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Cancer. 2019 Jul 15;125(14):2409-2422. doi: 10.1002/cncr.32053. Epub 2019 Apr 23.

Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53-altered tumors.

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Department of Biochemistry and Biology, University of Houston, Houston, Texas.
Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
UPMC Genome Center, Pittsburgh, Pennsylvania.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
Department of Molecular and Cellular Oncology, Division of Basic Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Genentech, Inc., South San Francisco, California.
10X Genomics Inc., Pleasanton, California.
SynerGene Therapeutics, Inc., Potomac, Maryland.
Department of Integrative Biology and Physiology, University of California, Los Angeles, California.
Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Center for RNAi and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Molecular Oncology, Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, Florida.



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.


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.


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.


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.


3-dimensional (3D) spheroids; B-cell lymphoma 2-like protein 11 (BIM); chemosensitization; cisplatin; leoyl-sn-glycero-3-phosphatidylcholine (DOPC); microRNA 130b (miR-130b); ovarian cancer; transactivation (TA) and N-terminally truncated (ΔN) isoforms of the p63 protein (TAp63/ΔNp63); tumor protein p53; tumor-targeted nanocomplex (scL)

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