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TGFβ splicing and canonical pathway activation in high-grade serous carcinoma

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Abstract

The present study analyzed the expression and clinical role of the transforming growth factor-β (TGFβ) pathway in high-grade serous carcinoma (HGSC), with focus on malignant effusions. TGFβ1–3 and TGFβRI–III mRNA expression by qRT-PCR was analyzed in 70 HGSC effusions and 55 solid specimens (28 ovarian, 27 abdominal metastases). Protein expression of Smad2 and Smad3 and their phosphorylated forms by Western blotting was analyzed in 73 specimens (42 effusions, 13 ovarian carcinomas, 18 solid metastases). Expression was analyzed for association with anatomic site and clinical parameters, including survival. TGFβRI and TGFβRII mRNA was overexpressed in effusions and solid metastases, particularly the former, compared to that in the ovarian tumors (p < 0.001 to p = 0.05), with anatomic site-dependent expression of splice variants. Conversely, Smad2, p-Smad2, and p-Smad3 were overexpressed in solid specimens (ovarian and peritoneal) compared to those in effusions (p < 0.001 for all). In univariate survival analysis, higher TGFβRI variant 1 and TGFβRIII mRNA levels were associated with a trend for shorter overall survival in patients with post-chemotherapy effusions (p = 0.066 and p = 0.087, respectively), and the latter was an independent prognostic marker in Cox multivariate analysis (p = 0.041). Smad3 protein expression was associated with a trend for shorter overall survival in univariate survival analysis (p = 0.052). TGFβ receptor splice variant expression is anatomic site-dependent in HGSC. Elevated levels of TGFβ signaling pathway mRNAs are seen in metastatic HGSC, but are not accompanied by increased Smad expression and activation in HGSC effusions, evidence of failure to activate canonical TGFβ signaling. Assessment of the prognostic role of this pathway in HGSC effusions merits further research.

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Acknowledgment

This work was supported by the Inger and John Fredriksen Foundation for Ovarian Cancer Research.

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Authors and Affiliations

  1. Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel

    Neriya Gutgold, Liora Jacobs Catane & Reuven Reich

  2. Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310, Oslo, Norway

    Ben Davidson, Arild Holth & Ellen Hellesylt

  3. Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, N-0316, Oslo, Norway

    Ben Davidson & Claes G. Tropé

  4. Department of Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310, Oslo, Norway

    Anne Dørum

  5. David R. Bloom Center for Pharmacy and the Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics, The Hebrew University of Jerusalem, Jerusalem, Israel

    Reuven Reich

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  1. Neriya Gutgold
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Correspondence to Ben Davidson or Reuven Reich.

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Informed consent was obtained according to national and institutional guidelines. Study approval was given by the Regional Committee for Medical Research Ethics in Norway (S-04300).

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Gutgold, N., Davidson, B., Catane, L.J. et al. TGFβ splicing and canonical pathway activation in high-grade serous carcinoma. Virchows Arch 470, 665–678 (2017). https://doi.org/10.1007/s00428-017-2127-x

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  • DOI: https://doi.org/10.1007/s00428-017-2127-x

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