Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma

Kamiya, Yûji; Puzianowska-Kuźnicka, Monika; McPhie, Peter; Nauman, J; Cheng, Sheue-yann; Nauman, A

doi:10.1093/carcin/23.1.25

Cited by 92 publications

(73 citation statements)

References 49 publications

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“…Deleted areas are in large brackets. Dotted lines represent the non-in frame new sequences with numbers of aminoacids in small brackets, and STOP indicates the appearance of abnormal termination codons work, these authors have reported mutations in seven TRb and three TRa RNAs in a series of 22 renal carcinomas (Kamiya et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer

et al. 2002

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The relation between thyroid status and diseases and cancer is unclear. No detailed analysis of thyroid hormone receptor (TR) expression in human breast cancer has been reported. We have analysed the expression and mutational status of the TRa1, encoded by the c-erbA proto-oncogene, TRb1 and TRb2 isoforms in 70 sporadic breast cancers. Alterations in the RNA level of TRb1, TRa1, or both were found in a number of patients. No expression of TRb2 RNA was detected. Western blotting analysis con®rmed the di erences in expression at the protein level in those cases where su cient tumor sample was available. Additionally, tumor-speci®c truncated TRb1 RNA was found in six patients. Strikingly, three transcripts shared the same breakpoint. Only one tumor carried the corresponding deletion at the genomic DNA level, suggesting that the remaining abnormal TRb1 transcripts are aberrant splicing products. Though no signi®cant correlation was found between TRb1 alteration and any clinical parameter, it showed a tendency to associate with early age of onset (550 years). Our results reveal speci®c alterations in the expression of TRb and TRa genes in a subset of breast cancer patients, suggesting that deregulation of thyroid hormone target genes may be involved in the generation of this neoplasia.

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Section: Discussionmentioning

confidence: 99%

Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer

et al. 2002

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“…In renal and hepatocellular carcinoma, 41,42 mutations have been found to affect either hormonebinding 43 or DNA-binding domains. 44 Chromosome 3p LOH in the vicinity of the TRb1 gene and TRb1 gene promoter hypermethylation are common in breast cancer, and are associated with decreased or absent nuclear expression of TRb1.…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormone receptor β1 in normal colon and colorectal cancer–association with differentiation, polypoid growth type and K‐ras mutations

Hörkkö

Tuppurainen

George

et al. 2005

Intl Journal of Cancer

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The precursors for colorectal cancer include polypoid (conventional), flat and serrated adenomas. Polypoid growth in polypoid adenomas and serrated adenomas is associated with K-ras mutations. The regulation of polypoid or nonpolypoid growth is not well known, but could be related to trophic stimuli, such as thyroid hormones. Hence, we investigated the expression pattern of thyroid hormone receptor TRb1 in colorectal mucosa and in colorectal tumours and its relationship to tumour growth type. One hundred fourteen colorectal carcinoma specimens were evaluated for TRb1. Normal mucosa, adjacent adenomatous component (N 5 46) and lymph node metastases (N 5 28) were analysed when present, and the results were confirmed by Western blot analysis in selected cases. Nuclear TRb1 was almost always present in normal epithelium (96%), but less frequent in adenomas (83%) and in cancer (68%; p < 0.001 and p < 0.001, respectively). TRb1 was associated with polypoid growth, presence of K-ras mutations and also with a higher WHO histological grade and advanced Dukes' stage. Cytoplasmic expression of TRb1 was observed in nonneoplastic and neoplastic epithelium. In Western blot analysis, a 58 kDa band corresponding to TRb1 was expressed in normal mucosa and in colorectal cancer specimens with positive immunohistochemistry. Association of TRb1 expression with growth pattern and the presence of K-ras mutations suggest that abnormalities in thyroid hormone signalling involving TRb1 play a role in the development of some types of colorectal adenocarcinomas. ' 2005 Wiley-Liss, Inc.Key words: colorectal cancer classification; thyroid hormone receptors beta; K-ras oncogene Colorectal cancer evolves via a sequence of alterations. In addition to the well-known adenoma-carcinoma sequence, some colorectal cancers are thought to arise either de novo or from flat adenomas. These 2 pathways are biologically different, as K-ras mutations occur with high frequency in polypoid adenomas, but are rare in flat adenomas and carcinomas.1,2 It has been thought that the oncogenic action of mutated K-ras protein results in increased proliferation common in polypoid adenomas. 3Thyroid hormones regulate growth, development, differentiation and metabolic processes. 4 The actions of 3,3 0 ,5-triiodo-L-thyronine (T3) are mediated by thyroid hormone nuclear receptors (TR), which regulate the expression of T3-targeted genes. T3, thyroxin (T4), as well as its lower iodinated metabolites exert direct biological effects by mechanisms not involving nuclear T3-receptors.5 T3 and its receptors regulate processes such as cell proliferation, differentiation and apoptosis in normal tissues and in some malignancies. [6][7][8][9][10][11] Knockout mice models have shown that T3 receptor TRa, but not TRb, is involved in the maturation of the intestine. 12,13 TRs are members of the steroid hormone and retinoic acid superfamily of ligand-dependent transcription factors, and are derived from two genes, TRa and TRb, located on human chromosomes 17 and 3, respectively. Both gene...

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“…The resulting defects in T3 sensing produce a variety of endocrine defects and, rarely, pituitary neoplasias, but do not typically manifest as overt peripheral neoplasia (Ando et al, 2001;Kamiya et al, 2003). Conversely, somatic mutations in human TRs are found at high frequency in human hepatocellular carcinoma (HCC), renal clear cell cancer (RCCC), and certain thyroid and gastric neoplasia (Lin et al, 1997b(Lin et al, , 1999(Lin et al, , 2001Kamiya et al, 2002;Wang et al, 2002). Whereas RTH-Syndrome mutations map almost exclusively to the TRb locus, mutations in both TRa and TRb are detected in human HCC and RCCC (Lin et al, 1997b(Lin et al, , 1999(Lin et al, , 2001Kamiya et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

Chan

Privalsky

2006

Oncogene

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Aberrant thyroid hormone receptors (TRs) are found in over 70% of the human hepatocellular carcinomas (HCCs) analysed. To better understand the role(s) of these TR mutants in this neoplasia, we analysed a panel of HCC mutant receptors for their molecular properties. Virtually all HCC-associated TR mutants tested retained the ability to repress target genes in the absence of T3, yet were impaired in T3-driven gene activation and functioned as dominant-negative inhibitors of wild-type TR activity. Intriguingly, the HCC TRa1 mutants exerted dominantnegative interference at all T3 concentrations tested, whereas the HCC TRb1 mutants were dominant-negatives only at low and intermediate T3 concentrations, reverting to transcriptional activators at higher hormone levels. The relative affinity for the SMRT versus N-CoR corepressors was detectably altered for several of the HCC mutant TRs, suggesting changes in corepressor preference and recruitment compared to wild type. Several of the TRa HCC mutations also altered the DNA recognition properties of the encoded receptors, indicating that these HCC TR mutants may regulate a distinct set of target genes from those regulated by wild-type TRs. Finally, whereas wild-type TRs interfere with c-Jun/AP-1 function in a T3-dependent fashion and suppress anchorageindependent growth when ectopically expressed in HepG2 cells, at least certain of the HCC mutants did not exert these inhibitory properties. These alterations in transcriptional regulation and DNA recognition appear likely to contribute to oncogenesis by reprogramming the differentiation and proliferative properties of the hepatocytes in which the mutant TRs are expressed.

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Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma

Cited by 92 publications

References 49 publications

Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer

Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer

Thyroid hormone receptor β1 in normal colon and colorectal cancer–association with differentiation, polypoid growth type and K‐ras mutations

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

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