MicroRNA dysregulation in cancer. Systems Plant Microbiology Hyun-Hee Lee

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1 MicroRNA dysregulation in cancer Systems Plant Microbiology Hyun-Hee Lee

2 Contents 1 What is MicroRNA? 2 mirna dysregulation in cancer 3 Summary

3 What is MicroRNA?

4 What is MicroRNA? MicroRNAs (mirnas) - They are short non-coding RNAs of nucleotide not translated into proteins. - They have emerged as key regulators of cancer-related pathways. Proliferation Cell cycle control Apoptosis Differentiation Migration

5 What is MicroRNA? Three types of Pre-miRNA (Primary-miRNA) - Intronic mirnas are processed from a protein-coding transcript by Microprocessor. - Precursor mirtrons are produced by the spliceosome. Rainer, J., et al. "Glucocorticoid-regulated micrornas and mirtrons in acute lymphoblastic leukemia." Leukemia 23.4 (2009):

6 What is MicroRNA? Pathway of mirna biogenesis and processing Lin, Shuibin, and Richard I. Gregory. "MicroRNA biogenesis pathways in cancer." Nature Reviews Cancer 15.6 (2015):

7 mirna dysregulation in cancer

8 mirna dysregulation in cancer 1. Pri-miRNA transcription 2. Defective Microprocessor 3. Pre-miRNA export 4. Pre-miRNA processing 5. Other mirna regulators

9 mirna dysregulation in cancer 1. Pri-miRNA transcription - The locus of mirna on chromosome is frequently deleted in B-cell chronic lymphocytic leukemia (B-CLL), which target BCL-2 mrna ecoding anti-apoptotic protein. - The CpG islands at the gene promoters of mirnas are frequently hypermethylated in cancer, leading to silencing of these mirnas. - Proto-oncoprotein MYC can contribute to the widespread repression of tumour suppressive mirnas in B cell lymphoma. Jansson, Martin D., and Anders H. Lund. "MicroRNA and cancer." Molecular oncology 6.6 (2012):

10 mirna dysregulation in cancer 2. Defective Microprocessor - In cervical squamous cell carcinomas, DROSHA expression levels are upregulated. - In lung adenocarcinoma cells, downregulation of DROSHA acting as a tumour suppressor increases proliferation and tumour growth. - Particulary, DROSHA and DGCR8 are frequently mutated in Wilms tumour samples. Jansson, Martin D., and Anders H. Lund. "MicroRNA and cancer." Molecular oncology 6.6 (2012):

11 mirna dysregulation in cancer 3. Pre-miRNA export - Pre-miRNAs are exported into the cytoplasm to be processed into mature mirnas. - The export of pre-mirnas is mediated by XPO5 and its cofactor, RanGTP41. - XPO5 mutations impair pre-mirna export and result in an accumulation of pre-mirnas in the nucleus, leading to defects in mirna biogenesis.

12 mirna dysregulation in cancer 4. Pre-miRNA processing - The mutation hot spots occur in the metal-binding residues which do not change DICER1 protein expression but instead cause defects in the function. - DICER1 RNase IIIb mutations reduce the expression of the members of the let-7 tumour-suppressive mirna family.

13 mirna dysregulation in cancer 5. Other mirna regulators Hippo?

14 Introduction Hippo signaling pathway in cancer - It controls organ size in animals through the regulation of cell proliferation and apoptosis. - The pathway takes its name from one of its key signaling components-the protein kinase Hippo (Hpo). - Mutations in this gene lead to tissue overgrowth, or a hippopotamus -like phenotype. Fruitfly Mouse liver Johnson, Randy, and Georg Halder. "The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment." Nature reviews Drug discovery 13.1 (2014):

15 Introduction Mode of action of Hippo signaling pathway Johnson, Randy, and Georg Halder. "The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment." Nature reviews Drug discovery 13.1 (2014):

16 Introduction Regulation of Microprocessor by Hippo pathway - At low cell density, Hippo pathway is inactive, and nuclear YAP1 binds to and sequesters DDX17(p72) to suppress pri-mirna processing. - At high cell densities, Hippo pathway is active, which leads to YAP1 phosphorylation and its retention in the cytoplasm. DDX17 is able to bind to pri-mirna, resulting in enhanced mirna biogenesis. Mori, Masaki, et al. "Hippo signaling regulates microprocessor and links cell-density-dependent mirna biogenesis to cancer." Cell (2014):

17 Introduction Cell-density-dependent mirna biogenesis Mori, Masaki, et al. "Hippo signaling regulates microprocessor and links cell-density-dependent mirna biogenesis to cancer." Cell (2014):

18 Introduction Cell-density-dependent mirna biogenesis - qrt-pcr analysis of mirna expression in HaCaT cells. - Elevated mirna expression at high cell density was observed. Mori, Masaki, et al. "Hippo signaling regulates microprocessor and links cell-density-dependent mirna biogenesis to cancer." Cell (2014):

19 Introduction Localization of YAP and p72 - Immunocytochemistry analysis of YAP localization - Immunocytochemistry of YAP and p72 in HaCaT cells at high density. Nuclei were stained with DAPI. Mori, Masaki, et al. "Hippo signaling regulates microprocessor and links cell-density-dependent mirna biogenesis to cancer." Cell (2014):

20 Summary

21 Summary - MicroRNAs have emerged as key regulators of cancer-related pathways. - In cancer, dysregulation of the mirna biogenesis pathway is occurred, resulted from primirna transcription, defective microprocessor, pre-mirna export, pre-mirna processing, - And also, there are various cancer-related pathways involved in the regulation of mirna biogenesis such as hippo signaling pathway.

22 THANK YOU