Project description:Liposarcomas are rare, heterogeneous and malignant tumors that can be divided into five histological subtypes with different characteristics and clinical behavior. Treatment consists of surgery in combination with systemic chemotherapy, but nevertheless mortality rates are high. More insight into the biology of liposarcoma tumorigenesis is needed to devise novel therapeutic approaches. MicroRNAs (miRNAs) have been associated with carcinogenesis in many tumors and may function as tumor suppressor or oncogene. In this study we examined miRNA expression in an initial series of 57 human liposarcomas (including all subtypes), lipomas and normal fat by miRNA microarrays. Supervised hierarchical clustering of the most differentially expressed miRNAs (p<0.0002) distinguished most liposarcoma subtypes and control tissues. The distinction between well differentiated liposarcomas and benign lipomas was blurred, suggesting these tumor types may represent a biological continuum. MiRNA signatures of liposarcoma subtypes were established and validated in an independent series of 58 liposarcomas and control tissues. The expression of the miR-143/145 and miR-144/451 cluster members was clearly reduced in liposarcomas compared to normal fat. Overexpression of miR-145 and miR-451 in liposarcoma cell lines decreased cellular proliferation rate, impaired cell cycle progression and induced apoptosis. In conclusion, we show that miRNA expression profiling can be used to discriminate liposarcoma subtypes, which could aid in objective diagnostic decision making. In addition, our data indicate that miR-145 and miR-451 act as tumor suppressors in adipose tissue and show that re-expression of these miRNAs could be a promising therapeutic strategy for liposarcomas. 57 samples discovery set, 58 samples in validation set, subdivided in 5 liposarcoma subtypes plus lipomas and normal fat as control samples. Each sample was analysed on one array. All array probes are present in duplicate.

Project description:The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3'UTR) of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63(-/-) and dicer(-/-) mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into how p53, p63, and p73 regulate the components of the miRNA processing; and how p53, TA-p63, and TA-p73 regulated miRNAs inhibit tumorigenesis, EMT, metastasis, and cancer stem cell proliferation.

Dataset Information

Involvement of tumor suppressors PTEN and p53 in the formation of multiple subtypes of liposarcoma.

Publications

Involvement of tumor suppressors PTEN and p53 in the formation of multiple subtypes of liposarcoma.

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