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Hormones and Cancer

, Volume 9, Issue 5, pp 326–337 | Cite as

RNA Sequencing of Carboplatin- and Paclitaxel-Resistant Endometrial Cancer Cells Reveals New Stratification Markers and Molecular Targets for Cancer Treatment

  • Raffaele Hellweg
  • Ashley Mooneyham
  • Zenas Chang
  • Mihir Shetty
  • Edith Emmings
  • Yoshie Iizuka
  • Christopher Clark
  • Timothy Starr
  • Juan H. Abrahante
  • Florian Schütz
  • Gottfried Konecny
  • Peter Argenta
  • Martina BazzaroEmail author
Original Paper

Abstract

Despite advances in surgical technique and adjuvant treatment, endometrial cancer has recently seen an increase in incidence and mortality in the USA. The majority of endometrial cancers can be cured by surgery alone or in combination with adjuvant chemo- or radiotherapy; however, a subset of patients experience recurrence for reasons that remain unclear. Recurrence is associated with chemoresistance to carboplatin and paclitaxel and consequentially, high mortality. Understanding the pathways involved in endometrial cancer chemoresistance is paramount for the identification of biomarkers and novel molecular targets for this disease. Here, we generated the first matched pairs of carboplatin-sensitive/carboplatin-resistant and paclitaxel-sensitive/paclitaxel-resistant endometrial cancer cells and subjected them to bulk RNA sequencing analysis. We found that 45 genes are commonly upregulated in carboplatin- and paclitaxel-resistant cells as compared to controls. Of these, the leukemia inhibitory factor, (LIF), the protein tyrosine phosphatase type IVA, member 3 (PTP4A3), and the transforming growth factor beta 1 (TGFB1) showed a highly significant correlation between expression level and endometrial cancer overall survival (OS) and can stratify the 545 endometrial cancer patients in the TCGA cohort into a high-risk and low-risk-cohorts. Additionally, four genes within the 45 upregulated chemoresistance-associated genes are ADAMTS5, MICAL2, STAT5A, and PTP4A3 codes for proteins for which small-molecule inhibitors already exist. We identified these proteins as molecular targets for chemoresistant endometrial cancer and showed that treatment with their correspondent inhibitors effectively killed otherwise chemoresistant cells. Collectively, these findings underline the utility of matched pair of chemosensitive and chemoresistant cancer cells to identify markers for endometrial cancer risk stratification and to serve as a pharmacogenomics model for identification of alternative chemotherapy approaches for treatment of patients with recurrent disease.

Keywords

Endometrial cancer Recurrence Gene expression Chemoresistance 

Notes

Acknowledgements

We would like to thank Mrs. Dinesha Walek (Genomic Center, University of Minnesota) for the help with preparation of the samples for RNA-seq analysis. We are grateful to Mr. Juri Habicht (Brandenburg Medical School, Neuruppin, Germany) for the critical reading of the manuscript and to Dr. Boris Winterhoof (University of Minnesota) for the helpful discussion.

Funding

This work was supported by the Department of Defense Ovarian Cancer Research Program (OCRP) OC093424, by the Minnesota Ovarian Cancer Alliance, and by the Randy Shaver Cancer Foundation to MB. Ashley Mooneyham was supported by Cancer Biology Training Grant NIH T32 CA009138. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12672_2018_337_MOESM1_ESM.docx (104 kb)
Supplementary Table 1 Complete list of the commonly DEGs in chemosenstive versus chemoresistant endometrial cancer cells. (DOCX 103 kb)
12672_2018_337_Fig8_ESM.png (891 kb)
Supplementary Table 2

Top 5 pathways enriched in IPA (Ingenuity Pathway Analysis) for each of the chemoresistant cell lines and for the commonly altered genes. (PNG 891 kb)

12672_2018_337_MOESM2_ESM.tif (552 kb)
High resolution image (TIF 551 kb)
12672_2018_337_Fig9_ESM.png (130 kb)
Supplementary Table 3

Sensitivity of paclitaxel resistant ECC-1 (ECC-1P) endometrial cancer cells to ADAMTS5, PTP4A3, STAT5A, and MICAL2 inhibitors. (PNG 129 kb)

12672_2018_337_MOESM3_ESM.tif (150 kb)
High resolution image (TIF 150 kb)
12672_2018_337_Fig10_ESM.png (121 kb)
Supplementary Table 4

Sensitivity of parental (sensitive) ECC-1 endometrial cancer cells to ADAMTS5, PTP4A3, STAT5A, and MICAL2 inhibitors. (PNG 120 kb)

12672_2018_337_MOESM4_ESM.tif (157 kb)
High resolution image (TIF 156 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Raffaele Hellweg
    • 1
    • 2
    • 3
  • Ashley Mooneyham
    • 1
    • 2
  • Zenas Chang
    • 2
  • Mihir Shetty
    • 1
    • 2
  • Edith Emmings
    • 1
  • Yoshie Iizuka
    • 1
    • 2
  • Christopher Clark
    • 1
    • 2
  • Timothy Starr
    • 1
    • 2
  • Juan H. Abrahante
    • 4
  • Florian Schütz
    • 3
  • Gottfried Konecny
    • 5
  • Peter Argenta
    • 2
  • Martina Bazzaro
    • 1
    • 2
    Email author
  1. 1.Masonic Cancer Center and Department of Obstetrics, Gynecology and Women’s HealthUniversity of Minnesota Twin CitiesMinneapolisUSA
  2. 2.Department of Women’s HealthUniversity of MinnesotaMinneapolisUSA
  3. 3.Heidelberg University Breast UnitHeidelbergGermany
  4. 4.University of Minnesota Informatics InstituteUniversity of MinnesotaMinneapolisUSA
  5. 5.Gynecologic Oncology, Hematology and Oncology DepartmentUCLA Medical CenterSanta MonicaUSA

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