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Xinna Zhang, PHD
Assistant Professor of Medical & Molecular Genetics
Our laboratory has long standing interest in protein regulators and noncoding RNAs in the DNA damage response, especially as they relate to genome stability, tumor initiation and progression. Wild-type p53-induced phosphatase 1 (Wip1) is a serine/threonine phosphatase that is up-regulated in response to various types of DNA damage. Our previous studies identified a number of Wip1 dephosphorylation targets in the ATM-p53 DNA damage signaling pathway, highlighting the critical role of Wip1 as a master inhibitor for the DNA damage response (DDR). Consistent with its oncogenic functions, Wip1 was shown to be amplified and overexpressed in human breast cancer. Our in-depth analysis of human breast cancer genomic DNA revealed an oncogenic microRNA (miRNA) gene, miR-21 in almost all the Wip1 amplicons. Moreover, the Wip1-miR-21 amplicon was found in 65.8% of human HER2+ breast tumors. Currently, our study is focused on the function of Wip1-miR-21 amplicon in HER2+ breast cancer and its role in resistance to anti-HER2 therapy.
Recent studies have identified a large number of miRNAs and lncRNAs (long non-coding RNAs) in mammalian transcriptomes. However, molecular mechanisms were unclear regarding the regulation of ncRNA expression and functions in the DDR. Posttranscriptional maturation is a critical step in miRNA biogenesis that determines mature miRNA levels. In addition to core components (Drosha and DGCR8) in the microprocessor, regulatory RNA-binding proteins may confer the specificity for recruiting and processing of individual pri-miRNAs. Our recent work identified the RNA-binding protein DDX1 as a regulatory protein that promotes the expression of a subset of miRNAs that determine the mesenchymal ovarian cancer subtype. Current studies in my laboratory are focused on a number of RNA-binding proteins that specifically bind primary miRNA transcripts and promote their processing in the Drosha microprocessor.
Pichler M, Stiegelbauer V, Vychytilova-Faltejskova P, Ivan C, Ling H, Winter E, Zhang X, Goblirsch M, Wulf-Goldenberg A, Ohtsuka M, Haybaeck J, Svoboda M, Gerger A, Okugawa Y, Hoefler G, Ajay A, Slaby O, Calin GA (2017). Genome-wide microRNA analysis identifies miR-188-3p as novel prognostic marker and molecular factor involved in colorectal carcinogenesis. Clin Cancer Res, 23:1323-33.
Kanlikilicer P, Rashed MH, Bayraktar R, Mitra R, Ivan C, Aslan B, Zhang X, Filant J, Silva AM, Rodriguez-Aguayo C, Bayraktar E, Pichler M, Ozpolat B, Calin GA, Sood AK, Lopez-Berestein G (2016). Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells. Cancer Res, 76:7194-207.
Han C, Yang L, Choi H, Baddou J, Achreja A, Liu Y, Li Y, Li J, Wan G, Huang C, Ji G, Zhang X, Nagrath D, Lu X (2016). Amplification of USP13 drives ovarian cancer metabolism. Nat Commun, 7:13525.
Zhang X*, Lopez-Berestein G, Sood AK, Calin GA (2016). Profiling long non-coding RNA expression using custom-designed microarray. Methods Mol Biol, 1402: 33-41 (*corresponding author).
Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, Jiang D, Rodriguez-Aguayo C, Lopez-Berestein G, Rao PH, Maru DM, Pahl A, He X, Sood AK, Ellis LM, Anderl J, Lu X (2015). TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature, 520(7549):697-701.
Challagundla KB, Wise PM, Neviani P, Chava H, Murtadha M, Xu T, Kennedy R, Ivan C, Zhang X, Vannini I, Fanini F, Amadori D, Calin GA, Hadjidaniel M, Shimada H, Jong A, Seeger RC, Asgharzadeh S, Goldkorn A, Fabbri M (2015). Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst, 107(7).
Han C, Liu Y, Wan G, Choi HJ, Zhao L, Ivan C, He X, Sood AK, Zhang X*, Lu X (2014). The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. Cell Rep, 8:1447-60 (*co-corresponding author).
Wan G, Zhang X, Langley RR, Liu Y, Hu X, Han C, Peng G, Ellis LM, Jones SN, Lu X (2013). DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway. Cell Rep, 3(6):2100-12.
Setoyama T, Zhang X, Natsugoe S, Calin GA (2011). MicroRNA-10b - a new marker or the marker of pancreatic ductal adenocarcinoma. Clin Cancer Res, 17(17):5527-9.
Zhang X, Berger FG, Yang J, Lu X (2011). USP4 inhibits p53 through deubiquitinating and Stabilizing ARF-BP1. EMBO J, 30(11):2177-89.
Zhang X, Wan G, Berger FG, He X, Lu X (2011). The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol Cell, 41(4):371-383.
Zhang X, Wan G, Mlotshwa S, Vance V, Berger F, Chen X, Lu X (2010). Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway. Cancer Res, 70(18):7176-86.
Moon SH, Lin L, Zhang X, Nguyen TA, Darlington Y, Waldman AS, Lu X, Donehower LA (2010). Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. J Biol Chem, 285(17):12935-47.