Members of the miR-34 family are induced by the tumor suppressor p53 and are known to inhibit epithelialto-mesenchymal transition (EMT) and therefore presumably suppress the early phases of metastasis. Here, we determined that exposure of human colorectal cancer (CRC) cells to the cytokine IL-6 activates the oncogenic STAT3 transcription factor, which directly represses the MIR34A gene via a conserved STAT3-binding site in the first intron. Repression of MIR34A was required for IL-6-induced EMT and invasion. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a conserved, direct miR-34a target. The resulting IL-6R/STAT3/miR-34a feedback loop was present in primary colorectal tumors as well as CRC, breast, and prostate cancer cell lines and associated with a mesenchymal phenotype. An active IL-6R/ STAT3/miR-34a loop was necessary for EMT, invasion, and metastasis of CRC cell lines and was associated with nodal and distant metastasis in CRC patient samples. p53 activation in CRC cells interfered with IL-6-induced invasion and migration via miR-34a-dependent downregulation of IL6R expression. In Mir34a-deficient mice, colitis-associated intestinal tumors displayed upregulation of p-STAT3, IL-6R, and SNAIL and progressed to invasive carcinomas, which was not observed in WT animals. Collectively, our data indicate that p53-dependent expression of miR-34a suppresses tumor progression by inhibiting a IL-6R/STAT3/miR-34a feedback loop.

About 20 years have passed since the discovery of the first microRNA (miRNA) and by now microRNAs are implicated in a variety of physiological and pathological processes. Since the discovery of the powerful effect miRNAs have on biological processes, it has been suggested that mutations affecting miRNA function may play a role in the pathogenesis of human diseases. Over the past several years microRNAs have been found to play a major role in various human diseases. In addition, many studies aim to apply miRNAs for diagnostic and therapeutic applications in human diseases. In this chapter, we summarize the role of miRNAs in pathological processes and discuss how miRNAs could be used as disease biomarkers.

In colorectal cancer patients, a high density of cytotoxic CD8 T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8 T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8 T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.

Following the publication of this article, the authors became aware that the epitope for the IL-6R antibody (SC-661, Santa Cruz Biotechnology Inc.) is not present in the soluble variant of IL-6R (s-IL-6R), which lacks the C-terminal domain. The authors originally designated the bands detected by SC-661 as membrane-bound IL-6R (m-IL-6R; ~70 kDa) and s-IL-6R (~50 kDa); however, the identity of the 50-kDa band is not known. Thus, no conclusions regarding s-IL-6R can be made from the data presented. Accordingly, the labels on Figures 2C, 3A, 3B, 3E, and 8D have been corrected to indicate that the 50-kDa band detected by SC-661 has not been characterized. The corrected figures appear at right.In addition, this error affected portions of the text in the Results and Discussion. The corrected sentences appear below:Results, 4th paragraph: Besides the membrane-bound IL-6R (m-IL-6R), we also observed a signal at 50 kDa, which represents an uncharacterized band. Densitometric quantification of IL-6R signals with normalization to β-actin showed a statistically significant decrease in m-IL-6R after DOX treatment (Supplemental Figure 3A).Results, 5th paragraph: Interestingly, the mesenchymal-like CRC lines SW480 and SW620 showed a more pronounced expression of m-IL-6R when compared with 5 CRC lines with epithelial traits. Furthermore, the mesenchymal lines displayed STAT3 phosphorylation, which was not detectable in the epithelial lines.Discussion, final paragraph: For activation of STAT3, the IL-6R requires the ligand IL-6, which allows binding to gp130. In vivo, IL-6 can be generated by tumor cells or by tumor stromal cells, such as macrophages or fibroblasts (12). The RNA used for the expression analysis of human CRC samples was isolated from nonmicrodissected tumors. Therefore, several stromal cells could have contributed to IL-6 expression. The analysis of human CRC samples suggests that the IL-6R/STAT3/miR-34a loop is also manifest in primary human colorectal tumors with mesenchymal characteristics and might represent a useful prognostic marker for cancer progression. In line with these findings, we recently showed that the loss of miR-34a expression by epigenetic silencing in primary tumors is associated with increased lymph node infiltration and metastasis in colon cancer patients (57). Besides STAT3 and IL-6R, which are already established targets for cancer treatment, our results suggest that restoring miR-34a function using mimetics may have therapeutic potential for the treatment of invasive CRCs. Furthermore, recombinant, soluble gp130 may be suitable for the treatment of invasive CRC displaying MIR34A inactivation and therefore upregulation of IL-6R expression.Finally, the following information in the supplemental data file has been corrected: (a) findings related to the quantification of soluble IL-6R protein expression have been removed, (b) the β-actin antibody utilized has been specified as Sigma-Aldrich (A2066), and (c) the unedited image for the β-actin blot corresponding to the p53 blot in Supplemental Fi...

MicroRNAs (miRNAs) have recently emerged as a new class of modulators of gene expression. miRNAs control protein synthesis by targeting mRNAs for translational repression or degradation at the posttranscriptional level. These noncoding RNAs are endogenous, single-stranded molecules approximately 22 nucleotides in length and have roles in multiple facets of immunity, from regulation of development of key cellular players to activation and function in immune responses. Recent studies have shown that dysregulation of miRNAs involved in immune responses leads to autoimmunity. Multiple sclerosis (MS) serves as an example of a chronic and organ-specific autoimmune disease in which miRNAs modulate immune responses in the peripheral immune compartment and the neuroinflammatory process in the brain. For MS, miRNAs have the potential to serve as modifying drugs. In this review, we summarize current knowledge of miRNA biogenesis and mode of action and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We also review the role of miRNAs in autoimmunity, focusing on emerging data regarding miRNA expression patterns in MS. Finally, we discuss the potential of miRNAs as a disease marker and a novel therapeutic target in MS. Better understanding of the role of miRNAs in MS will improve our knowledge of the pathogenesis of this disease.

The link between inflammation and cancer is well established. Chronic inflammation promotes cancer initiation and progression. Various studies showed that the underlying mechanisms involve epigenetic alterations. These epigenetic alterations might culminate into an epigenetic switch that transforms premalignant cells into tumor cells or non-invasive into invasive tumor cells, thereby promoting metastasis. Epigenetic switches require an initiating event, which can be inflammation, whereas the resulting phenotype is inherited without the initiating signal. Epigenetic switches are induced and maintained by DNA methylation, histone modifications, polycomb group (PcG)/trithorax group (TrxG) proteins, and feedback loops consisting of transcription factors and microRNAs. Since epigenetic switches are reversible, they might represent an important basis for the design of novel anticancer therapeutics. This review summarizes published evidence of epigenetic switches in cancer development that are induced by inflammation.

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Intranasal delivery (ID) of neuroprotective drugs is an area of great interest. Among the administration strategies used at present, ID of EPO is the most promising. Further preclinical and clinical studies are needed to evaluate the potential significance of this alternative route for increasing EPO bioavailability and decreasing side effects.