%0 Journal Article %J Cancer %D 2019 %T Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53-altered tumors. %A Gunaratne, Preethi H %A Pan, Yinghong %A Rao, Abhi K %A Lin, Chunru %A Hernandez-Herrera, Anadulce %A Liang, Ke %A Rait, Antonina S %A Venkatanarayan, Avinashnarayan %A Benham, Ashley L %A Rubab, Farwah %A Kim, Sang Soo %A Rajapakshe, Kimal %A Chan, Clara K %A Mangala, Lingegowda S %A Lopez-Berestein, Gabriel %A Sood, Anil K %A Rowat, Amy C %A Coarfa, Cristian %A Pirollo, Kathleen F %A Flores, Elsa R %A Chang, Esther H %K Animals %K Antineoplastic Agents %K Binding Sites %K Cell Line, Tumor %K Cell Movement %K Cisplatin %K Drug Resistance, Neoplasm %K Female %K Humans %K Liposomes %K Mice %K Mice, Nude %K MicroRNAs %K Mutation, Missense %K Neoplasm Invasiveness %K Ovarian Neoplasms %K Protein Isoforms %K Signal Transduction %K Transcription Factors %K Transcriptional Activation %K Transfection %K Tumor Suppressor Protein p53 %K Tumor Suppressor Proteins %K Xenograft Model Antitumor Assays %X

BACKGROUND: Over 96% of high-grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53, is rarely mutated in cancer.

METHODS: A novel strategy is presented for circumventing alterations in p53 by inducing the tumor-suppressor isoform TAp63 (transactivation domain of tumor protein p63) through its direct downstream target, microRNA-130b (miR-130b), which is epigenetically silenced and/or downregulated in chemoresistant ovarian cancer.

RESULTS: Treatment with miR-130b resulted in: 1) decreased migration/invasion in HEYA8 cells (p53 wild-type) and disruption of multicellular spheroids in OVCAR8 cells (p53-mutant) in vitro, 2) sensitization of HEYA8 and OVCAR8 cells to cisplatin (CDDP) in vitro and in vivo, and 3) transcriptional activation of TAp63 and the B-cell lymphoma (Bcl)-inhibitor B-cell lymphoma 2-like protein 11 (BIM). Overexpression of TAp63 was sufficient to decrease cell viability, suggesting that it is a critical downstream effector of miR-130b. In vivo, combined miR-130b plus CDDP exhibited greater therapeutic efficacy than miR-130b or CDDP alone. Mice that carried OVCAR8 xenograft tumors and were injected with miR-130b in 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) liposomes had a significant decrease in tumor burden at rates similar to those observed in CDDP-treated mice, and 20% of DOPC-miR-130b plus CDDP-treated mice were living tumor free. Systemic injections of scL-miR-130b plus CDDP in a clinically tested, tumor-targeted nanocomplex (scL) improved survival in 60% and complete remissions in 40% of mice that carried HEYA8 xenografts.

CONCLUSIONS: The miR-130b/TAp63 axis is proposed as a new druggable pathway that has the potential to uncover broad-spectrum therapeutic options for the majority of p53-altered cancers.

%B Cancer %V 125 %P 2409-2422 %8 2019 Jul 15 %G eng %N 14 %1 https://www.ncbi.nlm.nih.gov/pubmed/31012964?dopt=Abstract %R 10.1002/cncr.32053 %0 Journal Article %J PLoS One %D 2012 %T Integrated analyses of microRNAs demonstrate their widespread influence on gene expression in high-grade serous ovarian carcinoma. %A Creighton, Chad J %A Hernandez-Herrera, Anadulce %A Jacobsen, Anders %A Levine, Douglas A %A Mankoo, Parminder %A Schultz, Nikolaus %A Du, Ying %A Zhang, Yiqun %A Larsson, Erik %A Sheridan, Robert %A Xiao, Weimin %A Spellman, Paul T %A Getz, Gad %A Wheeler, David A %A Perou, Charles M %A Gibbs, Richard A %A Sander, Chris %A Hayes, D Neil %A Gunaratne, Preethi H %K 3' Untranslated Regions %K Breast %K Cell Line, Tumor %K DNA Copy Number Variations %K Female %K Gene Expression Regulation, Neoplastic %K Humans %K MicroRNAs %K Neoplasms, Cystic, Mucinous, and Serous %K Ovarian Neoplasms %X

BACKGROUND: The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.

METHODS AND RESULTS: Integration of miRNA and gene patterns yielded evidence that proximal pairs of miRNAs are processed from polycistronic primary transcripts, and that intronic miRNAs and their host gene mRNAs derive from common transcripts. Patterns of miRNA expression revealed multiple tumor subtypes and a set of 34 miRNAs predictive of overall patient survival. In a global analysis, miRNA:mRNA pairs anti-correlated in expression across tumors showed a higher frequency of in silico predicted target sites in the mRNA 3'-untranslated region (with less frequency observed for coding sequence and 5'-untranslated regions). The miR-29 family and predicted target genes were among the most strongly anti-correlated miRNA:mRNA pairs; over-expression of miR-29a in vitro repressed several anti-correlated genes (including DNMT3A and DNMT3B) and substantially decreased ovarian cancer cell viability.

CONCLUSIONS: This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers.

%B PLoS One %V 7 %P e34546 %8 2012 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/22479643?dopt=Abstract %R 10.1371/journal.pone.0034546