Expression of Peroxisome Proliferator-Activated Receptor γ in Renal Cell Carcinoma and Growth Inhibition by Its Agonists

Inoue, Ken‐ichiro; Kawahito, Yutaka; Tsubouchi, Yasunori; Kohno, Masataka; Yoshimura, Rikio; Yoshikawa, Toshikazu; Sano, Hajime

doi:10.1006/bbrc.2001.5640

Cited by 85 publications

(79 citation statements)

References 20 publications

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“…Rosiglitazone has been tested on various cancers including colon cancer [14][15][16][17][18][19][20] with wide effective dose ranges. However, the anticancer effect of rosiglitazone varies considerably in different cancers, and even in the same cancer type, the reported results are variable.…”

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confidence: 99%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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Ligands for peroxisome proliferator-activated receptor gamma (PPARc) possess anticancer properties. However, the efficacy of PPARc ligands varies in different cancers. In colon cancer, the role of PPARc and its ligands is controversial. We recently showed that downregulation of X-linked inhibitor of apoptosis protein (XIAP) could sensitize colon cancer cells to troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether rosiglitazone, another more clinically relevant PPARc ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP 1/1 cells and HCT116-XIAP 2/2 cells were treated with various concentrations of rosiglitazone. The effects of rosiglitazone on cell proliferation, apoptosis and growth of xenograft colon cancers were studied. Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that rosiglitazone strongly suppressed the growth of xenograft colon cancer, especially tumors derived from HCT116-XIAP 2/2 cells. The rosiglitazone-treated tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of PPARc by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP 2/2 cells, as well as in xenograft tumors derived from HCT116-XIAP 2/2 cells. We concluded that rosiglitazone significantly suppresses the growth of xenograft colon cancer, and downregulation of XIAP sensitizes the xenograft tumors to rosiglitazone-induced tumor suppression in vivo via upregulation of PTEN.

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confidence: 99%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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“…Peroxisome proliferator-activated receptorg is activated by natural ligands (fatty acids and eicosanoids) (Chawla and Lazar, 1994;Tontonoz et al, 1994;Forman et al, 1995;Kliewer et al, 1995) and by synthetic ligands (thiazolidinediones) (Lehmann et al, 1995). Peroxisome proliferator-activated receptorg activation was reported to inhibit the growth and, in some cases, to induce apoptosis or differentiation of tumour cells from different lineages: liposarcoma (Tontonoz et al, 1997;Demetri et al, 1999), breast cancer (Elstner et al, 1998;Mueller et al, 1998), prostate cancer (Kubota et al, 1998), colorectal cancer (Brockman et al, 1998;Sarraf et al, 1998;Kitamura et al, 1999), bladder cancer (Guan et al, 1999), nonsmall-cell lung carcinoma (Chang and Szabo, 2000), pancreatic cancer (Motomura et al, 2000), gastric cancer (Sato et al, 2000), renal carcinoma (Inoue et al, 2001), testicular cancer (Hase et al, 2002) and liver cancer (Toyoda et al, 2002). Kroll et al (2000) reported that t(2;3)(q13;p25), a chromosomal translocation detected in a subset of follicular thyroid carcinomas (FTCs), originates a fusion gene composed by DNA-binding domain of the thyroid transcription factor PAX8 and domains A to F of PPARg.…”

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confidence: 99%

“…Several studies have demonstrated that, compared to their normal counterparts, the expression of PPARg in tumour cells is either overexpressed, such as in renal cell carcinoma (Inoue et al, 2001) and testicular cancer (Hase et al, 2002), underexpressed, such as in oesophageal carcinomas (Terashita et al, 2002) or is equal to the normal tissue, such as in colonic adenocarcinomas . This last group has also identified somatic mutations of PPARg in four of 55 sporadic primary colorectal carcinomas .…”

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confidence: 99%

Underexpression of peroxisome proliferator-activated receptor (PPAR)γ in PAX8/PPARγ-negative thyroid tumours

et al. 2004

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The expression of peroxisome proliferator-activated receptor (PPAR)g in thyroid neoplasias and in normal thyroid (NT) tissues has not been fully investigated. The objectives of the present work were: to study and compare the relative expression of PPARg in normal, benign and malignant thyroid tissues and to correlate PPARg immunostaining with clinical/pathological features of patients with thyroid cancer. We analysed the expression of PPARg in several types of thyroid tissues by reverse transcription -polymerase chain reaction (RT -PCR), interphase fluorescent in situ hybridisation, real-time RT -PCR and immunohistochemistry. We have demonstrated that NT tissues express PPARg both at mRNA and at protein level. PAX8-PPARg fusion gene expression was found in 25% (six of 24) of follicular thyroid carcinomas (FTCs) and in 17% (six of 36) of follicular thyroid adenomas, but in none of the 10 normal tissues, 28 nodular hyperplasias, 38 papillary thyroid carcinomas (PTCs) and 11 poorly differentiated thyroid carcinomas (PDTCs). By real-time RT -PCR, we observed that tumours negative for the PAX8-PPARg rearrangement expressed lower levels of PPARg mRNA than the NT. Overexpression of PPARg transcripts was detected in 80% (four of five) of translocation-positive tumours. Diffuse nuclear staining was significantly (Po0.05) less prevalent in FTCs (53%; 18 of 34), PTCs (49%; 19 of 39) and PDTCs (0%; zero of 13) than in normal tissue (77%; 36 of 47). Peroxisome proliferator-activated receptorg-negative FTCs were more likely to be locally invasive, to persist after surgery, to metastasise and to have poorly differentiated areas. Papillary thyroid carcinomas with a predominantly follicular pattern were more often PPARg negative than classic PTCs (80% vs 28%; P ¼ 0.01). Our results demonstrated that PPARg is underexpressed in translocation-negative thyroid tumours of follicular origin and that a further reduction of PPARg expression is associated with dedifferentiation at later stages of tumour development and progression.

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“…These ligands induce apoptosis and exert anti-proliferative effects on several carcinoma cell lines and inhibit the growth of thyroid carcinoma cells in vivo (8)(9)(10)(11). In different types of cancer, several studies have shown that, compared to their normal counterparts, tumours can present either overexpression (12,13), underexpression (14) or similar expression of PPARÁ (15). Studies in human colon carcinomas, with monoallelic PPARÁ mutations, indicated that colon cancer is associated with loss-of-function mutations in PPARÁ (16).…”

Section: Introductionmentioning

confidence: 99%

Underexpression of PPARγ is associated with aneuploidy and lower differentiation of thyroid tumours of follicular origin

Espadinha

Pinto²,

Leite

2009

Oncol Rep

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Abstract. Peroxisome proliferator-activated receptor Á (PPARÁ) gene is a nuclear receptor that is involved in thyroid tumourigenesis. Recently, our group has shown that follicular carcinomas underexpressing PPARÁ protein are more prone to develop distant metastases, to invade locally, to present poorly differentiated areas and to persist after surgery. Aneuploidy is also observed in some thyroid tumours, particularly in the more advanced cases. The aim of the present study was to investigate the association of PPARÁ expression with the degree of differentiation and ploidy status of benign and malignant thyroid neoplasias. DNA cytometric studies, ploidy and S-phase fraction (SPF) determination, and quantitative RT-PCR analysis of molecular markers specific for thyroid follicular cells, namely Tg (thyroglobulin), TSHR (TSH receptor) and NIS (Na + /I -symporter) were compared between thyroid lesions with positive or negative PPARÁ protein expression. We observed that PPARÁ-negative tissues expressed lower levels of Tg mRNA [4.66x10 6 a.u. (arbitrary units) ± 1.49x10 6 ], and were more frequently aneuploid (36%), and presented higher SPF (3.1%±0.4) than PPARÁ-positive samples (Tg mRNA = 2.54x10 7 a.u. ± 9.72x10 6 , P=0.0006; aneuploidy=8%, P=0.0031; SPF=2.2%±0.2, P=0.0430). A similar trend was also observed for TSHR and NIS mRNA, although not reaching statistical significance. This study showed that underexpression of PPARÁ is associated with poor tumour differentiation, aneuploidy and higher cell proliferative activity. Therapies designed to modulate expression of PPARÁ may have an impact on the growth of thyroid neoplasias.

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Expression of Peroxisome Proliferator-Activated Receptor γ in Renal Cell Carcinoma and Growth Inhibition by Its Agonists

Cited by 85 publications

References 20 publications

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Underexpression of peroxisome proliferator-activated receptor (PPAR)γ in PAX8/PPARγ-negative thyroid tumours

Underexpression of PPARγ is associated with aneuploidy and lower differentiation of thyroid tumours of follicular origin

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