MiRNA-29: a microRNA family with tumor-suppressing and immune-modulating properties.

MicroRNAs (miRNAs) are ubiquitously expressed small, non-coding RNAs that negatively regulate gene expression at a post-transcriptional level. So far, over 1000 miRNAs have been identified in human cells and their diverse functions in normal cell homeostasis and many different diseases have been thoroughly investigated during the past decade. MiR-29, one of the most interesting miRNA families in humans to date, consists of three mature members miR-29a, miR-29b and miR-29c, which are encoded in two genetic clusters. Members of this family have been shown to be silenced or down-regulated in many different types of cancer and have subsequently been attributed predominantly tumor-suppressing properties, albeit exceptions have been described where miR-29s have tumor-promoting functions. MiR-29 targets expression of diverse proteins like collagens, transcription factors, methyltransferases and others, which may partake in abnormal migration, invasion or proliferation of cells and may favor development of cancer. Furthermore, members of the miR-29 family can be activated by interferon signaling, which suggests a role in the immune system and in host pathogen interactions, especially in response to viral infections. In this review, we summarize current knowledge on the genomic organization and regulation of the miR-29 family and we provide an overview of its implication in cancer suppression and promotion as well as in host immune responses. The numerous remarkable properties of these miRNAs and their often altered expression patterns might make the miR-29 family promising biomarkers and therapeutic targets for various diseases in future.

IL-24: physiological and supraphysiological effects on normal and malignant cells.

IL-24, previously known as melanoma differentiation antigen 7 (mda-7), is a member of the IL-10 family of cytokines and is mainly produced by Th2 cells and activated monocytes. Binding of IL-24 to either of its two heterodimeric receptors IL-20R1/IL-20R2 and IL-22R/IL-20R2 triggers phosphorylation and consequently activation of STAT3 and/or STAT1 in target tissues such as lung, testis, ovary, keratinocytes and skin. There is accumulating evidence that skin represents a major target tissue for IL-24 and related cytokines such as IL-19, -20, and -22. To date, the physiological properties of IL-24 are incompletely understood but available data indicate that it affects epidermal functions by increasing proliferation of dermal cells, suggestive of a possible role in psoriasis. However, the initial interest in IL-24 did not arise from its physiological signalling properties through its cognate receptors but rather because this cytokine has been reported to efficiently kill cancer cells independent of receptor expression and Jak-STAT signaling. These potentially intriguing properties have led to the development of adenovirally expressed IL-24, which was reported to induce selective cancer cell death in many different malignancies by activation or deactivation of a continuously growing list of distinct signaling pathways without harming surrounding healthy cells. In the present review we critically revisit and discuss the potential of IL-24 to become a selective and cancer cell-specific oncolytic drug and put these tentative properties into context with recent data on the physiological properties of this cytokine.

IL-24: a classic cytokine and/or a potential cure for cancer?

IL-24, a member of the IL-10 family of cytokines, is produced by monocytes and Th2 cells. Interestingly, immune cells do not appear to express specific IL-24 receptor chains (IL-20R1/IL-20R2 and IL-22R/IL-20R2), it is therefore unlikely that IL-24 has classical immune-modulating properties. Skin, on the other hand, seems to represent a major target tissue for IL-24 and related cytokines such as IL-19, -20, and -22. However, the initial interest in IL-24 did not arise from its physiological signalling properties through its cognate receptors but rather because of its tentative ability to selectively kill different cancer cells. In an attempt to further investigate the signalling events underlying the IL-24-induced cancer cell death, we found that melanoma cell lines did not react in the expected and previously described way. Using several different forms and delivery modes of IL-24, we were unable to detect any apoptosis-inducing properties of this cytokine in melanoma cells. In the present 'Point of view' we will briefly summarize these findings and put them in context of published reports stating that IL-24 might be a long sought after treatment for several types of cancer.

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR.

The aberrant expression of the transcription factors PAX3 and PAX3/FKHR associated with rhabdomyosarcoma (RMS), solid tumors displaying muscle cell features, suggests that these proteins play an important role in the pathogenesis of RMS. We could previously demonstrate that one of the oncogenic functions of PAX3 and PAX3/FKHR in RMS is protection from apoptosis. BCL-XL is a prominent anti-apoptotic protein present in normal skeletal muscle and RMS cells. In the present study, we establish that BCL-XL is transcriptionally modulated by PAX3 and PAX3/FKHR, since enhanced expression of both PAX proteins stimulates transcription of endogenous BCL-XL mRNA in a cell type specific manner. Further, we present evidence that both PAX3 and PAX3/FKHR can transcriptionally activate the Bcl-x gene promoter in cotransfection assays. Using electrophoretic mobility shift assays, an ATTA binding site for PAX3 and PAX3/FKHR could be localized in the upstream promoter region (position -42 to -39). Finally, ectopic overexpression of either PAX3, PAX3/FKHR or BCL-XL can rescue tumor cells from apoptosis induced by antisense treatment. These results suggest that at least part of the anti-apoptotic effect of PAX3 and PAX3/FKHR is mediated through direct transcriptional modulation of the prominent anti-apoptotic protein BCL-XL. Oncogene (2000).

Quantification of wild-type mitochondrial DNA and its 4.8-kb deletion in rat organs.

Oxidative damage to mitochondrial DNA (mtDNA) is considered a major contributor in aging. An age-dependent increase of oxidative damage and of the quantity of partially deleted mtDNA was reported for several rat and human organs. Here, a systematic investigation of ten different tissues and organs of 20-months-old rats was performed. The amount of mtDNA and age-dependent 4.8 kb deletion (delta mtDNA4834) was determined by competitive polymerase chain reaction, along with the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSHPx). The data were related to the corresponding metabolic rates. MtDNA content was highest in heart and lowest in spleen. delta mtDNA4834 was detected in all ten tissues and organs, and its amount was highest in liver and lowest in intestine. In heart, lung, muscle, and bone-marrow the deletion could not be quantified because of a point mutation, an A-->T transition at position 8107. Activities of SOD and GSHPx were highest in liver and lowest in intestinal mucosa. A negative correlation between mtDNA content and delta mtDNA4834, and a positive correlation between metabolic rate, GSHPx, and the deletion was found. These results suggest that the occurrence of delta mtDNA4834 in rat is related to oxidative stress.