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Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1

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Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1 Published OnlineFirst September 2, 2016; DOI: 10.1158/0008-5472.CAN-16-0980 Cancer Therapeutics, Targets, and Chemical Biology Research Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1 Jin-Gyoung Jung1, Ie-Ming Shih1,2,3, Joon Tae Park1, Emily Gerry1, Tae Hoen Kim1, Ayse Ayhan1,4,5, Karen Handschuh6, Ben Davidson7,8, Amanda N. Fader1,2,3, Licia Selleri6, and Tian-Li Wang1,2,3 Abstract The evolution of chemoresistance is a fundamental character- that overexpressed PBX1 sensitized them to platinum treatment istic of cancer that ultimately hampers its clinical management. and reduced their stem-like properties. An analysis of published However, it may be possible to improve patient outcomes sig- genome-wide chromatin immunoprecipitation data indicated nificantly by a better understanding of resistance mechanisms, that PBX1 binds directly to promoters of genes involved in stem which cancers rely upon during the evolution to an untreatable cell maintenance and the response to tissue injury. We con- state. Here we report an essential role of the stem cell reprogram- firmed direct regulation of one of these genes, STAT3, demon- ming factor, PBX1, in mediating chemoresistance in ovarian strating that the PBX1 binding motif at its promoter acted to carcinomas. In the clinical setting, high levels of PBX1 expression positively regulate STAT3 transcription. We further demonstrat- correlated with shorter survival in post-chemotherapy ovarian ed that a STAT3/JAK2 inhibitor could potently sensitize plat- cancer patients. In tumor cells with low endogenous levels of inum-resistant cells to carboplatin and suppress their growth PBX1, its enforced expression promoted cancer stem cell-like in vivo.Ourfindings offer a mechanistic rationale to target the phenotypes, including most notably an increase in resistance to PBX1/STAT3 axis to antagonize a key mechanism of chemore- platinum-based therapy used most commonly for treating this sistance in ovarian cancers and possibly other human cancers. disease. Conversely, silencing PBX1 in platinum-resistant cells Cancer Res; 76(21); 1–11. Ó2016 AACR. Introduction (HGSC) experience recurrence after first-line chemotherapy, and the 5-year survival rate is only approximately 40% in Cytoreductive surgery followed by cycles of platinum/tax- these patients (1). ane chemotherapy has become the standard treatment for Several theories have been proposed to explain the develop- advanced epithelial ovarian cancer. Although most ovarian ment of chemoresistance in human cancer. A prevailing view is tumors initially respond to chemotherapy, refractory tumors that heterogeneous cell subpopulations, which exhibit different often emerge as a result of clonal expansion of either acquir- degrees of tumor-initiating potentials and drug sensitivities, exist ed or innately resistant tumor cells, which ultimately develop within a tumor. Alternatively, cancer cells may acquire these into recurrent tumors. Consequently, up to 80% of women phenotypes during tumor evolution in the presence of selective with advanced stage ovarian high-grade serous carcinoma pressures such as cytotoxic agents and hypoxia. The dynamic interplay between tumor cells and their microenvironment may activate developmental pathways, such as Wnt and Notch, that 1Department of Pathology, Johns Hopkins Medical Institutions, Balti- allow them to survive and expand. Reactivation of developmental 2 more, Maryland. Department of Oncology, Johns Hopkins Medical pathways equips tumor cells with "stemness," which is charac- Institutions, Baltimore, Maryland. 3Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland. terized by self-renewal, repopulation, and resistance to cytotoxic 4Department of Pathology, Seirei Mikatahara Hospital, Hamamatsu, insult (2). Therefore, it is critical to identify genes and pathways Japan. 5Department of Pathology, Hamamatsu University School of 6 involved in this process to further understand the molecular Medicine, Hamamatsu, Japan. Department of Cell and Developmen- – tal Biology, Weill Medical College, Cornell University, New York, New underpinnings of stem cell like cancer cells (CSC) and their York. 7Department of Pathology, Oslo University Hospital, Norwegian relation to the bulk population of tumor cells (3). This new 8 Radium Hospital, Oslo, Norway. Faculty of Medicine, Institute of knowledge would guide the design of more effective cancer Clinical Medicine, University of Oslo, Oslo, Norway. therapeutic strategies. Note: Supplementary data for this article are available at Cancer Research In this study, we collected primary and matched recurrent/ Online (http://cancerres.aacrjournals.org/). chemoresistant tumor tissues from 41 patients with ovarian Current address for L. Selleri: Program in Craniofacial Biology, Departments of HGSC and analyzed the expression levels of stem cell factors. Orofacial Sciences & Anatomy, University of California, San Francisco, San We found that the homeodomain transcription factor PBX1 is Francisco, California. significantly upregulated in recurrent ovarian tumors. Func- Corresponding Author: Tian-Li Wang, Johns Hopkins Medical Institutions, tional studies demonstrated that PBX1 expression is essential CRBII, Room 306, 1550 Orleans Street, Baltimore, MD 21231. Phone: 410-502- for promoting platinum resistance. In addition, we delineated 0863; E-mail: [email protected] PBX1-regulated transcriptional networks that may account for doi: 10.1158/0008-5472.CAN-16-0980 its involvement in the development of drug resistance and Ó2016 American Association for Cancer Research. stemness. www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 2, 2016; DOI: 10.1158/0008-5472.CAN-16-0980 Jung et al. Materials and Methods plates at a density of 3,000 cells per well in triplicate and treated with serial dilutions of chemotherapeutic drugs. Cell viability was Tumor specimens and cell lines measured after 72 hours with CellTiter-Blue reagent (Promega) Tissue microarrays containing 41 pairs of matched primary and using a microplate reader (Fluostar, BMG). The data are presented recurrent tumor tissues were constructed using deidentified sam- as mean Æ SD, calculated from triplicate values, and IC was ples from HGSC patients who underwent optimal surgical 50 defined as the concentration that resulted in a 50% decrease in the debulking at the Johns Hopkins Hospital (Baltimore, MD). number of live cells. For the colony formation assay, 1,000 cells Another cohort consisted of ascites tumor samples from patients were seeded into a 35-mm culture dish. After 9 days, the cells were who had undergone optimal debulking surgery at the Norwegian stained with crystal violet dye (Sigma-Aldrich). Radium Hospital. Institutional review board approval was obtained for each study cohort. Human ovarian cancer cell lines, including OVCAR3, Luciferase reporter assay STAT3 SKOV3, and Hey, were purchased from the ATCC during year Human promoter regions of various lengths were fi 2006—8. IOSE-80PC, a cell line derived from normal ovarian ampli edandclonedintothepGL3-basicplasmid.Microdele- STAT3 surface epithelium, was a kind gift from Dr. Nelly Auersperg tion of the PBX1 consensus binding motif on the (University of British Columbia, British Columbia, Canada). promoter was generated using a Site-Directed Mutagenesis Kit MPSC1, a low-grade ovarian serous carcinoma cell line, was (Agilent). 293FT cells were then transfected with either PBX1 or previously described (4). To establish chemoresistant ovarian pcDNA6 and cotransfected with various STAT3 promoter con- Renilla cancer cells, SKOV3, OVCAR3, and MPSC1 cells were cultured structs. pRL- reporter plasmid (Promega) was cotrans- fi for 3–6 months in the continuous presence of 10 mmol/L fected for assessing transfection ef ciency. Luciferase activity carboplatin (Sigma-Aldrich). Primary and carboplatin-resistant was determined by the Dual-Luciferase reporter assay system fi fl Renilla cell lines as well as IOSE-80PC were authenticated by genetic (Promega); re y luciferase activity was normalized to profiling using eight polymorphic short tandem repeat (STR) luciferase activity. loci plus amelogenin in year 2015–2016. Mouse fallopian tube epithelium (mFTE) was cultured by In vitro dual-color competition assay fl/fl scraping the tubal mucosal surface from Pbx1 mice (5, 6). To PBX1-negative cells were transiently transfected with either establish immortalized cell lines, primary cultures were infected pcDNA6-PBX1-V5 or pcDNA6. CellTracker Red CMTPX Dye with the Simian virus 40 large T antigen (SV40 LTag), and single (Molecular Probes) was used to label pcDNA6-transfected cells clones were isolated. The epithelial origin of immortalized cell following the manufacturer's instructions. PBX1-positive and lines was confirmed by positivity for EpCAM or cytokeratin 8 PBX1-negative cells were mixed at a 1:1 ratio and cocultured in m protein markers. The Mullerian€ origin was supported by the a medium containing 0, 25, or 50 mol/L of carboplatin for 6 expression of PAX8 protein. Cells were incubated with Ade-Cre days. Cells were then briefly fixed using 4% paraformaldehyde in 7 – (1 Â 10 pfu) or with Ade-GFP for 12 hours. The deletion of the PBS, incubated with anti-V5-FITC antibody to stain for PBX1-V5 Pbx1 allele and the loss of Pbx1 protein were assessed by Western positive cells, and visualized by fluorescence microscopy (Nikon,
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  • Gene Name Forward Primer Reverse Primer ACTB
    Gene Name Forward Primer Reverse Primer ACTB CTGGAACGGTGAAGGTGACA AAGGGACTTCCTGTAACAATGCA ACVRL1 ACATGAAGAAGGTGGTGTGTGTGG CGGGCAGAGGGGTTTGGGTA ADAMDEC1 GGGGCCAGACTACACTGAAACATT ACCCGTCACAAGTACTGATGCTG AHI1 GTCCAAAACTACCCCATCAAGGCT GCAGCACAGGAACGTATCACCT ANGPT2 TGGCAGCGTTGATTTTCAGAGG GCGAAACAAACTCATTTCCCAGCC ANPEP TGAAGAAGCAGGTCACACCCCT AACTCCGTTGGAGCAGGCGG APOA1 GCCGTGCTCTTCCTGACGG TGGGACACATAGTCTCTGCCGC ATXN7 CACCGCCCACTCTGGAAAAGAA GGGTGCAGGGCTTCTTGGTG B2M TGCTGTCTCCATGTTTGATGTATCT TCTCTGCTCCCCACCTCTAAGT BAG4 AGGTTCCAGGATATCCGCCTT TCGGTCCTGATTGTGGAACACT BCL2 ACAACATCGCCCTGTGGATGA CCGTACAGTTCCACAAAGGCAT BCL2L14 GCTCAGGGTCAAAGGACGTTGG TCAGCTACTCGGTTGGCAATGG BCL7A GAACCATGTCGGGCAGGTCG CCCATTTGTAGATTCGTAGGGATGTGT BIN1 TGCTGTCGTGGTGGAGACCTTC GCCGTGTAGTCGTGCTGGG BIRC3 TGCTATCCACATCAGACAGCCC TCTGAATGGTCTTCTCCAGGTTCA BIRC5 TTCTCAAGGACCACCGCATCT AGTGGATGAAGCCAGCCTCG BLK TCGGGGTCTTCACCATCAAAGC GCGCTCCAGGTTGCGGATGA BTRC CCAAATGTGTCATTACCAACATGGGC GCAGCACATAGTGATTTGGCATCC BUB3 CGGAACATGGGTTACGTGCAGC CCAAATACTCAACTGCCACTCGGC CAGE1 TCCAAAATGCACAGTCTTCTGGCT GGAGGCTCTTCAGTTTTTGCAGC CASP1 CCTGTTCCTGTGATGTGGAGGAAA GCTCTACCATCTGGCTGCTCAA CASP3 AGCGAATCAATGGACTCTGGAATATCC GTTTGCTGCATCGACATCTGTACCA CCL5 TCATTGCTACTGCCCTCTGCG ACTGCTGGGTTGGAGCACTTG CCL18 CCCTCCTTGTCCTCGTCTGCA GCACTGGGGGCTGGTTTCAG CCL26 TTCCAATACAGCCACAAGCCCC GGATGGGTACAGACTTTCTTGCCTC CCND2 TCAAGTGCGTGCAGAAGGACAT CTTCGCACTTCTGTTCCTCACA CCND3 TGGCTGCTGTGATTGCACATGA GATGGCGGGTACATGGCAAAGG CCR3 ACGCTGCTCTGCTTCCTGG TCCTCAGTTCCCCACCATCGC CCR4 AGCATCGTGCTTCCTGAGCAA GGTGTCTGCTATATCCGTGGGGT CCR7 AGACAGGGGTAGTGCGAGGC
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