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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 8 3938-3942
Copyright © 2003 by The Endocrine Society

Changes in the Expression of the Peroxisome Proliferator-Activated Receptor {gamma} Gene in the Colonic Polyps and Colonic Mucosa of Acromegalic Patients

Fausto Bogazzi, Federica Ultimieri, Francesco Raggi, Dania Russo, Paolo Viacava, Denise Cecchetti, Aurelio Costa, Sandra Brogioni, Chiara Cosci, Maurizio Gasperi, Luigi Bartalena and Enio Martino

Departments of Endocrinology and Metabolism (F.B., F.U., F.R., D.R., S.B., C.C., M.G., E.M.) and Oncology (P.V., D.C., A.C.), University of Pisa, 56124 Pisa, Italy; Division of Endocrinology (L.B.), University of Insubria, 21100 Varese, Italy

Address all correspondence and requests for reprints to: Dr. Fausto Bogazzi, Dipartimento di Endocrinologia e Metabolismo, Università di Pisa, Ospedale di Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: f.bogazzi@endoc.med.unipi.it or fbogazzi{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Acromegalic patients have an increased prevalence of colonic neoplasms and lower peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) levels, the latter acting as a tumor suppressor gene. In this study we evaluated the expression of PPAR{gamma} in the biopsy samples of the polyps and outside polyps colonic mucosa from seven patients with active, untreated acromegaly, 11 with cured disease, and 15 controls. Serum GH and IGF-I levels were higher in patients with untreated acromegaly than in those with acromegaly in remission or controls (P = 0.003 and P = 0.002, respectively) The expression of PPAR{gamma} mRNA (mean ± SE) was 1) mucosa outside polyps, 24,188 ± 3,254 transcripts in the controls, 22,432 ± 2,006 transcripts in acromegaly in remission, and 1,952 ± 342 transcripts in untreated acromegaly (P < 0.0001 vs. controls and acromegaly in remission); and 2) polyps mucosa, 1,554 ± 236 transcripts in the controls, 1,112 ± 143 in acromegaly in remission, and 1,570 ± 251 in untreated acromegaly (P = NS among polyps groups and mucosa outside polyps of untreated acromegaly; P < 0.0001 vs. mucosa outside polyps of controls and acromegaly in remission). Eighty-five percent of the cells in the mucosa outside polyps from controls or acromegaly in remission were positive at immunohistochemistry, at variance with 45% of the cells from polyps mucosa from each group and from those of mucosa outside polyps of untreated acromegaly (P = 0.0002). In conclusion, patients with untreated acromegaly have reduced expression of PPAR{gamma} in the mucosa outside polyps, which might be reversed by curing the disease; conversely, patients with acromegaly in remission have the same low levels of expression of PPAR{gamma} in the polyps mucosa as untreated acromegaly or controls, supporting the concept that reduced expression of PPAR{gamma} might be an early event in colonic tumorigenesis.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PEROXISOME PROLIFERATOR-ACTIVATED receptor {gamma} (PPAR{gamma}) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily (1); it is highly expressed in adipose tissue, where it plays a key role in the regulation of adipocyte differentiation and fat metabolism (2, 3) and in colonic mucosa, where it exerts important functions in the differentiation process (4, 5, 6). A growing body of evidence indicates that PPAR{gamma} is a functional receptor for the thiazolidinedione class of antidiabetic drugs and may function as a tumor suppressor gene (7, 8): a fusion of PPAR{gamma} to PAX8 was reported in thyroid papillary carcinomas (9); and PPAR{gamma} activation by troglitazone induces differentiation of liposarcoma (10), prostate cancer (11), or several transformed cells, the growth of which is inhibited (4, 12).

PPAR{gamma} levels in the colonic mucosa are similar to those found in adipose tissue, and increased expression is found during differentiation of colonic epithelial cells (13, 14). Activation of PPAR{gamma} in cultured colon cancer cells induces growth inhibition and increases markers of cellular differentiation (4). Furthermore, PPAR{gamma} activation decreases premalignant intestinal lesions in rats treated with azoxymethane (15). On the other hand, activation of PPAR{gamma} in C57BL/6J-APCMin/+ mice promotes the development of colonic tumors (14, 16). These discrepant reports are due to the fact that PPAR{gamma} may act as a tumor suppressor gene only in the presence of an intact adenomatous polyposis coli gene (APC), which is disrupted in C57BL/6J-APCMin/+ mice (17). In humans, somatic mutations in one allele of the PPAR{gamma} gene associated with a loss of function of the receptor were found in 4 of 55 patients with primary colorectal cancer, being localized exclusively in exons 5 and 3, which encode for the ligand binding domain and the DNA binding domain, respectively (18). On the other hand, others failed to detect mutations of the PPAR{gamma} gene in a large series of tumor samples and cell lines (19).

We recently observed that patients with active acromegaly have reduced expression of PPAR{gamma} in the colonic mucosa, which is related to the increased serum IGF-I levels (20). This reduced PPAR{gamma} expression might have the same role of loss of function mutations, contributing to colonic tumor development. In fact, heterozygous loss of PPAR{gamma} was associated with an increased sensitivity to chemical carcinogenesis (17).

The aim of the present study was to evaluate the levels of expression of PPAR{gamma} in the colonic polyps and the mucosa outside polyps of patients with acromegaly.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

The study, which was approved by the institutional review committee, included the following groups of subjects: 18 consecutive patients with acromegaly referred to our institution in the years 2000–2002, including: group A, 7 acromegalic patients (4 men and 3 women; mean ± SD age, 49 ± 11 yr) with active, untreated acromegaly; group B, 11 patients (5 men and 6 women; mean age, 53 ± 7 yr) with acromegaly in remission after pituitary adenomectomy; and group C, 15 nonacromegalic patients investigated because of colonic polyps (9 men and 6 women; mean age, 52 ± 9 yr; controls). Four patients of the latter group had a positive family history for colorectal neoplasia, whereas no acromegalic patient had colonic cancer or a positive family history for colonic neoplasia. Patients were selected among consecutive acromegalic or nonacromegalic patients based on the presence of colonic polyps; all gave their informed consent. The diagnosis of acromegaly was based on clinical and laboratory features, including an increase in serum IGF-I levels and the lack of suppression of serum GH levels below 2 µg/liter after a 75-g oral glucose tolerance test (Table 1Go). Acromegaly was caused by a pituitary GH-secreting microadenoma in 6 cases (33%) and by a macroadenoma in 12 cases (67%).


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  		TABLE 1. Clinical and biochemical features of the study groups

 
Pancolonoscopy

Colonoscopy examination was performed using a CFQ14SL apparatus (Olympus, New Hyde Park, NY) by the same operator (A.C.). Polyps and extrapolyps mucosa samples were recovered during colonoscopy and immediately processed; part of the sample was formalin-fixed and paraffin-embedded, and part was placed in liquid nitrogen until further examination.

RNA extraction

Total RNA was prepared using an RNA-DNA mini-kit (QIAGEN, Milan, Italy) according to the manufacturer’s instructions. Total RNA was resuspended in diethylpyrocarbonate-treated water and quantitated by spectrophotometry.

RT-PCR and sequencing analysis

One microgram of human colonic epithelial total RNA obtained from acromegalic patients or controls was reverse transcribed in 50 mM Tris-HCl (pH 8.3), 75 mM KCl, 3 mM MgCl2, 10 mM dithiothreitol, 200 µM each of deoxy-NTP, 10 mM oligo(deoxythymidine) primer, 20 U RNasin (Promega Corp., Madison, WI), and 200 U Moloney murine leukemia virus reverse transcriptase in a final volume of 20 µl. The reaction was terminated by heating at 95 C for 5 min. Five microliters of the reaction were then amplified in a final volume of 25 µl in 1x PCR buffer (TaqMan Universal PCR Master Mix, PE Applied Biosystems, Foster City, CA), 300 mM of each primer, and 200 nM of fluoresceinate probe for 40 cycles as previously reported (20). The primers and probe were previously reported (20). The primer set amplifies an 83-bp fragment, the identity of which was confirmed by DNA sequencing. A control in which RT was omitted before PCR amplification was always included to eliminate the possibility that any amplification was due to contaminating genomic DNA. Each experiment was performed in triplicate; data are expressed as the number of copies of PPAR{gamma}.

Immunohistochemistry

Five-micrometer sections were deparaffined with xylene and rehydrated by ethanol treatment. Sections were pretreated with 1% hydrogen peroxide in methanol for 10 min at room temperature to inactivate endogenous peroxide activity. To unmask the antigens, slides were microwaved in 10 mM citrate buffer, pH 6, for 10 min. Nonspecific binding sites within the sections were blocked by incubating the sections with 1.5% normal donkey serum and 5% nonfat dry milk. Sections were incubated with the 1:50 diluted primary antibody (rabbit polyclonal antibody anti-PPAR{gamma}, H-100, Santa Cruz Biotechnology, Santa Cruz, CA) at 4 C for 12 h and then with the 1:500 diluted biotin-labeled secondary antibody at room temperature for 30 min, followed by incubation with avidin-biotin complex (Vector Laboratories, Inc., Burlingame, CA) for an additional 30 min. The resultant immune peroxidase activity was developed in 0.5% 3,3'-diaminobenzidine tetrahydrochloride (Sigma-Aldrich Corp., St Louis, MO). Sections were counterstained with hematoxylin, dehydrated, and mounted. Negative controls were obtained by omitting the anti-PPAR{gamma}-specific primary antibodies, which were replaced by rabbit immunoglobulins that did not react with PPAR{gamma}. The extent of PPAR{gamma} positivity was calculated as the number of positive cells, expressed as a percentage of the total number of cells. An average of 200 cells in each sample were counted.

Assays

Serum GH and IGF-I (Nichols Institute Diagnostics, San Juan Capistrano, CA) were determined using commercial kits. Normal values in our laboratory are as follows: GH, 0–5 µg/liter; and IGF-I, 182–780 µg/liter (16–24 yr), 90–492 µg/liter (25–50 yr), and 71–290 µg/liter (>50 yr).

Statistics

The results of serum GH and IGF-I measurements were expressed as the mean ± SD, and those of PPAR{gamma} were expressed as the mean ± SE. Comparison of parameters among the study groups was performed with ANOVA. The relationship between the levels of expression of PPAR{gamma} and serum GH or IGF-I levels was evaluated by linear regression.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
As illustrated in Table 1Go, patients with untreated acromegaly had significantly higher serum GH (37 ± 39 µg/liter) and IGF-I (791 ± 301 µg/liter) levels than patients with acromegaly in remission (GH, 0.9 ± 1.1 µg/liter; IGF-I, 221 ± 94 µg/liter) or controls (GH, 0.7 ± 0.6 µg/liter; IGF-I, 211 ± 71 µg/liter; P = 0.003 and P = 0.002, respectively). Patients with untreated acromegaly and those with acromegaly in remission did not differ in the estimated duration of acromegaly. Histological examination, performed in seven polyps from patients with untreated acromegaly and in nine polyps from patients with acromegaly in remission revealed tubular adenoma in all samples; two very small polyps from patients with acromegaly in remission were not used for histological examination. All control subjects had tubular adenoma.

PPAR{gamma} expression was measured in either polyps mucosa or mucosa outside polyps in each group. Nonacromegalic subjects had 24,190 ± 3,250 copies of PPAR{gamma} in the mucosa outside polyps; patients with untreated acromegaly had 1,950 ± 340 copies of PPAR{gamma} (P < 0.0001); patients with acromegaly in remission had 21,430 ± 2,006 copies of PPAR{gamma} (P < 0.0001 vs. untreated acromegaly; P = NS vs. controls). The expression of PPAR{gamma} in the polyps mucosa was greatly reduced in untreated acromegaly (1,570 ± 251), acromegaly in remission (1,112 ± 143), and controls (1,554 ± 236; P < 0.0001 vs. mucosa outside polyps of controls and acromegaly in remission; P = NS vs. mucosa outside polyps from untreated acromegaly; Fig. 1Go). A significant inverse correlation was found between the levels of expression of PPAR{gamma} and serum GH or IGF-I levels in the mucosa outside polyps (r = 0.57; P < 0.002 and r = 0.55; P < 0.003, respectively), but not in polyps.



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  		FIG. 1. A, Representative standard curve for quantitative RT-PCR for PPAR{gamma}. The threshold cycles (Ct; that is, the PCR cycle number at which the fluorescence signal reached above baseline) was -3.04 (starting copy number) + 37.34 (r = 0.996). B, PPAR{gamma} levels in the polyps and mucosa outside polyps of the study groups. Values in the mucosa outside polyps of untreated acromegalics (AcroUntr) were lower than those in controls or patients with acromegaly in remission after pituitary adenomectomy (AcroRem; P < 0.0001). The level of expression of PPAR{gamma} in the polyps mucosa of AcroUntr, AcroRem, or controls was lower than that in mucosa outside polyps of controls or AcroRem (P < 0.0001). The results represent the mean ± SE of three different experiments, each performed in triplicate, meaning that the level of expression of PPAR{gamma} in each sample was assessed three times.

 
The expression of PPAR{gamma} was analyzed in the same specimen using immunohistochemistry. As shown in Fig. 2Go PPAR{gamma} protein was intensively expressed in the colonic mucosa outside polyps from the controls, which showed 85% positive nuclei (Fig. 2AGo) and acromegaly in remission (87% positive nuclei; Fig. 2CGo), at variance with the specimens from untreated acromegaly, which had reduced expression (45% positive nuclei; Fig. 2EGo). Polyps of patients with untreated acromegaly had 45–47% positive nuclei (Fig. 2FGo), patients with acromegaly in remission had 44–48% positive nuclei (Fig. 2DGo), and controls had 43–47% positive nuclei (Fig. 2BGo).



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  		FIG. 2. Immunolocalization of PPAR{gamma} in the study groups. Immunohistochemistry was performed using a specific antibody against the N terminus of PPAR{gamma}. Nonacromegalic patients (controls): A, mucosa outside polyps; B, polyps. Patients with acromegaly in remission after surgery (AcroRem): C, mucosa outside polyps; D, polyps. Patients with active untreated acromegaly (AcroUntr): E, mucosa outside polyps; F, polyps. The negative control was normal colonic mucosa incubated in absence of the primary antibody (G). Original magnification, x250. Immunohistochemical analysis revealed a lower number of positive nuclei from each polyps group (B, D, and F) and from mucosa outside polyps from AcroUntr (E) than that in the mucosa outside polyps from controls (A) or AcroRem (C; P < 0.0002; H).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Patients with acromegaly have an increased prevalence of colonic polyps (21, 22), and an association between colonic polyps and elevated serum IGF-I levels was observed in vivo (23) and in cell lines (24). An additional risk for colonic neoplasia in acromegalic patients might be a previous history of colonic adenoma (23). This increased risk might also reflect a generalized and sustained proliferative stimulation of the colonic epithelium by the high serum IGF-I levels.

Recently, we reported an interaction between IGF-I and PPAR{gamma} in the colonic epithelium of acromegalic patients, suggesting a possible link between IGF-I action and the induction of polyps, as indicated by the fact that patients with active, untreated acromegaly had lower levels of PPAR{gamma} expression than those with cured disease (20).

Genetic studies (18, 19) showed either the presence or absence of somatic loss of function mutations in the gene encoding PPAR{gamma} in patients with colonic cancer. A recent study reported that PPAR{gamma} is a tumor suppressor gene in the colon, and that loss of one allele of this gene causes an increased sensitivity to chemical carcinogenesis (17).

Activation of PPAR{gamma} in colonic cancer cells induces growth arrest and morphological changes consistent with differentiation (25). The role of PPAR{gamma} as a tumor suppressor gene might be related either to the increased expression of genes that regulate the adhesive interaction between microvilli or to the down-regulation of genes that stimulate intestinal epithelial proliferation (25). In mice, PPAR{gamma} decreases colonic tumors by down-regulating the ß-catenin gene in the presence of a normal APC gene (17).

Thus, disruption of the PPAR{gamma} gene or loss of function mutations might contribute to tumorigenesis in the colon and other tissues (18, 26, 27, 28). The results of the present study extend our previous data that showed a down-regulation of PPAR{gamma} gene expression in active, untreated acromegaly (20). More importantly, the present study, albeit cross-sectional, suggests that when acromegaly is cured, down-regulation of PPAR{gamma} might be reversed in the mucosa outside polyps, but not in the polyps. Thus, it is likely that a sustained reduced expression of PPAR{gamma} may represent an early event in the formation of colonic polyps in acromegalic patients. The observation that polyps from control patients, with normal GH and IGF-I levels and normal PPAR{gamma} expression in the mucosa outside polyps, also show a reduced PPAR{gamma} level of expression suggests that reduced PPAR{gamma} expression may contribute to the development of polyps outside acromegaly. However, the diffuse reduced PPAR{gamma} expression in the colonic mucosa of acromegalic patients may play a relevant role in colonic tumorigenesis of acromegaly.


   Footnotes
 
This work was supported in part by grants from the University of Pisa (Fondi d’Ateneo) and Ministero dell’ Istruzione, dell’ Università, della Ricerca (M.I.U.R.), Rome (to E.M.), from the University of Insubria at Varese (to L.B.), and from M.I.U.R., Rome (Project Studies on the Relationship between Fetal Microchimersim and Thyroid Autoimmune Diseases; to L.B.).

Abbreviations: APC, Adenomatous polyposis coli; PPAR, peroxisome proliferator-activated receptor {gamma}.

Received February 19, 2003.

Accepted April 29, 2003.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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