ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.

The molecular genetic events underlying thyroid carcinogenesis are poorly understood. Mice harboring a knock-in dominantly negative mutant thyroid hormone receptor b (TRb PV/PV mouse) spontaneously develop follicular thyroid carcinoma similar to human thyroid cancer. Using this mutant mouse, we tested the hypothesis that the peroxisome proliferator-activated receptor c (PPARc) could function as a tumor suppressor in thyroid cancer in vivo. Using the offspring from the cross of TRb PV/ þ and PPARc þ /À mice, we found that thyroid carcinogenesis progressed significantly faster in TRb PV/PV mice with PPARc insufficiency from increased cell proliferation and reduced apoptosis. Reduced PPARc protein abundance led to the activation of the nuclear factor-jB signaling pathway, resulting in the activation of cyclin D1 and repression of critical genes involved in apoptosis. Treatment of TRb PV/PV mice with a PPARc agonist, rosiglitazone, delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and activation of apoptosis. These results suggest that PPARc is a critical modifier in thyroid carcinogenesis and could be tested as a therapeutic target in thyroid follicular carcinoma.

Overexpression of pituitary tumor-transforming 1 (PTTG1) is associated with thyroid cancer. We found elevated PTTG1 levels in the thyroid tumors of a mouse model of follicular thyroid carcinoma (TRβ PV/PV mice). Here we examined the molecular mechanisms underlying elevated PTTG1 levels and the contribution of increased PTTG1 to thyroid carcinogenesis. We showed that PTTG1 was physically associated with thyroid hormone β receptor (TRβ) as well as its mutant, designated PV. Concomitant with thyroid hormone-induced (T3-induced) degradation of TRβ, PTTG1 proteins were degraded by the proteasomal machinery, but no such degradation occurred when PTTG1 was associated with PV. The degradation of PTTG1/TRβ was activated by the direct interaction of the liganded TRβ with steroid receptor coactivator 3 (SRC-3), which recruits proteasome activator PA28γ. PV, which does not bind T3, could not interact directly with SRC-3/PA28γ to activate proteasome degradation, resulting in elevated PTTG1 levels. The accumulated PTTG1 impeded mitotic progression in cells expressing PV. Our results unveil what we believe to be a novel mechanism by which PTTG1, an oncogene, is regulated by the liganded TRβ. The loss of this regulatory function in PV led to an aberrant accumulation of PTTG1 disrupting mitotic progression that could contribute to thyroid carcinogenesis. IntroductionFollicular and papillary thyroid carcinomas are the most common thyroid malignancies. Although both are well-differentiated cancers, each has distinguishable morphological and pathological characteristics (1). Follicular thyroid carcinoma has a greater tendency than does papillary cancer to metastasize to distant sites. Such distant metastasis predicts a poor response to treatment and subsequent progression and mortality from thyroid cancer. Despite recent progress in the identification of key genetic alterations and aberrant molecular pathways, the precise mechanisms underlying the initiation and progression of follicular thyroid cancer are not fully understood.The development of a mouse model of follicular thyroid cancer (TRβ PV/PV mice) has provided a valuable tool to elucidate the molecular basis underlying thyroid carcinogenesis (2). The TRβ PV/PV mouse was created by a targeted mutation of thyroid hormone β receptor (TRβ) via homologous recombination and the Cre-LoxP system (3). The TRβ mutant (referred to here as PV) was identified in a patient with resistance to thyroid hormone (RTH) (4). RTH is caused by mutations of the TRβ gene and manifests symptoms as a result of decreased sensitivity to