Open Access

Aberrant differentiation of Tsc2-deficient teratomas associated with activation of the mTORC1-TFE3 pathway

  • Authors:
    • Haruna Kawano
    • Yoshitaka Ito
    • Fumio Kanai
    • Eri Nakamura
    • Norihiro Tada
    • Setsuo Takai
    • Shigeo Horie
    • Toshiyuki Kobayashi
    • Okio Hino
  • View Affiliations

  • Published online on: September 8, 2015     https://doi.org/10.3892/or.2015.4254
  • Pages: 2251-2258
  • Copyright: © Kawano et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The model animal of renal cell carcinoma (RCC), the Eker rat, has a germline mutation in the tuberous sclerosis 2 (Tsc2) gene. Heterozygous mutants develop RCCs by second hit in the wild-type Tsc2 allele, whereas homozygous mutants are embryonic lethal. In the present study, a new cell differentiation model was developed to study the mechanism of Tsc2 mutation-associated pathogenesis by generating Tsc2-deficient embryonic stem cells (ESCs) from Eker rats. Tsc2+/+, Tsc2+/- and Tsc2-/- ESCs were all capable of generating three germ layers: mesoderm, ectoderm, and endoderm. Interestingly, epithelial tumor-like abnormal ductal structures were reproducibly observed in Tsc2-/- teratomas from different ESC lines. Immunohistochemical analysis revealed that mammalian target of rapamycin complex 1 (mTORC1) signaling was activated in abnormal ducts of Tsc2-/- teratomas, on the basis of positive staining for p-S6 and p-4EBP1. In these abnormal ducts, expression levels of epithelial markers (i.e., megalin and cubilin) and the cytoplasmic localization of E-cadherin and β-catenin were similar to those in Eker rat RCCs. Moreover, a transcription factor regulated by mTORC1, named TFE3, was located in the nuclei of abnormal ducts and Eker rat RCCs. As a negative regulator of ESC differentiation, TFE3 may result in tissue-specific differentiation defects related to tumorigenesis in Eker rats and Tsc2-/- teratomas. The present study suggests that ESCs derived from Eker rats constitute a novel experimental tool with which to analyze differentiation defects and cell-type specific pathogenesis associated with Tsc2 deficiency.
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November-2015
Volume 34 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Kawano H, Ito Y, Kanai F, Nakamura E, Tada N, Takai S, Horie S, Kobayashi T and Hino O: Aberrant differentiation of Tsc2-deficient teratomas associated with activation of the mTORC1-TFE3 pathway. Oncol Rep 34: 2251-2258, 2015
APA
Kawano, H., Ito, Y., Kanai, F., Nakamura, E., Tada, N., Takai, S. ... Hino, O. (2015). Aberrant differentiation of Tsc2-deficient teratomas associated with activation of the mTORC1-TFE3 pathway. Oncology Reports, 34, 2251-2258. https://doi.org/10.3892/or.2015.4254
MLA
Kawano, H., Ito, Y., Kanai, F., Nakamura, E., Tada, N., Takai, S., Horie, S., Kobayashi, T., Hino, O."Aberrant differentiation of Tsc2-deficient teratomas associated with activation of the mTORC1-TFE3 pathway". Oncology Reports 34.5 (2015): 2251-2258.
Chicago
Kawano, H., Ito, Y., Kanai, F., Nakamura, E., Tada, N., Takai, S., Horie, S., Kobayashi, T., Hino, O."Aberrant differentiation of Tsc2-deficient teratomas associated with activation of the mTORC1-TFE3 pathway". Oncology Reports 34, no. 5 (2015): 2251-2258. https://doi.org/10.3892/or.2015.4254