Activation of Notch signaling is required for cholangiocarcinoma progression and is enhanced by inactivation of p53 in vivo
Authors: Ruben R Plentz
Mona El Khatib
Przemyslaw Bozko
Ludwig Wilkens
Nisar P Malek
Vindhya Palagani
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: Cholangiocarcinoma; Notch signaling; γ-secretase inhibitor IX; cell proliferation; migration
Affiliations: Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany.

Abstract:  Cholangiocacinoma (CC) is a cancer disease with rising incidence. Notch signaling has been shown to be deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of CC is still not fully explored. In this study, we investigated the effects of Notch inhibition by γ-secretase inhibitor IX (GSI IX) in cultured human CC cell lines and we established a transgenic mouse model with liver specific expression of the intracellular domain of Notch (Notch-ICD) and inactivation of tumor suppressor p53. GSI IX treatment effectively impaired cell proliferation, migration, invasion, epithelial to mesenchymal transition and growth of softagar colonies. In vivo overexpression of Notch-ICD together with an inactivation of p53 significantly increased tumor burden and showed CC characteristics. Conclusion: Our study highlights the importance of Notch signaling in the tumorigenesis of CC and demonstrates that additional inactivation of p53 in vivo. 

Retracted: No

PubPeer comments:
 Figure 4A. Two panels (DMSO and 5 uM) appear to look identical. Shown below with blue boxes. ![file] , 
 Figure 5: The Snail and E-cadherin panels in Figure 5A (SZ1 cells) and 5B (TFK1 cells) appear to look unexpectedly similar. The angle of the blots appears to be different as well. The size of the proteins appears to have been switched in one of the 2 panels as well. Shown below with green and red boxes: ![file] , 
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 2019 expression of concern. https: journals.plos.org plosone article?id=10.1371 journal.pone.0226310 After this article was corrected and republished [1, 2] to address image concerns, additional errors were noted in three panels of Fig 5. Each panel ought to include data for 7 samples, as indicated in the figure labels, but the incorrect number of lanes were presented in the following: Fig 5A: The Actin panel for the Snail and E-cadherin experiments has 8 lanes instead of 7. Fig 5B: The Actin panel for the Snail and E-cadherin experiments has 8 lanes instead of 7. Fig 5B: The N-cadherin panel and corresponding Actin panel each have 6 lanes instead of 7. The authors explained that these images were cropped incorrectly when the original figure was composed such that they included control lanes (Actin panels for Snail and E-cadherin, Fig 5A and 5B) or excluded DMSO lanes (N-cadherin and corresponding Actin panels, Fig 5B). Please see the updated Fig 5 in which these issues are addressed here. Note, the original images underlying Fig 5 are no longer available except for those included in the prior Correction [2]. The underlying data supporting Fig 4 of the article [1] are provided here in S1 and S2 Files. The underlying data supporting other results in this article are not available. In light of the cumulative concerns about this article and the unavailability of supporting data, the PLOS ONE Editors issue this Expression of Concern. For reference, the original version of the article is included here in S3 File. Note that the original version of Fig 3A included an image that was not licensed for reproduction and distribution under the terms of the Creative Commons Attribution License. When the previous Correction [2] was posted, the article was republished to remove the previously published content from the article. The image in question is redacted in S3 File. The work reported in this article [1] was completed when the corresponding author (RRP) was affiliated with Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany, as is noted on the published article. RRP is currently affiliated with Department of Internal Medicine II, Gesundheit Nord Klinikverbund Bremen. References 1.El Khatib M, Bozko P, Palagani V, Malek NP, Wilkens L, Plentz RR (2013) Activation of Notch Signaling Is Required for Cholangiocarcinoma Progression and Is Enhanced by Inactivation of p53 In Vivo. PLoS ONE 8(10): e77433. https: doi.org 10.1371 journal.pone.0077433 3 comments on PubPeer (by: Lotus Azoricus, Leonid Schneider) pmid:24204826 View ArticlePubMed NCBIGoogle Scholar 2.El Khatib M, Bozko P, Palagani V, Malek NP, Wilkens L, Plentz RR (2018) Correction: Activation of Notch Signaling Is Required for Cholangiocarcinoma Progression and Is Enhanced by Inactivation of p53 In Vivo. PLoS ONE 13(11): e0206953. https: doi.org 10.1371 journal.pone.0206953 pmid:30383871 ,