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Study on the Function of miR-483 and miR-34a

Author: SunFang
Tutor: SunZhiXian;ZhengXiaoFei
School: PLA Military Academy of Medical Sciences
Course: Biochemistry and Molecular Biology
Keywords: miR-483 miR-34a IGF2 IGFBP CCND1 CDK6
CLC: Q343
Type: PhD thesis
Year: 2008
Downloads: 485
Quote: 0
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microRNAs (miRNAs) are short 20–25 nucleotides noncoding RNA molecules, which come from hairpin precursors and play important role in regulating gene expressions. Recent studies show that, miRNAs have been discovered to play a vital role in regulation eukaryotic gene expression at post-transcriptional level by inhibiting translation or by targeting mRNA for degradation. And miRNAs have been shown to control a wide range of biological functions such as cellular proliferation, cell differentiation, apoptosis process and cell cycle control. Recent evidence indicates that miRNAs involve in tumorigenesis and cell canceration. More than half of the annotated miRNAs map within cancer cell genome easy variation of the region, including loss of heterozygosity allele, genome fracture point and fragile sites of chromosomes. These regions of cancer cells are always involved in chromosome exchange, chromosome translocation, chromosome deletion, chromosome amplification and chromosome abnormal integration.First of all, to study functions of miRNAs in liver, we identified five new miRNAs from human fetal liver by our new miRNA cloning method and analyzed the effect of some miRNAs on cell proliferation as well as the function of regulating gene expression in normal hepatocyte and hepatoma carcinoma cell. We identified that miR-483 locate in the seventh intron of insulin-like growth factor 2(IGF2). IGF2 is a multifunctional cell proliferation regulatory factor, which plays an important role in fetal development, central nervous system development and cancer cell proliferation. The biological activity of IGF2 is regulated by a complex regulatory network, including different types of receptors, IGF binding proteins and IGF binding related proteins. To study mechanisms of miR-483 in liver proliferation and cancerization, we identified the relationship of miR-483 and its host gene IGF2 and analyzed the target of miR-483. Our results would like to reveal the mechanisms that miR-483 participates regulating gene expression in hepatoma carcinoma cell proliferation.Secondly, our study focused on miR-34a function of tumor cell cycle regulation. The study on miR-34a function showed that miR-34a induced cell cycle arrest in coordination with downregulating multiple cell cycle proteins. Our results revealed that miR-34a might be the tumor suppressor.The main progresses are listed:1. miR-483 and its host gene IGF2 are coordinate expressed in hepatoma carcinoma cell lines and hepatoma tissues. miR-483 and its host gene IGF2 expressions were detected in nine specimens of hepatoma patient and three different hepatoma carcinoma cell lines. Results showed that miR-483 and IGF2 are all expressed in HepG2, BEL-7402 and SMMC-7721. There are four hepatoma tissues have high expression of IGF2 in all detected nine different hepatoma tissues. miR-483 are overexpressed in fraction of IGF2 overexpression hepatoma tissue compare with normal tissue beside the tumor. Meanwhile, abnormal expression of IGF2 in hepatoma tissues mainly due to overexpression of transcripts from embryo promoter P3 and P4.2. In other different type cell lines, miR-483 and its host gene IGF2 are not coordinate expressed. The processing of miR-483 maturation may be regulated in other different cell lines. In human embryo kindey HEK293 cells, IGF2 and pre-miR-483 are overexpressed, but the mature miR-483 is almost not detected. In chronic lymphatic leukemia K562 cells, IGF2 is detected, miR-483 expression is low. In human uterine cervix cancer HeLa cells, IGF2 is not expressed, but miR-483 can be detected. There are probable some factors that specifically recognize pre-miR-483 and regulate cleavage process.3. miR-483 negatively regulates IGFBP3 and involves in the IGF2 mediated cell proliferation and apoptosis regulation in HepG2 liver cancer. miR-483 gene was cloned and eukaryon expression plasmid was constructed. Cell model, which was stably expressed miR-483 in HepG2 cell line, was constructed successfully. Use of chip technology with bioinformatics analysis found many potential miR-483 target genes. Results showed that miR-483 could downregulate IGFBP3 mRNA and protein expression, and IGFBP3 protein was upregulated after inhibiting miR-483. Ectopic expression of miR-483 reduced the upregulation of IGFBP3 by ATRA. Cell proliferation and apoptosis induced by ATRA were inhibited by miR-483.4. miR-34a induces a significant G1 cell-cycle arrest by downregulating CCND1 and CDK6. Dual luciferase reporter experiments showed that miR-34a directly targeted the 3′-untranslated region of CCND1 as well as CDK6. Ectopic expression of miR-34a inhibited CCND1 and CDK6 protein levels and reduced mRNA stability. miR-34a is involved in cell cycle progression and cellular proliferation in coordination with regulating multiple cell cycle proteins.On the whole, our investigation revealed the mechanisms that miR-483 participated regulating gene expression in hepatoma carcinoma cell proliferation. The study on miR-34a function showed that miR-34a was involved in cell cycle progression and cellular proliferation in coordination with regulating multiple cell cycle proteins.

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CLC: > Biological Sciences > Genetics > Genetics subdiscipline > Cytogenetic
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