PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer

Abstract

Inactivation and silencing of PTEN have been observed in multiple cancers, including follicular thyroid carcinoma. PTEN (phosphatase and tensin homologue deleted from chromosome 10) functions as a tumour suppressor by opposing the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Despite correlative data, how deregulated PTEN signalling leads to thyroid carcinogenesis is not known. Mice harbouring a dominant-negative mutant thyroid hormone receptor β (TRβPV/PV mice) spontaneously develop follicular thyroid carcinoma and distant metastases similar to human cancer. To elucidate the role of PTEN in thyroid carcinogenesis, we generated TRβPV/PV mice haploinsufficient for Pten (TRβPV/PVPten+/− mouse). PTEN deficiency accelerated the progression of thyroid tumour and increased the occurrence of metastasis spread to the lung in TRβPV/PVPten+/− mice, thereby significantly reducing their survival as compared with TRβPV/PVPten+/+ mice. AKT activation was further increased by two-fold in TRβPV/PVPten+/− mice thyroids, leading to increased activity of the downstream mammalian target of rapamycin (mTOR)–p70S6K signalling and decreased activity of the forkhead family member FOXO3a. Consistently, cyclin D1 expression was increased. Apoptosis was decreased as indicated by increased expression of nuclear factor-κB (NF-κB) and decreased caspase-3 activity in the thyroids of TRβPV/PVPten+/− mice. Our results indicate that PTEN deficiency resulted in increased cell proliferation and survival in the thyroids of TRβPV/PVPten+/− mice. Altogether, our study provides direct evidence to indicate that in vivo, PTEN is a critical regulator in the follicular thyroid cancer progression and invasiveness.

Lessons from Mouse Models of Thyroid Cancer

“…Importantly, these findings raise the possibility that TRb could be tested as a novel therapeutic target in thyroid cancer. The TRb PV=PV mouse is a unique model, as it closely resembles human FTC in pathological progression and its underlying genetic alterations (84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)96,97). Though it is not known whether the only reported patient with homozygous mutation of the TRb gene (81) developed thyroid cancer, abnormal expression or somatic mutations of TR are associated with several human cancers including PTCs (98,99).…”

Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response

“…The PI3K/AKT signaling pathway mediates tumor progression via downstream regulation of BCL-2 family proteins, NF-κB, and FOXO transcription factors. The FOXO transcription factors have been identified as putative tumor suppressor genes and have been shown to induce apoptosis in lung cancer cell lines (34)(35)(36). AKTmediated phosphorylation of FOXO factors results in CRM-1-dependent nuclear export, proteasomal degradation, and diminished transcriptional activity (17,37).…”

Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model

“…Mice harboring the ThrbPV gene (Thrb PV/PV mice) were prepared via homologous recombination, and genotyping was carried out using the PCR method, as previously described (Guigon et al 2009). Pten C/K mice were kindly provided by Dr Ramon Parsons (Columbia University, NY, USA).…”

“…Thrb PV/PV Pten C/K mice express a potent dominantly negative thyroid hormone receptor b (TRbPV) and haploinsufficiency in the Pten gene (phosphatase and tensin homolog deleted from chromosome 10). As Thrb PV/PV Pten C/K mice age, they spontaneously develop aggressive follicular thyroid cancer similar to human cancer (Guigon et al 2009). Treatment of these mice with a high fat diet (HFD) led to obesity with increased weight of body and fat tissues, enlarged adipocytes, and markedly elevated serum leptin levels (Kim et al 2013b).…”