Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumors of the small bowel are quite rare for unknown reasons, although they resemble colorectal tumors in many respects. The purpose of this study was to determine whether abnormalities in the expression of several cell cycle control genes are of importance in small bowel tumorigenesis by comparing a series of samples of normal mucosa, adenomatous polyps, and adenocarcinomas. The levels of cyclin D1, cyclin E, p16, p21, p27, and p53 proteins were determined by immunohistochemistry in samples of normal small bowel (n = 16), small bowel adenomas (n = 20), and small bowel adenocarcinomas (n = 24). Normal small bowel mucosa expressed p27 protein, but not the other cell cycle-related proteins. About 20% of the tumors displayed a decrease in the expression of this protein. The most frequent alteration in the tumors was an increase in the p16 protein. Increased expression of p53 was associated with tumor progression because it was overexpressed in 45% of the adenomas and 65% of the adenocarcinomas (P<0.05). Advanced age and increased detection of cyclin D1 and p53 were associated with a decreased 3-year survival (P<0.05). Cell cycle abnormalities are early and important events in the multistep process of small bowel tumorigenesis, thus resembling colorectal carcinogenesis. As in colon cancer, deregulated expression of G1 proteins may perturb cell cycle control in benign adenomas of the small bowel and thereby enhance tumor progression. Increased expression of cell cycle inhibitors in tumors may serve as a defense mechanism for tumor progression.
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PMID:Abnormalities in the expression of cell cycle-related proteins in tumors of the small bowel. 1061 43

In order to investigate the hypothesis that aberrant expression of cell-cycle regulatory proteins may represent early events in the process of carcinogenesis, levels of expression of the negative regulators p21(waf1/cip1) (p21), p27(kip1) (p27), and p16(ink4a) (p16) and/or the positive regulators cyclin D(1) and cyclin E were examined by western blot analysis in cells transformed in vitro by ionizing radiation. The levels of these proteins in 12 independently derived mouse 10T(1/2) cell clones transformed by 1.5 Gy of alpha radiation were compared with those in nine similarly derived nontransformed control clones. Constitutive levels of p21 were very low in all control clones, whereas p21 expression was significantly elevated in nine of 12 transformed clones. Two of the three transformed clones displaying low levels of p21 expressed increased levels of p53. p21 regulation was also altered in response to radiation in transformed clones as compared with controls, only minimal induction was observed 4 h following gamma irradiation. Western blot analysis indicated a constant expression of p27 protein but slightly decreased levels of p16 in these transformed clones. Cyclin D(1) was overexpressed in 11 of 12 transformed clones; in only two of these were the levels of cyclin E elevated. Overall, the results suggest that alterations in the expression of cell cycle regulatory proteins may represent important events in radiation-induced oncogenic transformation in vitro. Although the specific alterations vary among different transformed clones, overexpression and aberrant regulation of p21 appear to be the most frequent ones.
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PMID:Overexpression of p21 protein in radiation-transformed mouse 10T(1/2) cell clones. 1065 6

The present study was designed to assess the effect of Se-methylselenocysteine or triphenylselenonium chloride treatment on cell proliferation [bromodeoxyuridine (BrdUrd) labeling] and cell cycle biomarkers [proliferating cell nuclear antigen (PCNA), cyclin D1, and p27/Kip 1] in the intact mammary gland of rats. Immunohistochemical assays of the above end points were carried out in different morphological structures: (a) terminal end bud cells and alveolar cells of a maturing mammary gland undergoing active differentiation; and (b) premalignant mammary intraductal proliferations (IDPs) identified at 6 weeks after carcinogen dosing. Neither compound was found to affect BrdUrd labeling or the expression of cell cycle biomarkers in the normal terminal-end bud cells and alveolar cells. Se-methylselenocysteine reduced the total number of IDP lesions by approximately 60%. Interestingly, this was not accompanied by decreases in BrdUrd labeling or the proportion of IDP cells expressing PCNA and cyclin D1. An enhancement in the fraction of p27/Kip 1-positive IDP cells, however, was detected as a result of Se-methylselenocysteine treatment. Although triphenylselenonium chloride did not reduce the total number of IDPs, there were more of the smaller-sized lesions and fewer of the larger-sized lesions compared with those found in the control group. Triphenylselenonium chloride also significantly decreased the proportion of IDP cells incorporating the BrdUrd label or expressing PCNA and cyclin D1. The above findings suggest that early transformed cells are sensitive to selenium intervention, whereas normal proliferating cells are not. It is possible that Se-methylselenocysteine blocks carcinogenesis by a pathway that may not involve cell growth inhibition as a primary response; in contrast, triphenylselenonium chloride is likely to act by a cytostatic mechanism. The data also imply that selenium efficacy testing in intervention trials is possible with the use of biomarkers, provided that the appropriate biomarkers are matched with the selenium compound of interest and that the pathological characteristics of the cell population to be evaluated are taken into consideration.
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PMID:Selenium modulation of cell proliferation and cell cycle biomarkers in normal and premalignant cells of the rat mammary gland. 1066 63

Apigenin is a plant flavonoid that is thought to play a role in the prevention of carcinogenesis. However, its mechanism of action has not yet been elucidated. Because of the importance of angiogenesis in tumor growth, we investigated the effect of apigenin on endothelial and smooth-muscle cells in an in vitro model. Apigenin markedly inhibited the proliferation, and, to a lesser degree, the migration of endothelial cells, and capillary formation in vitro, independently of its inhibition of hyaluronidase activity. In contrast, it strongly stimulated vascular smooth-muscle-cell proliferation. The molecular mechanisms of apigenin activity were analyzed in these 2 types of cells. Our results show that apigenin inhibits endothelial-cell proliferation by blocking the cells in the G(2)/M phase as a result of the accumulation of the hyperphosphorylated form of the retinoblastoma protein. Apigenin stimulation of smooth-muscle cells was attributed to the reduced expression of 2 cyclin-dependent kinase inhibitors, p21 and p27, which negatively regulate the G(1)-phase cyclin-dependent kinase.
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PMID:Apigenin inhibits endothelial-cell proliferation in G(2)/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression. 1069 50

Cancer that occurs at numerous organ sites, including the colon and breast, is inhibited by energy restriction, and the inhibition is proportional to the degree of restriction imposed. In an effort to identify the mechanism(s) by which energy restriction exerts this effect, a short term model system of experimentally induced mammary carcinogenesis was used. Given that carcinogenesis is known to involve a dysregulation to tissue size homeostasis in which cell proliferation and cell death are in dysequilibrium, we hypothesized that energy restriction exerts its effect by altering one or more aspects of cell cycle regulation. It was observed that energy restriction inhibited cell proliferation and increased cell death due to apoptosis. Thus attention was next focused on aspects of cell cycle regulation that might be affected by energy restriction. It was observed that the amount of p27 protein, one member of the Cip/Kip family of genes that are involved in cell cycle arrest, was increased dose dependently by energy restriction. Based on this and related observations, the hypothesis is advanced that energy restriction inhibits carcinogenesis, at least in part, by delaying cell cycle progression via shifting cell populations into a G(0)/G(1)state. Ongoing work indicates that corticosteroids, which are produced in increased amounts in response to energy restriction, may be involved in mediating this effect.
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PMID:Mechanisms by which energy restriction inhibits carcinogenesis. 1070 76

Down-regulation of p27(Kip1) has been reported to correlate with poor survival of various carcinoma patients including oral squamous cell carcinomas (OSCCs). It is still unclear, however, at what stage of oral carcinogenesis the down-regulation of this protein occurs. In this study, therefore, we evaluated immunoexpression of p27(Kip1) protein in 17 cases of oral epithelial dysplasia and succeeding invasive OSCC in the same patient. We reported here that 88% cases showed high p27(Kip1) expression in dysplastic lesions, whereas 82% cases of succeeding invasive OSCC exhibited reduced expression. The reduction of p27(Kip1) expression was also observed in 16 of 19 (84%) early invasive lesions and well correlated with Ki-67 expression which is good indicator of cell proliferation. We also investigated immunoexpression of p53 protein of which abnormality has been known to occur during the early stage of OSCC development. Overexpression of p53 protein was demonstrated in 29% of dysplastic lesions, 42% of early invasive and 71% of invasive OSCCs. These findings suggest that abnormalities of both p53 and p27(Kip1) are involved in the carcinogenesis of OSCC, but they seem to play their role at different stages of oral cancer development, respectively. Reduced expression of p27(Kip1) may concern the cancer invasion directly or indirectly as well as abnormal proliferation.
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PMID:Reduced expression of p27(Kip1) correlates with an early stage of cancer invasion in oral squamous cell carcinoma. 1073 17

Carcinogenesis is characterized by deregulation of the cell cycle. Although p53 is still the most important cell-cycle regulator in human malignancies, there is an increased body of evidence indicating that the aberrant expression of cyclins and cyclin-dependent kinase (CDK) inhibitors is considered as one of the most important events in malignant transformation of various human cancers. Among these cell-cycle regulators, the role of cyclin E and p27(KIP1) in the tumorigenesis of the uterine cervix has been poorly defined. Using formalin-fixed, paraffin-embedded cervical tissues, we investigated the expression of cyclin E and p27(KIP1) by immunohistochemistry, and human papillomavirus (HPV) types 16 and 18 by nested polymerase chain reaction (PCR) in 22 control cases, 23 cases with cervical intraepithelial neoplasia (CIN), and 45 patients with invasive cervical carcinoma (ICC). The p27 index (P27I) was significantly lower in patients with ICC and CIN compared to those with a normal cervix. Patients with either invasive cancer or CIN were found to have a significantly higher cyclin E index (CEI) than the controls (P<0.05). Our results were consistent with the concept that the deregulated expression of cyclin E and p27(KIP1) may play an important role in the neoplastic transformation of cervical carcinoma.
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PMID:Expression of cyclin E and p27(KIP1) in cervical carcinoma. 1077 28

We performed the immunohistochemical staining for six G1 check point cell cycle proteins to study their expression patterns and roles in the gastric carcinogenesis. We studied 76 cases of paraffin blocks that included the sections of 18 tubular adenomas (TA), 38 early gastric carcinomas (EGC) (20 cases of mucosal type, nine cases of submucosal type with no nodal metastasis, nine cases of submucosal type with nodal metastasis), 20 advanced gastric carcinomas (AGC) (ten cases with no nodal metastasis, ten cases with nodal metastasis). We found that abnormal expression of p16 and p27 increased with the progression of tubular adenomas to advanced gastric cancers. Inverse relationship between pRb and p16 proteins was found in a small portion of the gastric tumors. Expressions of pRb and cdk4 were consistently high in benign and malignant gastric tumors. Expression of cyclin D1 and cyclin E rather decreased with the tumor progression. In conclusion, losses of p16 and p27 seem to play a significant role during the gastric carcinogenesis, and the G1 checkpoint cell cycle proteins such as pRb, cdk4, cyclin D1, and cyclin E variably participate in the gastric carcinogenesis and metastasis by the mechanisms which are yet unknown; thus, further studies need to be performed to elucidate the mechanisms.
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PMID:Loss of p16 and p27 is associated with progression of human gastric cancer. 1077 41

The multistage process of carcinogenesis involves the progressive acquisition of mutations, and epigenetic abnormalities in the expression, of multiple genes that have highly diverse functions. An important group of these genes are involved in cell cycle control. Thus, cyclin D1 is frequently overexpressed in a varety of human cancers. Cylin D1 plays a critical role in carcinogenesis because (i) overexpression enhances cell transformation and tumorigenesis, and enhances the amplification of other genes, and (ii) an antisense cyclin D1 cDNA reverts the malignant phenotype of carcinoma cells. Therefore, cyclin D1 may be a useful biomarker in molecular epidemiology studies, and inhibitors of its function may be useful in both cancer chemoprevention and therapy. We discovered a paradoxical increase in the cell cycle inhibitors protein p27(Kip1) in a subset of human cancers, and obtained evidence for homeostatic feedback loops between cyclins D1 or E and p27(Kip1). Furthermore, derivatives of HT29 colon cancer cells with increased levels of p27(Kip1) showed increased sensitivity to induction of differentiation. This may explain why decreased p27(Kip1) in a subset of human cancers is associated with a high grade (poorly differentiated) histology and poor prognosis. Agents that increase cellular levels of p27(Kip1) may, therefore, also be useful in cancer therapy. Using an antisense Rb oligonucleotide we obtained evidence that the paradoxical increase in pRb often seen in human colon cancers protects these cells from growth inhibition and apopotosis. On the basis of these, and other findings, we hypothesize that homeostatic feedback mechanisms play a critical role in multistage carcinogenesis. Furthermore, because of their bizarre circuitry, cancer cells suffer from 'gene addiction' and 'gene hypersensitivity' disorders that might be exploited in both cancer prevention and chemotherapy.
Carcinogenesis 2000 May
PMID:Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. 1078 4

Human papillomavirus (HPV) survives by reactivating DNA replication in post-mitotic cells. In the present study, we describe a mouse model of HPV-dependent disease. In these mice, DNA synthesis is activated in suprabasal keratinocytes, leading to acanthosis, parakeratosis and enhanced desquamation. The full-length E6/E7 transcript and two alternately spliced products are produced and in most lines the predominant product is E6*. In the present study, we examine the effects of E6/E7 on cell cycle regulatory protein expression. E6/E7 expression in mouse epidermis is correlated with increased levels of the p53, p21, p27, cdk2, cdk4, cdk6, cyclin D1 and cyclin E regulatory proteins. Hyperproliferation is also observed in the buccal mucosa and the tongue epithelia of E6/E7 mice, and p53 levels are markedly increased in these epithelia. These results suggest that the major changes in cell cycle regulatory protein expression are in response to the presence of E7 and that E6 has a lesser impact.
Carcinogenesis 2000 May
PMID:Suprabasal expression of the human papillomavirus type 16 oncoproteins in mouse epidermis alters expression of cell cycle regulatory proteins. 1078 29


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