Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • Consistent with the phenotypic response to

    2018-11-09

    Consistent with the phenotypic response to ANXA suppression (Fig. 6), suppression of ANXA2 led to an alteration of not only mesenchymal signatures but also cell cycle related pathways, such as cell cycle checkpoint genes (Gene Set Enrichment Analysis p=8.6×10, q=8.6×10, Supp Table 1). Intriguingly, additional pathways are also detected as significantly affected by ANXA2 perturbation, including e.g. Tumor Necrosis Factor Signaling (p=1.2×10, q=2.08×10) and MHC class II antigen presentation (p=1.02×10, q=1.38×10). Thus further studies will be needed to elucidate the full cellular impact of ANXA2 knockdown. In order, an extended study of ANXA2 knockdown in more cell lines is motivated, e.g. to determine differences in vulnerability to ANXA2 suppression. Such a systematic study appears quite possible, since ANXA2 is broadly expressed in glioma cells and does not co-vary significantly with cell culture passage (Supp Fig 11). Our data provides new evidence of a functional interaction between ANXA2 and transcription factors (TFs) known to be involved in GBM mesenchymal programs. Previously, STAT3 phosphorylation has been linked to regulation of three TFs that regulate mesenchymal genes: RUNX1, FOSL2, and BHLHB2 (Carro et al., 2010). It is notable that ANXA2 knockdown in BTSCs suppresses both STAT3 phosphorylation and all three target transcription factors. This would place ANXA2 upstream in a regulatory hierarchy. Interestingly, ANXA2 is not categorized as a transcription factor (TF), the class of protein most commonly associated with the gene expression master regulator function (Bhat et al., 2011; Carro et al., 2010). Danussi et al. identified the RhoA-binding protein, RHPN2, as an example of mesenchymal signature driver that does not belong to the TF category (Danussi et al., 2013). Similarly, ANXA2 might represent a mechanism to control cellular programs alternative to the canonical TF drive. Further studies would be required to fully understand the ANXA2 downstream activation mechanism. Since ANXA2 cellular localization is more accessible than that of TFs, which generally pose as difficult drug targets, our identification of ANXA2 as a regulator of the mesenchymal signature might represent an opportunity to therapeutically target this molecule in order to more efficiently treat diltiazem hcl tumors and improve patients\' survival.
    Author Contributions
    Conflict of Interest
    Acknowledgments This study was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, CA 1246/2-1 to M.S. Carro) and project grants from the Swedish Research Council (2014-03314), the Swedish Childhood Cancer Foundation (PR2014-0143), the strategic research network eSSENCE, and the Swedish Cancer Society (CAN 2014/579) (to S. Nelander). We thank E. Kling and L. Platania for technical assistance, T. Unterkircher for assistance in ANXA2 subcloning (all from University Freiburg), L. Zheng (Johns Hopkins University) for LV-ANXA2 vector, V. Baekelandt (University of Leuven) for PCHMWS-eGFP-IRES vector and M. Prinz (University of Freiburg) for histology samples. We also thank Anna Dimberg and Linda Holmfeldt for comments on the manuscript.
    Introduction Deaths from papillary thyroid cancer, in excess of 30,000/year worldwide, are typically preceded by dedifferentiation and resistance to radioactive iodine treatment (Ferlay et al., 2013). Thyroid development and follicular cell function is defined by co-expression of the transcription factors, TTF1 (Nkx2-1) and Pax8, but how these transcription factors are regulated in thyroid malignant disease is unclear (Antonica et al., 2012). Follicular cell dedifferentiation, with disrupted thyroglobulin synthesis and NaI symporter (NIS) function, is considered central to poor outcomes in PTC (Grogan et al., 2013; Lundgren et al., 2006; Xing, 2013; Ke et al., 2013). Patients with aggressive PTC variants often require multiple doses of radioactive iodine or repeated surgeries to address metastatic disease (Dadu and Cabanillas, 2013; Schneider et al., 2013; Haugen et al., 2016; Randolph et al., 2012). The Cancer Genome Atlas project defines PTC as an ERK-driven cancer, but the differentiation status of tumors is complex and the regulation of TTF1 and Pax8 defies individual assessments of BRAF or RAS gene mutations (Cancer Genome Atlas Research Network, 2014). Treatments including resveratrol, rapamycin, and retinoic acid have been examined for their ability to slow tumor growth or induce differentiation (Liu et al., 2007; Kogai et al., 2008; Vivaldi et al., 2009; Fernandez et al., 2009; Hou et al., 2010; Zhang et al., 2011; Oh et al., 2011; Malehmir et al., 2012; Coelho et al., 2011; Sherman et al., 2013; Yu et al., 2013; Giuliani et al., 2014; Plantinga et al., 2014). As yet, the benchtop results are conflicting and selective changes in NIS protein expression and iodide uptake in many of these studies have failed to translate into clinically relevant and durable responses in radioactive iodine therapy.