Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of Skp2, the ubiquitin ligase subunit that targets p27(Kip1) for degradation, is commonly overexpressed in human cancers. p27(Kip1) is a negative regulator of the cell cycle that plays an important role in tumor suppression. Loss of p27(Kip1) secondary to enhanced ubiquitin-mediated degradation results in uncontrolled proliferation and promotes tumor progression. In the present study the prognostic implications of Skp2 are reviewed and the mechanisms that regulate its expression in different human cancers. A review and analysis of the English literature was undertaken. Overexpression of Skp2 mRNA and protein levels was observed in many aggressive cancers and was commonly associated with down-regulation of p27(Kip1) levels and loss of tumor differentiation. Skp2 is an independent prognostic marker for disease-free and overall survival and may provide additional predictive information to that provided by p27(Kip1) alone. Targeting Skp2 in experimental models resulted in up-regulation of p27(Kip1) and arrested cellular proliferation. Alterations in Skp2 expression have profound effects on cancer progression and may serve as an accurate and independent prognostic marker. Thus, determination of levels of Skp2 and p27(Kip1) by readily available immunohistochemical studies may be a useful tool in the assessment of prognosis, especially in patients with intermediate disease, and may potentially assist in the planning of adjuvant therapy. Skp2 may be an attractive target for the development of novel interventional therapy.
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PMID:Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer. 1826 93

The aim of the present study was to evaluate the tumor suppressor genes p53, p21 WAF1/CIP1 and p27 KIP1 expression in astrocytic tumors, correlating the findings with the histopathological grade (WHO). An immunohistochemical study of the p53, p21 and p27 proteins using the streptavidin-biotin-peroxidase method was performed in fifty-five astrocytomas (13 grade I, 14 grade II, 7 grade III and 21 grade IV) and five samples of non-tumor brain tissue (negative control). p53 positive indices (PI) and labeling indices (LI) showed tendency to increase according to malignant progression. The nuclear expression of p27 presented similar inclination, except for the PI reduction verified in grade IV tumors. Otherwise, the cytoplasmic p27 staining was more evident between high-grade tumors (III and IV). p53 and nuclear p27 expression was correlated with the histological classification (p<0.01; test H). On the other hand, p21 indices revealed a propensity to reduction in agreement with malignant evolution of the astrocytic tumors, except for high scores observed in grade IV tumors. The non-tumor samples did not show any expression of these proteins. These results indicated the p53 mutation as an initial, relevant and potentially predictor of tumor progression event in astrocytomas, with the detection of p21 protein as an important resource for the deduction of functional situation of this gene. Moreover, the activation of p27 KIP1 was preserved in the astrocytic tumors and its cytoplasmic manifestation seems to be resultant of its nuclear expression, not demonstrating a direct impact in astrocytomas tumorigenesis.
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PMID:Immunoexpression of tumor suppressor genes p53, p21 WAF1/CIP1 and p27 KIP1 in humam astrocystic tumors. 1834 13

TSC1/hamartin is a tumor suppressor gene involved in the development of various malignancies, including bladder cancer. In vitro studies showed that hamartin controls cell proliferation partly by up-regulating p27 and 14-3-3sigma. This study was designed to explore the value of these biomarkers in predicting outcome in pTa/pT1 tumors and validate the regulation of p27 and 14-3-3sigma by hamartin in vivo using human bladder cancer tissue. A tissue microarray of 134 pTa and pT1 tumors was constructed, and sections were stained with hamartin, 14-3-3sigma, and p27 antibodies. In multiple Cox regression analysis, pTa/pT1 tumors with reduced or low expression of hamartin tended to have higher risk of progression (P = .030). High-grade tumors tended to be at higher risk of progression in comparison with low-grade tumors (P < .001). The combination of expression of these 3 biomarkers did not add predictive value regarding disease outcomes. Low hamartin expression and high tumor grade are independent factors in predicting faster pTa/pT1 tumor progression. In a subset of pTa/pT1 tumors, hamartin has a role in bladder carcinogenesis by positively regulating 14-3-3sigma and p27.
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PMID:Association of TSC1/hamartin, 14-3-3sigma, and p27 expression with tumor outcomes in patients with pTa/pT1 urothelial bladder carcinoma. 1848 9

Maspin is a key tumor suppressor gene in prostate and breast cancers with diverse biological functions. However, how maspin regulates prostate tumor progression is not fully understood. In this study, we have used maspin heterozygous knockout mice to determine the effect of maspin haploinsufficiency on prostate development and tumor progression. We report that loss of one copy of maspin gene in Mp(+/-) heterozygous knockout mice leads to the development of prostate hyperplastic lesions, and this effect was mediated through decreased level of cyclin-dependent kinase inhibitors p21 and p27. Prostate hyperplastic lesions in Mp(+/-) mice also induced stromal reaction, which occurred in both aged prostate tissues and in neonatal prostates during early ductal morphogenesis. We showed that maspin was also expressed in prostate smooth muscle cells (PSMC), and recombinant maspin increased PSMC cell adhesion but inhibited cell proliferation. We also observed a defective interaction between epithelial cells and basement membrane in the prostate of Mp(+/-) mice, which was accompanied with a changed pattern of matrix deposition and a loss of epithelial cell polarity. Therefore, we have identified a novel property of maspin, which involves the control of the proliferation in prostate epithelial and smooth muscle cells. This is the first report that a partial loss of maspin caused an early developmental defect of the prostate and prostate hyperplastic lesions in mouse.
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PMID:Haploinsufficiency of the maspin tumor suppressor gene leads to hyperplastic lesions in prostate. 1859 13

The inhibins are secreted alpha:beta heterodimers of the TGF-beta superfamily that are mainly synthesized in Sertoli cells and granulosa cells, and are critical regulators of testicular and ovarian development and function. Mice homozygous for a targeted deletion of the inhibin alpha subunit gene (Inha(-/-)) develop sex cord-stromal tumors in a gonadotropin-dependent manner. Here, we determine the contribution of LH to gonadal tumorigenesis by generating mice deficient in both inhibins and LH. Inha(-/-)Lhb(-/-) mice have increased survival and delayed tumor progression, and these observations correlate with lower serum FSH and estradiol levels compared to Inha(-/-) controls. Double mutant testicular tumors demonstrate decreased expression of cyclin D2, while double mutant ovarian tumors have elevated expression of p15(INK4b) and trend toward higher levels of p27(Kip1). We conclude that LH is not required for tumor formation in the absence of inhibins but promotes tumor progression, likely through alterations in serum hormone levels and cell cycle regulators.
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PMID:Luteinizing hormone promotes gonadal tumorigenesis in inhibin-deficient mice. 1865 90

The immunohistochemical expression of phosphorylated (activated) Akt (pAkt) in 50 advanced gastric carcinomas has been analyzed and the results correlated with age, sex, location in the stomach, histotype, stage, survival, mitotic and apoptotic index, some cell cycle regulators (cyclin D1, cyclin E, p34/cdc2, p27/kip1), and cell proliferation. There was a statistically significant direct correlation between pAkt expression (both cytoplasmatic and nuclear) and depth of infiltration of the tumor, number of infiltrated lymph nodes and p34/cdc2 expression, and between prevalently nuclear pAkt and cyclin D1 and cyclin E. Conversely, there was a significant inverse correlation between nuclear pAkt and apoptotic index and between cytoplasmatic and nuclear pAkt and patient survival. No correlation was found between pAkt and sex, age, tumor location, histotype, mitotic index, and cell proliferation. These findings suggest that pAkt may be considered an indicator of tumor progression and patient survival in gastric cancer.
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PMID:Activated Akt as an indicator of prognosis in gastric cancer. 1884 91

Genetic polymorphisms play an important role in clinical response to cytotoxic therapies. We hypothesized that polymorphisms in cell cycle genes may modulate response to preoperative chemoradiation and survival of pancreatic cancer patients. We evaluated 12 single-nucleotide polymorphisms (SNPs) of ten cell cycle genes in 88 patients with resectable adenocarcinoma of the pancreatic head who were treated with neoadjuvant concurrent gemcitabine and radiotherapy. Response was assessed by computerized tomography obtained before and 4-6 weeks after preoperative treatment. Time to tumor progression and survival after treatment were measured. Patients underwent pancreaticoduodenectomy (PD) if no disease progression was found at restaging after preoperative therapy. MDM2 T309G and p16 C580T genotype distributions were significantly different in the patients who underwent PD and those who did not (P = 0.025 for MDM2; P = 0.016 for p16). The MDM2 and p27 genotypes had a significant effect on survival times after treatment (log-rank test, P = 0.010 and P = 0.050, respectively). A strong joint effect of these two genes was observed (log-rank test, P = 0.010). The p73 and p16 polymorphic genotypes were significantly associated with shorter time to tumor progression (log-rank test, P = 0.021 and P = 0.039, respectively). A gene-dosage effect on time to tumor progression was observed for polymorphisms in the p73, p16, and MDM2 genes. The hazard ratios for patients with one, two, or three adverse genotypes were 2.13 (1.04-4.36), 3.18 (1.37-7.39), and 10.09 (3.17-32.05), respectively. These findings suggest these polymorphisms in the cell cycle genes are promising prognostic markers for patients with pancreatic cancer.
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PMID:Polymorphisms of p16, p27, p73, and MDM2 modulate response and survival of pancreatic cancer patients treated with preoperative chemoradiation. 1902 Sep 40

Genetic and biochemical studies have provided considerable insight into the multiple functions of cyclin-dependent kinase subunit (cks)1 in cell division cycle. In addition to enhanced substrate targeting by specific ubiquitin ligases SCF(skp2) and APC/C, its direct interaction with proteasome components normalizes multiple cell cycle regulators. Importantly, it also acts as a transcriptional regulator. cks1 overexpression reflects poor prognosis in malignancy thus indicating its possible role in tumour diagnosis and management. The present review compiles the multiple functional roles of cks1 in cell division with specific emphasis on its molecular mechanisms. Its docking functions and the possible downstream proteolytic and transcriptional targets are described. The spatial configuration of cks1-cdk2 complex and the structural organization of cks1-p27-skp2 assembly required for p27 ubiquitination are discussed in detail. In addition to enhanced p27 degradation, the possible other mechanisms which underlie its pathological functions in human cancer progression are also discussed. Though there are apparent gaps in information, the turnover mechanism of cks1 is well addressed and presents opportunity to exploit the target for disease management.
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PMID:Loss of cks1 homeostasis deregulates cell division cycle. 1922 69

p27(kip1) (p27) is a cell cycle inhibitor and tumor suppressor whose expression is tightly regulated in the cell. Translational control of p27 mRNA has emerged as a prominent mechanism to regulate p27 expression during differentiation, quiescence, and cancer progression. The microRNAs miR-221 and miR-222 repress p27 expression in various cancer cells, and this repression promotes tumor cell proliferation. In addition, the presence of an internal ribosome entry site in the 5' untranslated region (UTR) of p27 mRNA has been reported. Here, we show that p27 mRNA is translated via a cap-dependent mechanism in HeLa and HL60 cells and that the previously reported IRES activity can be attributed to cryptic promoters in the sequence corresponding to the p27 5' UTR. Furthermore, cap-dependent translation of p27 mRNA is repressed by miR-181a in undifferentiated HL60 cells. Repression by miR-181a is relieved during differentiation of HL60 into monocyte-like cells, allowing the accumulation of p27, which is necessary to fully block cell cycle progression and reach terminal differentiation. These results identify miR-181a as a regulator of p27 mRNA translation during myeloid cell differentiation.
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PMID:miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells. 1927 99

Galectin-3, a beta-galactoside-binding protein, has been implicated in a variety of biological functions including cell proliferation, apoptosis, angiogenesis, tumor progression, and metastasis. The present study was undertaken to understand the role of galectin-3 in the progression of prostate cancer. Immunohistochemical analysis of galectin-3 expression revealed that galectin-3 was cleaved during the progression of prostate cancer. Galectin-3 knockdown by small interfering RNA (siRNA) was associated with reduced cell migration, invasion, cell proliferation, anchorage-independent colony formation, and tumor growth in the prostates of nude mice. Galectin-3 knockdown in human prostate cancer PC3 cells led to cell-cycle arrest at G(1) phase, up-regulation of nuclear p21, and hypophosphorylation of the retinoblastoma tumor suppressor protein (pRb), with no effect on cyclin D1, cyclin E, cyclin-dependent kinases (CDK2 and CDK4), and p27 protein expression levels. The data obtained here implicate galectin-3 in prostate cancer progression and suggest that galectin-3 may serve as both a diagnostic marker and therapeutic target for future disease treatments.
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PMID:Regulation of prostate cancer progression by galectin-3. 1928 70


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