RESUMO
Today, colorectal cancer is regarded as a heterogeneous disease. Its heterogeneity is caused by genetic alterations, molecular aberrations, different developing pathways as well as by micro- and macroenviromental agents. In the last decade, beside the classic genetic model for colorectal tumuorgenesis that follows the adenoma-carcinoma sequence, an alternative pathway has been identified. This pathway is called the serrated pathway and it is responsible for approximately one third of all colorectal lesions. Beyond their dissimilar molecular characteristics, these tumours also show different macroscopic and histologic appearance. Moreover, their malignant potency and progressive ability distinguish them from tumours of the classic genetic model. The aim of this review is to summarize the molecular and pathologic features of serrated lesions and the serrated pathway to colorectal cancer and to highlight their clinical impact. Orv Hetil. 2018; 159(6): 206-2014.
Assuntos
Adenoma/patologia , Carcinoma/patologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Adenoma/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Humanos , Lesões Pré-Cancerosas/patologiaRESUMO
INTRODUCTION: 1,25-Dihydroxy vitamin D3 mediates antitumor effects in hepatocellular carcinoma. AIM: We examined mRNA and protein expression differences in 1,25-Dihydroxy vitamin D3-inactivating CYP24A1, mRNA of activating CYP27B1 enzymes, and that of VDR between human hepatocellular carcinoma and surrounding non-tumorous liver. METHODS: Snap-frozen tissues from 13 patients were studied for mRNA and protein expression of CYP24A1. Paraffin-embedded tissues from 36 patients were used to study mRNA of VDR and CYP27B1. mRNA expression was measured by RT-PCR, CYP24A1 protein was detected by immunohistochemistry. RESULTS: Expression of VDR and CYP27B1 was significantly lower in hepatocellular carcinoma compared with non-tumorous liver (p<0.05). The majority of the HCC samples expressed CYP24A1 mRNA, but neither of the non-tumorous liver. The gene activation was followed by CYP24A1 protein synthesis. CONCLUSIONS: The presence of CYP24A1 mRNA and the reduced expression of VDR and CYP27B1 mRNA in human hepatocellular carcinoma samples indicate decreased bioavailability of 1,25-Dihydroxy vitamin D3, providing an escape mechanism from the anti-tumor effect. Orv. Hetil., 2016, 157(48), 1910-1918.
Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Carcinoma Hepatocelular/metabolismo , Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , RNA Mensageiro/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Colestanotriol 26-Mono-Oxigenase/metabolismo , Família 2 do Citocromo P450/metabolismo , Humanos , Neoplasias Hepáticas/genética , Vitamina D3 24-Hidroxilase/metabolismoRESUMO
The incidence of thyroid cancers is increasing worldwide. Some somatic oncogene mutations (BRAF, NRAS, HRAS, KRAS) as well as gene translocations (RET/PTC, PAX8/PPAR-gamma) have been associated with the development of thyroid cancer. In our study, we analyzed these genetic alterations in 394 thyroid tissue samples (197 papillary carcinomas and 197 healthy). The somatic mutations and translocations were detected by Light Cycler melting method and Real-Time Polymerase Chain Reaction techniques, respectively. In tumorous samples, 86 BRAF (44.2%), 5 NRAS (3.1%), 2 HRAS (1.0%) and 1 KRAS (0.5%) mutations were found, as well as 9 RET/PTC1 (4.6%) and 1 RET/PTC3 (0.5%) translocations. No genetic alteration was seen in the non tumorous control thyroid tissues. No correlation was detected between the genetic variants and the pathological subtypes of papillary cancer as well as the severity of the disease. Our results are only partly concordant with the data found in the literature.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Papilar/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Proteínas ras/genética , Carcinoma Papilar/epidemiologia , Carcinoma Papilar/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Genótipo , Humanos , Hungria/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
AIM: The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological half-life of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity. METHODS: We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhodamine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by real-time reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity. RESULTS: In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by co-administration of 1,25-D3 and KD-35, a CYP24A1-inhibiting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation. CONCLUSION: These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC.
Assuntos
Antineoplásicos/farmacologia , Calcitriol/farmacologia , Neoplasias Colorretais/enzimologia , Inibidores Enzimáticos/farmacologia , Esteroide Hidroxilases/antagonistas & inibidores , Tetralonas/farmacologia , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Indução Enzimática , Humanos , RNA Mensageiro/biossíntese , Esteroide Hidroxilases/biossíntese , Esteroide Hidroxilases/genética , Fatores de Tempo , Vitamina D3 24-HidroxilaseRESUMO
AIM: 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits cell growth and induces apoptosis in numerous types of tumors. We aimed to examine the mRNA and protein expression of 1,25(OH)(2)D(3)-inactivating CYP24A1 and mRNA expression of the activating CYP27B1 enzymes, as well as that of vitamin D receptor (VDR), in hepatocellular carcinoma (HCC) cell cultures in response to 1,25(OH)(2)D(3) administration. MATERIALS AND METHODS: Increasing amounts of 1,25(OH)(2)D(3) (0.256-10 nM) were added to cultures of HepG2, Huh-Neo, Hep3B, Huh5-15 human HCC cell lines and cells then incubated for various time periods (30 min-28 h). The mRNA expression was analyzed by real time reverse transcription-polymerase chain reaction (RT-PCR). CYP24A1 protein in HepG2 cells was detected by immuncytochemistry. RESULTS: CYP24A1 mRNA expression significantly (p<0.0001) increased in response to 1,25(OH)(2)D(3) administration in two cell lines: in HepG2 cells, the CYP24A1 mRNA level exhibited 5,300-fold elevation, reaching a maximum value at 8 h; in Huh-Neo cells, the increase was 152-fold that of the baseline value, with the maximum being reached at 14 h. There was no significant change in Hep3B and Huh5-15 cell lines, nor was there any change in CYP27B1 and VDR gene expression in any cell cultures. Immuncytochemistry in HepG2 cells proved that gene activation was followed by CYP24A1 protein synthesis. CONCLUSION: Our novel data indicate that administration of 1,25(OH)(2)D(3) results in a marked increase of CYP24A1 mRNA expression in some, but not all, human HCC lines in vitro. These differences could be dependent upon the origin of the tumor cells.