Regulation of by the aryl hydrocarbon receptor in IL-22-producing immune cells has sex-dependent consequential impact on colitis.

Introduction: Colitis is an inflammatory bowel disease (IBD) characterized by immune cell dysregulation and alterations in the gut microbiome. In our previous report, we showed a natural product in cruciferous vegetables and ligand of the aryl hydrocarbon receptor (AhR), indole-3-carbinol (I3C), was able to reduce colitis-induced disease severity and microbial dysbiosis in an interleukin-22 (IL-22) dependent manner.

Methods: In the current study, we performed single-cell RNA sequencing (scRNAseq) from colonocytes during colitis induction and supplementation with I3C and show how this treatment alters expression of genes involved in IL-22 signaling.

Publisher Correction: Early-onset colorectal cancer: initial clues and current views.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Early-onset colorectal cancer: initial clues and current views.

Over the past several decades, the incidence of early-onset colorectal cancer (EOCRC; in patients <50 years old) has increased at an alarming rate. Although robust and scientifically rigorous epidemiological studies have sifted out environmental elements linked to EOCRC, our knowledge of the causes and mechanisms of this disease is far from complete. Here, we highlight potential risk factors and putative mechanisms that drive EOCRC and suggest likely areas for fruitful research.

CDK8 Selectively Promotes the Growth of Colon Cancer Metastases in the Liver by Regulating Gene Expression of TIMP3 and Matrix Metalloproteinases.

: Unresectable hepatic metastases of colon cancer respond poorly to existing therapies and are a major cause of colon cancer lethality. In this study, we evaluated the therapeutic viability of targeting the mediator kinase CDK8, an early clinical stage drug target, as a means to suppress metastasis of colon cancer. CDK8 was amplified or overexpressed in many colon cancers and CDK8 expression correlated with shorter patient survival.

Six1 promotes colorectal cancer growth and metastasis by stimulating angiogenesis and recruiting tumor-associated macrophages.

The homeoprotein Six1 is overexpressed in many human cancers and is associated with increased tumor progression and metastasis. Recent studies have shown that Six1 is associated with poorer overall survival in advanced-stage colorectal cancer (CRC). In the current study, we explored the functional changes and molecular events associated with Six1 overexpression in a mouse model of CRC.

Elevated interleukin-27 levels in human neonatal macrophages regulate indoleamine dioxygenase in a STAT-1 and STAT-3-dependent manner.

Microbial infections are a major cause of infant mortality as a result of limitations in immune defences. Interleukin-27 (IL-27) is a heterodimeric cytokine produced primarily by leucocytes and is immunosuppressive toward lymphocytes and leucocytes. Our laboratory demonstrated that human neonatal macrophages express IL-27 more abundantly than adult macrophages.

IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis.

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor.

Redox potential ultrasensitive nanoparticle for the targeted delivery of camptothecin to HER2-positive cancer cells.

Ideal "smart" nanoparticles for drug delivery should enhance therapeutic efficacy without introducing side effects. To achieve that, we developed a drug delivery system (HCN) based on a polymer-drug conjugate of poly[2-(pyridin-2-yldisulfanyl)]-graft-poly(ethylene glycol) and camptothecin with an intracellularly cleavable linker and human epidermal growth factor receptor 2 (HER2) targeting ligands. An in vitro drug release study found that HCN was stable in the physiological environment and supersensitive to the stimulus of elevated intracellular redox potential, releasing all payloads in less than 30 min.

Six1 promotes epithelial-mesenchymal transition and malignant conversion in human papillomavirus type 16-immortalized human keratinocytes.

Six1, a member of the Six family of homeodomain transcription factors, is overexpressed in various human cancers, and SIX1 overexpression is associated with tumor progression and metastasis. Six1 messenger RNA levels increase during in vitro progression of human papillomavirus type 16 (HPV16)-immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. In this study, we show that HKc/DR-overexpressing Six1 exhibited a more mesenchymal phenotype, as characterized by a fibroblastic appearance and increased invasion.

Development and characterization of a reliable mouse model of colorectal cancer metastasis to the liver.

Colorectal cancer (CRC) is the third most frequent cancer and the third leading cause of cancer deaths in the United States (American Cancer Society, Cancer facts and figures 2012, 20121). The major cause of death is metastasis and frequently, the target organ is the liver. Successful metastasis depends on acquired properties in cancer cells that promote invasion and migration, and on multiple interactions between tumors and host-derived cells in the microenvironment.

Neonatal macrophages express elevated levels of interleukin-27 that oppose immune responses.

Microbial infections are a major cause of infant mortality worldwide because of impaired immune defences in this population. The nature of this work was to further understand the mechanistic limitations of the neonatal and infant immune response. Interleukin-27 (IL-27) is a heterodimeric cytokine of the IL-12 family that is produced primarily by antigen-presenting cells and is immunosuppressive toward a variety of immune cell types.

Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1.

Tumor-associated macrophages are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. However, its role on tumorigenesis in a genetic mouse model of colon cancer has not been explored.

Synthetic lectin arrays for the detection and discrimination of cancer associated glycans and cell lines.

Aberrant glycosylation is a hallmark of various disease states, including cancer, and effective detection and discrimination between healthy and diseased cells is an important challenge for the diagnosis and treatment of many diseases. Here, we describe the use of boronic acid functionalized synthetic lectins (SLs) in an array format for the differentiation of structurally similar cancer associated glycans and cancer cell lines; discrimination is based on subtle variations in glycosylation patterns. We further demonstrate the utility of our SLs in recognizing glycoproteins with up to 50-fold selectivity, even in 95% human serum.

Hematopoietic derived cell infiltration of the intestinal tumor microenvironment in Apc Min/+ mice.

Tumors consist of a heterogeneous population of neoplastic cells infiltrated by an equally heterogeneous collection of nonneoplastic cells that comprise the tumor microenvironment. Tumor growth, invasion, and metastasis depend on multiple interactions between these cells. To assess their potential as therapeutic targets or vehicles for tumor specific delivery of therapeutic agents, we examined the contribution of bone marrow derived cells (BMDCs) to the intestinal tumor microenvironment.

Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study.

Background: We are developing a cross-species comparison strategy to distinguish between cancer driver- and passenger gene alteration candidates, by utilizing the difference in genomic location of orthologous genes between the human and other mammals. As an initial test of this strategy, we conducted a pilot study with human colorectal cancer (CRC) and its mouse model C57BL/6J ApcMin/+, focusing on human 5q22.2 and 18q21.

Activity level, apoptosis, and development of cachexia in Apc(Min/+) mice.

Criteria for diagnosing cachexia in adults include unintentional loss in body weight, decreased strength, fatigue, anorexia, and low muscle mass. Cachexia is also associated with systemic inflammation, altered metabolism, and anemia. The Apc(Min/+) mouse is a model of cachexia directly related to intestinal tumor burden and subsequent chronic inflammation.

Replacement of Val3 in human thymidylate synthase affects its kinetic properties and intracellular stability .

Human and other mammalian thymidylate synthase (TS) enzymes have an N-terminal extension of approximately 27 amino acids that is not present in bacterial TSs. The extension, which is disordered in all reported crystal structures of TSs, has been considered to play a primary role in protein turnover but not in catalytic activity. In mammalian cells, the variant V3A has a half-life similar to that of wild-type human TS (wt hTS) while V3T is much more stable; V3L, V3F, and V3Y have half-lives approximately half of that for wt hTS.

The intrinsically disordered N-terminal domain of thymidylate synthase targets the enzyme to the ubiquitin-independent proteasomal degradation pathway.

The ubiquitin-independent proteasomal degradation pathway is increasingly being recognized as important in regulation of protein turnover in eukaryotic cells. One substrate of this pathway is the pyrimidine biosynthetic enzyme thymidylate synthase (TS; EC 2.1.

The interaction of a high-fat diet and regular moderate intensity exercise on intestinal polyp development in Apc Min/+ mice.

Diet and exercise are two environmental factors that can alter colon cancer risk. The purpose of this study was to determine if regular moderate-intensity treadmill exercise training could attenuate polyp formation in Apc(Min/+) mice fed the Western-style diet. Four-week-old male Apc(Min/+) mice (n = 12 per group) were assigned to AIN-76A Control, AIN-76A Exercise, Western Control, or Western Exercise treatment groups.

Beta-catenin induces beta-TrCP-mediated PER2 degradation altering circadian clock gene expression in intestinal mucosa of ApcMin/+ mice.

Proliferation of intestinal epithelial cells is rhythmic throughout the day. This temporal organization occurs through the interaction between the endogenous peripheral circadian clock and pathways controlling cell cycle progression. Per2, a core clock gene with tumour suppresser function, is critical to clock function and to the regulation of cellular proliferation.

Period 2 mutation accelerates ApcMin/+ tumorigenesis.

Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene.

Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc ( Min/+ ) mouse.

Interleukin-6 (IL-6) is necessary for cachexia in Apc ( Min/+ ) mice, but the mechanisms inducing this myofiber wasting have not been established. The purpose of this study was to examine gastrocnemius muscle wasting in the Apc ( Min/+ ) mouse and to determine IL-6 regulated mechanisms contributing to muscle loss. Gastrocnemius type IIB mean fiber cross-sectional area (CSA) from Apc ( Min/+ ) mice decreased 32% between 13 and 22 weeks of age.

Effect of exercise on biological pathways in ApcMin/+ mouse intestinal polyps.

Many epidemiological studies have demonstrated that level of exercise is associated with reduced colorectal cancer risk. Treadmill training can decrease Apc(Min/+) mouse intestinal polyp number and size, but the mechanisms remain unclear. Understanding the molecular changes in the tumor following exercise training may provide insight on the mechanism by which exercise decreases Apc(Min/+) mouse polyp formation and growth.

Interleukin-6 and cachexia in ApcMin/+ mice.

The Apc(Min/+) mouse has a mutation in the Apc tumor suppressor gene and develops intestinal polyps, beginning at 4 wk of age. This mouse develops cachexia by 6 mo, characterized by significant loss of muscle and fat tissue. The purpose of the present study was to determine the role of circulating interleukin-6 (IL-6) and the polyp burden for the development of cachexia in Apc(Min/+) mice.