Altered expression of UPIa, UPIb, UPII, and UPIIIa during urothelial carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in rats

Zupančič, Daša; Ovčak, Zdenka; Vidmar, Gaj; Romih, Rok

doi:10.1007/s00428-011-1045-6

Cited by 16 publications

(17 citation statements)

References 46 publications

(50 reference statements)

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“…Therefore it is important to know whether the total UPs are expressed in preneoplastic or neoplastic urothelium, and whether all the urothelial plaques contain all four UPs, specific pairs of UPs or only individual UPs. We showed recently that during urothelial carcinogenesis, the expression of UPII is diminished (Zupančič et al 2011). We showed here by immunohistochemical staining, however, that all four UPs are expressed in some, but none in other areas of preneoplastic urothelium.…”

Section: Discussioncontrasting

confidence: 63%

Expression and localization of four uroplakins in urothelial preneoplastic lesions

Zupančič¹,

Zakrajšek²,

Zhou

et al. 2011

Histochem Cell Biol

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In superficial umbrella cells of normal urothelium, uroplakins (UPs) are assembled into urothelial plaques, which form fusiform vesicles (FVs) and microridges of the apical cell surface. Altered urothelial differentiation causes changes in the cell surface structure. Here, we investigated ultrastructural localization of UPIa, UPIb, UPII and UPIIIa in normal and cyclophosphamide-induced preneoplastic mouse urothelium. In normal urothelium, terminally differentiated umbrella cells expressed all four UPs, which were localized to the large urothelial plaques covering mature FVs and the apical plasma membrane. The preneoplastic urothelium contained two types of superficial cells with altered differentiation: (1) poorly differentiated cells with microvilli and small, round vesicles that were uroplakin-negative; no urothelial plaques were observed in these cells; (2) partially differentiated cells with ropy ridges contained uroplakin-positive immature fusiform vesicles and the apical plasma membrane. Freeze-fracturing showed small urothelial plaques in these cells. We concluded that in normal urothelium, all four UPs colocalize in urothelial plaques. However, in preneoplastic urothelium, the growth of the uroplakin plaques was hindered in the partially differentiated cells, leading to the formation of immature FVs and ropy ridges instead of mature FVs and microridges. Our study demonstrates that despite a lower level of expression, UPIa, UPIb, UPII and UPIIIa maintain their plaque association in urothelial preneoplastic lesions.

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Section: Discussioncontrasting

confidence: 63%

Expression and localization of four uroplakins in urothelial preneoplastic lesions

Zupančič¹,

Zakrajšek²,

Zhou

et al. 2011

Histochem Cell Biol

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“…For example, others have found that normal rat control urothelium displays CK20 immunoreactivity in all superficial cells with none in intermediate and basal cells. 34 In rats administered the urinary bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine, hyperplasias Figure 5. o-Nitroanisole, 18 000 ppm, 15 months.…”

Section: Discussionmentioning

confidence: 99%

“…Previous experiments showed modification of uroplakin expression during chemically induced rat urinary bladder carcinogenesis. 23,34 Using the differentiation markers CK20 and UPIII, we tested the hypothesis that the ability of urothelium to terminally differentiate is progressively lost during tumor progression. As urinary bladder cancer is a common cancer in humans and one of the most expensive cancers to treat overall, 4 there is a need to identify similarities and differences between urinary bladder cancers in humans and those in rats, since rodents are important models in carcinogenicity testing.…”

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confidence: 99%

Immunohistochemical Expression of Cyclin D1, Cytokeratin 20, and Uroplakin III in Proliferative Urinary Bladder Lesions Induced by o-Nitroanisole in Fischer 344/N Rats

et al. 2015

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o-Nitroanisole is an intermediate in the manufacture of azo dyes. In a National Toxicology Program stop-exposure study, o-nitroanisole induced hyperplasia, papillomas, and papillary carcinomas in the urinary bladder of Fischer 344/N rats. o-Nitroanisole was investigated since occupational or environmental exposure to aniline and azo dyes is a risk factor for urinary bladder cancer in humans. The current study describes the morphology of urinary bladder neoplasms seen in rats with respect to those observed in humans. This study also evaluated immunohistochemical expression of the cell cycle-related proteins cyclin D1 and p53 and the differentiation markers cytokeratin 20 and uroplakin III in hyperplastic (n ¼ 11) and neoplastic (n ¼ 6 papillomas, n ¼ 11 carcinomas) lesions of the urinary bladder epithelium from rats treated with o-nitroanisole and in normal (n ¼ 6) urinary bladders from untreated rats. The tumors observed were more similar to the papillary type rather than the muscle-invasive type of urinary bladder cancer in humans. The preneoplastic and neoplastic lesions observed suggest progression from hyperplasia to papilloma to papillary carcinoma. With neoplastic progression (hyperplasia to papilloma to carcinoma), cyclin D1 immunoreactivity progressively increased in intensity, percentage of cells staining, and distribution. Overexpression of p53 was not found. Cytokeratin 20 staining decreased in superficial cells, while uroplakin III staining increased in intermediate and basal cells with progression from hyperplasia to carcinoma. The results are consistent with increased cell cycle dysregulation or proliferation (cyclin D1), decreased differentiation (cytokeratin 20), and abnormal differentiation (uroplakin III) as lesions progress toward malignancy.Keywords cyclin D1, cytokeratin 20, immunohistochemistry, o-nitroanisole, rats, urinary bladder, uroplakin III, urothelial carcinoma Urinary bladder neoplasia is the sixth-most common cancer in humans in the United States, with urothelial carcinoma the most common subtype. 27 The most important risk factors for urinary bladder cancer in the Western world are cigarette smoking, followed by occupational or environmental exposure to aniline and azo dyes and aromatic amines.25 o-Nitroanisole (2-nitroanisole, 2-methoxynitrobenzene) is a single-ring aromatic nitro compound used as an intermediate in the preparation of o-anisidine and the production of azo dyes.22 o-Nitroanisole is reasonably anticipated to be a human carcinogen based on sufficient evidence of malignant tumor formation at multiple tissue sites in multiple species of experimental rodents, including the urinary bladder in rats of both sexes. 22 In the present study, we used immunohistochemistry to characterize the expression patterns of cell cycle-related markers (cyclin D1 and p53) and differentiation markers (cytokeratin 20 [CK20] and uroplakin III [UPIII]) in o-nitroanisole-induced urothelial (transitional cell) hyperplasia and neoplasia in rat urinary bladders to compare with findings ...

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“…The Uroplakin 1A (UPK1A) gene belongs to the transmembrane 4 super family (TM4SF), also known as the tetraspanin family [7], [8]. The expression of UPK1A is known to be highly specific to normal urothelium [9], and can be observed in the normal genitourinary tract, uterus and prostate [10]. Recently, a study by Kar and colleagues [11] found that UPK1A can be used as a molecular biomarker and is a significant tumor suppressor in esophageal squamous cell carcinoma (ESCC), which demonstrated that UPK1A plays a role in inhibiting cell proliferation, clonogenicity, cell motility, and tumor formation.…”

Section: Introductionmentioning

confidence: 99%

Reduced Expression of Uroplakin 1A Is Associated with the Poor Prognosis of Gastric Adenocarcinoma Patients

Zheng

Wang

et al. 2014

PLoS ONE

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BackgroundThe aim of this study was to investigate the expression and prognostic significance of Uroplakin1A (UPK1A) in gastric adenocarcinoma patients. Functional studies were also analyzed in vitro.Methodology/Principal FindingsReal-time quantitative PCR (RT-qPCR), western blotting, and immunohistochemical (IHC) staining methods were used to analyze the expression of UPK1A in primary gastric adenocarcinoma tissue samples. Compared with matched adjacent non-tumor, the expression of UPK1A in fresh surgical specimens was reduced, which was confirmed by RT-qPCR (P<0.01) and western blotting analysis (P<0.01). The paraffin specimens from a consecutive series of 445 gastric adenocarcinoma patients who underwent surgery between 2003 and 2006 were analyzed by IHC staining. The relationship between UPK1A expression, clinicopathological factors, and survival were evaluated. IHC staining analysis revealed that the reduced expression of UPK1A was observed in 224 cases (50.3%). Additionally, the correlation analysis of clinicopathological factors demonstrated that reduced expression of UPK1A was significantly associated with histological grade (P = 0.022), node metastasis (P<0.001) and tumor node metastasis (TNM) stage (P = 0.008) (7th edition of the International Union Against Cancer (UICC)). Furthermore, Kaplan-Meier survival analysis revealed that the reduced expression of UPK1A was significantly associated with poor prognosis (P = 0.043). Cox hazards model analysis indicated that UPK1A expression was an independent risk factor at the 0.1 level (P = 0.094). The function of UPK1A in cell cycle, migration, and invasion was investigated by overexpressing UPK1A in the MKN45 gastric cancer cell line. The elevated expression of UPK1A cells induced G1 phase arrest and significantly inhibited migration and invasion.Conclusions/SignificanceThe reduced expression of UPK1A might play a role in the progression of gastric cancer. Thus, UPK1A could be a potential favorable biomarker associated with gastric cancer prognosis.

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Altered expression of UPIa, UPIb, UPII, and UPIIIa during urothelial carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in rats

Cited by 16 publications

References 46 publications

Expression and localization of four uroplakins in urothelial preneoplastic lesions

Expression and localization of four uroplakins in urothelial preneoplastic lesions

Immunohistochemical Expression of Cyclin D1, Cytokeratin 20, and Uroplakin III in Proliferative Urinary Bladder Lesions Induced by o-Nitroanisole in Fischer 344/N Rats

Reduced Expression of Uroplakin 1A Is Associated with the Poor Prognosis of Gastric Adenocarcinoma Patients

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