Dataset Information

Identification of functionally distinct TRAF proinflammatory and phosphatidylinositol 3-kinase/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (PI3K/MEK) transforming activities emanating from RET/PTC fusion oncoprotein.

ABSTRACT: Thyroid carcinomas that harbor RET/PTC oncogenes are well differentiated, relatively benign neoplasms compared with those expressing oncogenic RAS or BRAF mutations despite signaling through shared transforming pathways. A distinction, however, is that RET/PTCs induce immunostimulatory programs, suggesting that, in the case of this tumor type, the additional pro-inflammatory pathway reduces aggressiveness. Here, we demonstrate that pro-inflammatory programs are selectively activated by TRAF2 and TRAF6 association with RET/PTC oncoproteins. Eliminating this mechanism reduces pro-inflammatory cytokine production without decreasing transformation efficiency. Conversely, ablating MEK/ERK or PI3K/AKT signaling eliminates transformation but not pro-inflammatory cytokine secretion. Functional uncoupling of the two pathways demonstrates that intrinsic pro-inflammatory pathways are not required for cellular transformation and suggests a need for further investigation into the role inflammation plays in thyroid tumor progression.

SUBMITTER: Wixted JH

PROVIDER: S-EPMC3281745 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Identification of functionally distinct TRAF proinflammatory and phosphatidylinositol 3-kinase/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (PI3K/MEK) transforming activities emanating from RET/PTC fusion oncoprotein.

Wixted Josephine H F JH Rothstein Jay L JL Eisenlohr Laurence C LC

The Journal of biological chemistry 20111209 6

Thyroid carcinomas that harbor RET/PTC oncogenes are well differentiated, relatively benign neoplasms compared with those expressing oncogenic RAS or BRAF mutations despite signaling through shared transforming pathways. A distinction, however, is that RET/PTCs induce immunostimulatory programs, suggesting that, in the case of this tumor type, the additional pro-inflammatory pathway reduces aggressiveness. Here, we demonstrate that pro-inflammatory programs are selectively activated by TRAF2 and ...[more]

PMID: 22158616

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Project description:BackgroundHashimoto Thyroiditis (H.T.) is a destructive autoimmune thyroid condition whose precise molecular pathogenesis remains unclear. ret/PTC-1 is a chimeric transcript which has been described in autoimmune thyroid disease (AITD) and thyroid neoplasia. The purpose of this study was to observe the immunogenic effect exposure to H.T. and control lymphocyte supernatant would have on normal (Nthy-ori) and ret/PTC-1 (TPC-1) expressing thyroid cell line models.ResultsA 2 x 2 matrix comprising Nthy-ori and TPC-1 cell lines and H.T. and control lymphocyte supernatant was designed and utilised as follows; activated lymphocytic supernatant from a H.T. and normal control were co-cultured with a cell line derived from normal thyroid (Nthy-ori) and also a cell line derived from a papillary thyroid carcinoma that endogenously expresses ret/PTC-1 (TPC-1). The co-cultures were harvested at 0, 6 and 18 hour time points. Gene expression analysis was performed on RNA extracted from thyrocytes using TaqMan Immune profiling Low-Density Arrays (Applied Biosystems, CA, USA) comprising gene expression markers for 93 immune related targets plus 3 endogenous controls. Stimulation of the normal thyroid cell line model with activated T cell supernatant from the H.T. donor yielded global up-regulation of immune targets when compared with control supernatant stimulation. In particular, a cohort of targets (granzyme B, CD3, CD25, CD152, CD45) associated with cytotoxic cell death; T cell receptor (TCR) and T cell signaling were up-regulated in the normal cell line model. When the ret/PTC-1 expressing thyroid cell line was co-cultured with H.T. lymphocyte supernatant, in comparison to control supernatant stimulation, down-regulation of the same subset of immune targets was seen.ConclusionCo-culturing H.T. lymphocyte supernatant with a normal thyroid cell line model leads to over-expression of a subset of targets which could contribute to the pathogenesis of H.T. via cytotoxic cell death and TCR signalling. Stimulation of the ret/PTC-1 positive cell line with the same stimulus led to a down-regulated shift in the gene expression pattern of the cohort of immune targets. We hypothesize that ret/PTC-1 activation may dampen immunogenic responses in the thyroid, which could possibly facilitate papillary thyroid carcinoma development.

Dataset Information

Identification of functionally distinct TRAF proinflammatory and phosphatidylinositol 3-kinase/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (PI3K/MEK) transforming activities emanating from RET/PTC fusion oncoprotein.

Publications

Identification of functionally distinct TRAF proinflammatory and phosphatidylinositol 3-kinase/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (PI3K/MEK) transforming activities emanating from RET/PTC fusion oncoprotein.

Similar Datasets

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