabolism , Phenotype , Tumor Cells, CulturedABSTRACT
Inflammatory cytokines have been implicated in the pathology of multiple neurologic diseases, including multiple sclerosis. We examined the role of the TNF family member TWEAK in neuroinflammation. Cuprizone-fed mice undergo neuroinflammation and demyelination in the brain, but upon removal of cuprizone from the diet, inflammation is resolved and remyelination occurs. Using this model, we demonstrate that mice lacking TWEAK exhibit a significant delay in demyelination and microglial infiltration. During remyelination, mice lacking the TWEAK gene demonstrate only a marginal delay in remyelination. Thus, this study identifies a primary role of TWEAK in promoting neuroinflammation and exacerbating demyelination during cuprizone-induced damage.
