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@ARTICLE{Frensemeier:181681,
      author       = {K. Frensemeier$^*$ and A. Holzer$^*$ and K.
                      Hoppe-Seyler$^*$ and F. Hoppe-Seyler$^*$},
      title        = {{D}ickkopf-1 expression is repressed by oncogenic human
                      papillomaviruses ({HPV}s) and regulates the {C}isplatin
                      sensitivity of {HPV}-positive cancer cells in a
                      {JNK}-dependent manner.},
      journal      = {International journal of cancer},
      volume       = {151},
      number       = {12},
      issn         = {0020-7136},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2022-02161},
      pages        = {2215-2228},
      year         = {2022},
      note         = {#EA:F065#LA:F065# / 2022 Dec 15;151(12):2215-2228},
      abstract     = {Oncogenic human papillomavirus (HPV) types control the
                      phenotype of cervical cancer cells through the sustained
                      expression of the viral E6/E7 oncogenes. Here, we show that
                      they strongly restrain expression of the putative tumor
                      suppressor protein Dkk1 (Dickkopf-1) in HPV-positive
                      cervical cancer cells through the restriction of p53
                      expression by the continuously expressed endogenous E6
                      oncoprotein. Moreover, our study reveals that compromised
                      Dkk1 expression is linked to increased resistance of
                      HPV-positive cervical cancer cells toward the proapoptotic
                      activity of Cisplatin. Although Dkk1 can act as a Wnt
                      antagonist, the antiapoptotic effect resulting from Dkk1
                      repression is not linked to an activation of this pathway.
                      Rather, transcriptome and functional analyses uncover that
                      Dkk1 repression leads to a strongly diminished stimulation
                      of c-Jun N-terminal kinase (JNK) signaling which is required
                      for efficient apoptosis induction by Cisplatin in cervical
                      cancer cells. Further, we observed that Dkk1-depleted
                      cervical cancer cells induce senescence under Cisplatin
                      treatment instead of apoptosis, suggesting that Dkk1 levels
                      can strongly influence the phenotypic response of these
                      cells toward Cisplatin. Collectively, these results provide
                      new insights into the virus/host cell crosstalk in cervical
                      cancer cells by identifying Dkk1 as a cellular target which
                      is maintained under strong negative control by the
                      continuous expression of the HPV oncogenes. Moreover, they
                      identify Dkk1 as a critical determinant for the sensitivity
                      of cervical cancer cells toward Cisplatin, showing that Dkk1
                      repression leads to increased Cisplatin resistance by
                      impairing proapoptotic JNK signaling.},
      keywords     = {Cisplatin (Other) / Dickkopf-1 (Other) / c-Jun N-terminal
                      kinase (Other) / cervical cancer (Other) / human
                      papillomavirus (Other)},
      cin          = {F065},
      ddc          = {610},
      cid          = {I:(DE-He78)F065-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36094276},
      doi          = {10.1002/ijc.34250},
      url          = {https://inrepo02.dkfz.de/record/181681},
}