Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is associated with tumor stage.

PURPOSE: Although the decreased expression of p27(kip-1), a cyclin-dependent kinase inhibitor, has been correlated with advanced tumor stage and short survival of patients with colorectal adenocarcinomas (CRCs), its prognostic value based on the tumor site, tumor stage, and patient ethnicity was not assessed. Therefore, in this study, we investigated whether the prognostic value of p27(kip-1) expression varies with the tumor site, tumor stage and patient ethnicity. EXPERIMENTAL DESIGN: We evaluated 206 (85 African Americans and 121 Caucasians) archival tissue specimens of first primary CRCs for immunohistochemical expression of p27(kip-1), and its prognostic significance was analyzed using univariate Kaplan-Meier and multivariate Cox regression survival methods. RESULTS: Although, similar proportion of CRCs with decreased p27(kip-1) expression was observed in all stages (range, 26-36%), the decreased p27(kip-1) expression has been shown as a marker of poor prognosis only for patients with stage III tumors both in univariate (log-rank test, P = 0.014) and multivariate (hazard ratio = 3.2, 95% confidence interval = 1.3-7.7; P = 0.01) survival analyses. The decreased expression of p27(kip-1) was associated with a high histologic grade (P = 0.016) in stage II CRCs, and with distal tumors (P = 0.001), tumor invasion (P = 0.044), and with local recurrence (P = 0.008) in stage III CRCs. CONCLUSIONS: No prognostic significance was found for p27(kip-1) expression in stages I, II, or IV CRCs, and its prognostic value was not associated with either ethnicity or tumor location. These studies suggest that decreased expression of p27(kip-1) is an indicator of poor prognosis and aids in identifying a subset of patients with aggressive forms of stage III CRCs.     

p27蛋白在结肠直肠癌中的表达与预后的关系

背景与目的：有研究表明p27蛋白在组织中表达水平的高低与某些肿瘤的预后有关,本研究拟探讨p27蛋白在结肠直肠癌中的表达水平与预后的关系。方法;用免疫组化法检测p27蛋白在82例结肠直肠癌中的表达水平。然后用X^2检验检测其与临床病理学特征的关系,Log rank检验p27蛋白的表达与生存时间的关系。Cox回归模型作单因素和多因素预后分析。结果：p27蛋白在结肠直肠癌中的高表达率为53.66%(44/82),低表达率为46.34%(38/82),p27蛋白低表达与肿瘤在肠壁的深浸润及淋巴结转移显著相关;Log rank检验发现p27蛋白的表达与结肠直肠癌患者的生存期呈正相关。Cox模型则显示p27蛋白可作为结肠直肠癌的一个预后指标。结论：p27蛋白低表达与肿瘤在肠壁的深浸润,易发生淋巴结转移,预后差,生存期短显著相关,p27蛋白高表达则相反,p27蛋白可作为结肠直肠癌患者预后的一个独立指标。     

Low expression of p27(Kip1) is associated with tumor size and poor prognosis in patients with renal cell carcinoma

BACKGROUND: Proliferative activity in tumors depends on regulation of the cell cycle. p27(Kip1) (p27) plays a pivotal role as a negative regulator of the cell cycle. A decrease in p27 expression has been reported in many kinds of tumors, but little is known regarding p27 in patients with renal cell carcinoma (RCC). METHODS: Expression of p27 and the related cyclins (cyclin A, cyclin E, and cyclin D1) was examined immunohistochemically in 67 patients with of clear cell RCC. The Ki-67 labeling index (MIB-1 LI) and clinicopathologic parameters related to a poor prognosis also were analyzed. To determine their prognostic significance, univariate and multivariate survival analyses were performed. RESULTS: In tumors, there was considerable immunoreactivity for cyclin A, cyclin D1, and MIB-1, and the mean values for each were 1.08%, 16.1%, and 1.5%, respectively. Cyclin E expression was rare. The expression of p27 was correlated strongly with the expression of cyclin A (correlation coefficient, 0.432; P < 0.0004) and cyclin D1 (correlation coefficient, 0.476; P < 0.0004). Also, an inverse correlation was present between p27 expression and tumor size (P = 0.0377). In univariate analysis, the unfavorable prognostic factors were high TNM stage (P < 0.0001), large tumor size (P = 0.0016), high histologic grade (P = 0.0104), and low p27 expression (P < 0.0001). In multivariate analysis, high TNM stage (P = 0.0035) and low p27 expression (P = 0.0235) were independent prognostic factors for disease specific survival in patients with RCC. CONCLUSIONS: The results of this study suggest that low p27 expression may be a significant and independent, unfavorable prognostic factor in patients with renal cell carcinoma.     

Loss of p16 contributes to p27 sequestration by cyclin D(1)-cyclin-dependent kinase 4 complexes and poor prognosis in hepatocellular carcinoma.

PURPOSE: p27(Kip1) (p27) might act as an adverse prognostic marker for various types of cancers. However, its clinical usefulness remains uncertain, because it is sometimes overexpressed in aggressive types. EXPERIMENTAL DESIGN: To precisely evaluate the practical significance of p27 in hepatocellular carcinoma (HCC), we immunohistochemically compared the level of p27 expression with Ki-67 labeling in 74 HCCs and focused on tumors in which cell proliferation increased despite a high level of p27 expression. We then analyzed the status of p27 and related cell-cycle regulators using kinase and immunoprecipitation assays, Western blotting, and methylation-specific PCR to understand the rationale for the functional inactivation of p27 in HCC. We also evaluated relationships between the key biological characteristics of HCC and survival. RESULTS: Immunohistochemical studies showed that 40 (54%) of 74 HCCs expressed high levels of p27 (>50% of the tumor cells). Of these, the Ki-67 labeling index was low (<20%) in 26 (65%) and high (>20%) in 14 (35%). Increased proliferative activities were closely correlated with elevated kinase activities, sequestration of p27 protein, and p16 gene methylation. The association between a loss of p16 and poor prognosis was significant when p27 expression was high (P < 0.01). CONCLUSIONS: The loss of p16 appears to be closely related to the functional inactivation of p27, and assessment of p16 status may be useful for a precise prognostic prediction of individuals with HCC expressing high levels of p27.     

p27蛋白在乳腺癌中的表达及预后关系

目的 :探讨p2 7蛋白在乳腺癌中的表达及其与预后的关系。方法 :采用免疫组化方法检测 60例乳腺癌组织p2 7蛋白的表达 ,分析与临床病理学特征的关系。结果 :p2 7在乳腺癌中的高表达率为61 67% (37 60 ) ,低表达率为 38.33% (2 3 60 )。p2 7低表达与乳腺癌肿瘤直径、分期、淋巴结转移、远处转移、预后差相关。结论 :p2 7蛋白的检测对鉴定无淋巴结转移但预后较差的乳腺癌患者 ,指导术后辅助治疗具有一定的意义     

p27Kip1 expression is associated with clinical outcome in advanced epithelial ovarian cancer: multivariate analysis.

Few biological parameters have been shown to have a prognostic role in patients with advanced ovarian cancer. p27Kip1 is a cyclin-dependent kinase inhibitor, and its loss may contribute to tumor progression. We determined whether p27Kip1 protein expression in advanced ovarian cancer could be associated with prognosis. p27Kip1 status was assessed by immunohistochemical analysis of tissue sections from primary tumors of 99 patients with stages III-IV ovarian carcinoma and was analyzed in relation to clinicopathological variables, time to progression (TTP), and overall survival (OS). p27Kip1 expression was detected in 47 (47%) of the 99 patients. p27 expression did not correlate with any of the classical clinicopathological parameters. Loss of p27 protein was significantly associated with a short TTP (P = 0.0004) and decreased OS (P = 0.0302). The 5-year TTP rate in p27-positive patients was 50% versus 11% in p27-negative patients. p27-positive cases showed a 5-year OS rate of 53% compared with 43% of p27-negative cases. In multivariate analysis, p27 expression was an independent predictor of progression of disease (P = 0.0009) and survival (P = 0.0032) when considered together with stage of disease, presence of ascites, and residual tumor at surgery. Loss of p27Kip1 conferred poor prognosis independently of proliferative index, as assessed by proliferating cell nuclear antigen immunostaining. p27 immunoreactivity can be used to predict progression of disease and survival in patients with advanced epithelial ovarian cancer and therefore may represent a new prognostic marker.     

Low p27 expression correlates with poor prognosis for patients with oral tongue squamous cell carcinoma

BACKGROUND: p27, a cyclin-dependent kinase inhibitor, regulates progression from G1 to S phase. There have been a few clinical reports of low p27 expression associated with poor survival among patients with cancer; however, there have been no reports of such an association in cases of head and neck cancer. The authors investigated whether p27 expression in patients with oral tongue squamous cell carcinoma was associated with their prognosis. METHODS: Ninety-four patients with oral tongue squamous cell carcinoma were analyzed. The authors performed p27 immunohistochemistry on all patients and Western blot analysis on 19 available patients. Cox proportional hazards regression analysis that included gender, history of smoking and alcohol usage, presence of multiple primary cancers, stage, histologic grade, and p27 status was used to identify the multivariate predictive value of prognostic factors. RESULTS: Twenty-six patients had high p27 expression (> or =50% tumor cell nuclei positive), and 68 patients had low p27 expression (<50%) by immunohistochemistry. In those with low p27 expression, N(+) and advanced T (T3 or T4) were significantly higher than in those with high p27 expression (P = 0.02 and 0.04). The 5-year survival rate in the low p27 group was 44%, whereas that in the high p27 group was 68%, indicating a significant difference (P = 0.04). p27 expression was inferred from Western blot analysis, and an arbitrary quantity (<1, 1-5, or > or =5) from the ratio of tumor to normal tissue density was used to characterize, resulting in 8 (42%), 3 (16%), and 8 (42%) patients in the low (<1-fold), intermediate (1-5-fold), and high (> or =5-fold) groups, respectively. Results of immunohistochemical analysis for p27 were significantly correlated with those of Western blot analysis (P = 0.02). Multivariate analysis revealed that low intensity of p27 expression and advanced stage (Stage III or IV) were predictors of reduced survival (P = 0.02 and 0.001). CONCLUSIONS: Low p27 expression was associated with increasing lymph node metastasis and stage of tumor and resulted in a poor prognosis for patients with oral tongue squamous cell carcinoma. p27 is apparently a significant predictor of survival.     

Low level of p27(Kip1) protein expression in gastric adenocarcinoma is associated with disease progression and poor outcome

BACKGROUND AND OBJECTIVES: Low tumor expression of the p27(Kip1) protein, which is involved in cell cycle control and apoptosis, is considered a negative prognostic factor in different types of cancer. The aim of this study was to evaluate the clinical and pathological significance of low p27(Kip1) protein expression in patients who had undergone resection for gastric adenocarcinoma. METHODS: p27(Kip1) protein was studied by immunohistochemistry in formalin-fixed tumor sections from 95 patients who underwent resection for gastric adenocarcinoma between 1991 and 1996. Based on the median value of protein expression, p27(Kip1) protein expression was classified as low or high. RESULTS: Low p27(Kip1) protein expression was significantly associated with tumor de-differentiation, increased penetration through the gastric wall, lymph node metastasis, and advanced tumor stage. In the group of 84 patients who underwent curative surgery, 5-year survival was 74% in cases with high p27(Kip1) protein expression and 38% in those with low p27(Kip1) protein expression (P < 0.001). At multivariate analysis, low p27(Kip1) protein expression was an independent negative prognostic factor for survival (RR = 3.671; P = 0.004). CONCLUSIONS: In gastric adenocarcinoma, low p27(Kip1) protein expression is associated with poorly differentiated and advanced tumors and is a negative prognostic factor of potential clinical value.     

Expression of cell cycle regulator p27Kip1 is correlated with survival of patients with astrocytoma.

p27Kip1 is a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation by mediating cell cycle arrest in G1. This study was undertaken to assess the prognostic value of p27Kip1 for astrocytomas. Tissue samples from 130 astrocytomas (WHO grade 1, 5 cases; grade 2, 23 cases; grade 3, 64 cases; grade 4, 38 cases), including 92 primary and 38 recurrent tumors, were examined immunohistochemically for Ki-67 and p27Kip1 expression. Patient charts were reviewed for clinical presentation, and survival was followed. The p27Kip1 labeling index (LI) ranged from 2.3 to 98.4%, with a mean value of 47.5% (+/-23.4%). The p27Kip1 LI decreased with increasing tumor grade but did not correlate with other parameters. There was no correlation between Ki-67 LI and p27Kip1 LI. For patients with primary astrocytomas, the 50% survival times of those with low p27Kip1 LI (<50%) and those with high p27Kip1 LI (> or =50%) were 17.1 and 69.6 months, respectively. For patients with high-grade tumors, the 50% survival times were 13.1 months for those with low p27Kip1 LI and 33.7 months for those with high LI. On multivariate analysis, p27Kip1 was one of the most significant prognostic factors, indicating that low p27Kip1 LI was associated with poor prognosis (primary, risk ratio = 2.5, P = 0.0023; high-grade, risk ratio = 2.2; P = 0.0139). The expression of p27Kip1 was inversely related to tumor grade and positively related to favorable outcome of patients with astrocytoma, suggesting that p27Kip1 may be a candidate for prognostic factor for this tumor.     

Low expression of p27(Kip1), a cyclin-dependent kinase inhibitor, is a marker of poor prognosis in synovial sarcoma

BACKGROUND: Low expression of p27(kip1), a dominant cyclin-dependent kinase inhibitor involved in G1-S transition of the cell cycle, recently has been reported to be associated with aggressive tumor growth. It has been shown that active cell proliferation alludes to poor prognosis in patients with synovial sarcoma. However, to the authors' knowledge, little is known about the clinicopathologic significance of p27(kip1) in synovial sarcoma. METHODS: p27(kip1) expression was examined immunohistochemically in 55 cases of primary synovial sarcoma, and the relations between p27(kip1) expression and several cell proliferation markers, i.e., mitotic index (MI), Ki-67 labeling index (Ki-67 LI), and clinicopathologic parameters related to poor prognosis, were determined. Univariate and multivariate survival analyses were performed to evaluate the prognostic significance of p27(kip1) expression in synovial sarcomas. RESULTS: p27(kip1) labeling index (p27(kip1) LI) correlated inversely with MI (r = -0.44, P = 0.0007) and Ki-67 LI (r = -0.63, P < 0.0001). Of the clinicopathologic parameters examined, tumor necrosis (P = 0.019) and American Joint Committee on Cancer (AJCC) stage (P = 0.021) correlated significantly with p27(kip1) LI. Survival analysis showed that p27(kip1) LI was an independent prognostic factor for overall survival in patients with synovial sarcoma (P = 0.0031). CONCLUSIONS: The study results suggested that low expression of p27(kip1) may be useful as a marker of poor-prognosis synovial sarcoma.     

Identification of Homer1 as a Potential Prognostic Marker for Intrahepatic Cholangiocarcinoma

Background: The aim of the present study was to analyze whether Homer1 is a potential prognostic markerfor intrahepatic cholangiocarcinoma (ICC). Materials and Methods: The expression of Homer1 in ICC tissuewas detected with immunohistochemistry and levels of protein in ICC and paratumor tissues were evaluated byWestern blotting. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance.Results: Homer1 expression was high in 67.4% (58/86) of ICC samples, and there was significant differencebetween ICC and adjacent noncancerous tissues (p<0.001); high expression was associated with poor histologicdifferentiation (p=0.019), TNM stage (p=0.014), lymph node metastasis (p=0.040), and lymphatic invasion(p=0.025). On Kaplan-Meier analysis, a comparison of survival curves of low versus high expressors of Homer1revealed a highly significant difference in OS (p=0.001) and DFS (p=0.006), indicating that high expressionof Homer1 was linked with a worse prognosis. Multivariate analyses showed that Homer1 expression was anindependent risk factor predicting overall survival[Hazard ratio(HR), 7.52; 95% confidence interval (CI), 2.63-21.47; p=0.002] and disease-free survival (HR, 11.56; 95%CI, 5.17-25.96; p<0.001) in ICC. Conclusions: Homer1promotes lymphatic invasion and associates with lymph node metastasis and poor prognosis of ICC. The currentstudy shows that Homer1 may be an independent prognostic factor for ICC patients after curative resection,and it provides an important basis for screening/treating high-risk patients.     

p27 expression correlates with short-term, but not with long-term prognosis in breast cancer

New prognostic and predictive factors are needed to adjust more appropriate therapy for individual patients after operation. p27 is a cell cycle regulator, and a low tissue expression of this protein has been shown to correlate with poor prognosis in colorectal, lung, gastric, prostate, and breast cancer. In this study on 197 breast cancer patients with a median follow-up of 17 years, the prognostic value of immunohistochemical p27 expression was evaluated. After 5 years of follow-up patients with a p27 expression in less than 50% of the tumor cells had a significantly lower survival rate than those with an expression above this level (p=0.01). However, after longer follow-up the difference decreased and was no longer significant at 7 years (p=0.1) or when the entire follow-up period was examined (p=0.67). Tests for associations showed that a low p27 expression correlated with a high histologic grade, a high S-phase fraction (SPF), an advanced TNM stage and negative hormone receptor status. In conclusion: Tissue expression of p27 is a significant predictor of 5-year, but not of 10- or 15-year breast cancer specific survival.     

Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial V

BACKGROUND: The objective of this study was to clarify the prognostic and predictive value of immunoreactivity for the cyclin-dependent kinase inhibitor p27(Kip1) in patients with early-stage breast carcinoma and to investigate its relation with clinicopathologic features and other markers. METHODS: Immunoreactivity for p27 protein was analyzed on tumor slides from 461 patients who were enrolled in the International Breast Cancer Study Group (IBCSG) Trial V (median follow-up, 13 years), including 198 patients with lymph node negative disease and 263 patients with lymph node positive disease. Tumors with < 50% immunoreactive neoplastic cells were considered low expressors. Immunoreactivity for p27 was correlated with several clinicopathologic characteristics. Disease free survival (DFS) and overall survival were analyzed according to p27 immunoreactivity and treatment group. RESULTS: In the lymph node negative population, decreased p27 immunoreactivity was associated with higher tumor grade (P = 0.001) and HER-2/neu overexpression (P = 0.04). In the lymph node positive population, low p27 expression was associated with higher tumor grade (P = 0.01), low expression of thymidylate synthase (P = 0.001), and higher Ki-67 expression (P = 0.007). DFS was not significantly different according to p27 status in either lymph node negative patients (10-year DFS: low p27 expression, 53% +/- 5%; high p27 expression, 55% +/- 5%) or in lymph node positive patients (10 year DFS: low p27 expression, 33% +/- 4%; high p27 expression, 32% +/- 4%). However, in the lymph node negative population, the benefit of one course of perioperative chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil was confined exclusively to patients with tumors that showed reduced p27 immunoreactivity (P = 0.03; test for interaction). CONCLUSIONS: This analysis indicates that p27 immunoreactivity has little if any prognostic value in patients with early-stage breast carcinoma. However, these findings suggest that, in patients with breast carcinoma who have negative lymph node status, reduced p27 immunoreactivity is associated with HER-2/neu overexpression and may be predictive of a benefit from the early administration of adjuvant chemotherapy.     

Prognostic impact of cyclin-dependent kinase inhibitor p27kip1 in node-positive breast cancer

BACKGROUND AND OBJECTIVES: p27kip1 (p27) plays an important role as a negative regulator of cell cycle-dependent kinase activity during progression of the cell cycle. The most important prognosticator of breast cancer is nodal status, and the aim of this study was to determine the prognostic implication of p27 in breast cancer patients with lymph node metastases. METHODS: Immunohistochemical staining for p27 was performed on tissues from 102 patients with node-positive breast cancer. RESULTS: A nuclear staining over 50% was defined as high expression. High expression of p27 was shown in 59 patients (57.8%). A significant correlation was found between high p27 and positive estrogen receptor status, but there was no correlation between p27 staining and age, menopausal status, nodal status, or tumor size. Low expression of p27 was significantly associated with shorter survival. A multivariate analysis also showed that the only independent variable was p27. CONCLUSIONS: The results indicated that low expression of p27 was an independent factor associated with poor prognosis. Therefore, p27 can be an important tool in making therapeutic decisions.     

The cooperative role of p27 with cyclin E in the prognosis of advanced gastric carcinoma

BACKGROUND: Cyclin E and p27 play opposing roles in the cell cycle. This study investigated the protein expression of p27 with cyclin E in the progression and prognosis of gastric carcinoma. METHODS: Of 241 patients with advanced gastric carcinoma, 38 had muscular layer invasion, 113 had subserosal layer invasion, and 90 had serosal invasion. Anti-p27 and cyclin E antibodies were used for immunohistochemical staining. RESULTS: Positive expression of p27 and cyclin E was 32.4% and 38.2%, respectively. Both p27 and cyclin E expression were related to histology of tumors but not to depth of invasion, lymph node metastasis, or stage grouping. A positive correlation was observed between p27 and cyclin E expression (P < 0. 05). Tumors were divided into two groups according to the expression of cyclin E. Within the cyclin E positive tumors, the five-year survival rate was higher in patients with a p27 positive tumor than in those with a p27 negative tumor (P < 0.05). Patients with cyclin E positive tumors showing low expression of p27 had a poor prognosis. In cyclin E negative group tumors, no significant differences were observed irrespective of p27 expression. CONCLUSIONS: Reduced p27 expression is a negative prognostic factor for patients with cyclin E positive tumors.     

Prognostic role of p27(Kip1) expression in oral squamous cell carcinoma in Taiwan

The cyclin-dependent kinase inhibitor p27(Kip1) can inhibit the G1 to S transition of the cell cycle and is a putative tumor suppressor. Decreased expression of p27(Kip1) protein has been correlated with poor prognosis in a variety of human tumors. We examined the expression of p27(Kip1) in oral squamous cell carcinoma (SCC), epithelial dysplasia (ED) and normal oral mucosa (NOM) using antibodies to p27(Kip1). Positive p27(Kip1) nuclear staining was detected in all the specimems from ED and NOM, whereas positive p27(Kip1) staining was observed in 16 of the 63 (25%) cases of oral SCC. The labeling index for p27(Kip1) protein was significantly reduced from NOM through ED to oral SCCs, indicating that changes of p27(Kip1) protein expression may be an early event in oral carcinogenesis in Taiwan. The Kaplan-Meier analysis showed patients with p27(Kip1)-positive tumors had significantly higher overall survival than those with p27(Kip1)-negative tumors in a total of 63 patients (P=0.015) and 47 patients with areca quid chewing habit (P=0.026). Multivariate analysis showed decreased p27(Kip1) protein expression was an independent significant predictor of poor overall survival in the patients with oral SCCs. These results indicate that p27(Kip1) protein expression may serve as a putative new adjuvant prognostic marker for routine assessment of oral SCC patients.     

EYA4 gene functions as a prognostic marker and inhibits the growth of intrahepatic cholangiocarcinoma

Background: The molecular prognostic markers and carcinogenesis of intrahepatic cholangiocarcinoma (ICC) have not been well documented. The purpose of this study was to investigate the prognostic value of the eyes absent homolog 4 (EYA4) gene in ICC and its biological effects on ICC growth in vitro and in vivo. Methods: One hundred twelve patients with ICC who underwent hepatectomy were enrolled in the study. EYA4 mRNA and EYA4 protein levels in ICC and adjacent non?tumoral tissues were evaluated using real?time quantitative polymerase chain reaction and immunohistochemical staining, respectively. EYA4 protein levels in ICC cells were determined using western blot analysis. The associations between EYA4 expression and clinicopathologic features of ICC were analyzed. To identify independent prognostic factors, univariate and multivariate analyses were performed. The biological effects of EYA4 on ICC cells were evaluated by establishing stable EYA4?overexpressing transfectants in vitro, and EYA4’s effects on tumor growth were evaluated by intra?tumoral injection of EYA4?expressing plasmids in a NOD/SCID murine model of xenograft tumors. Results: ICC tissues had signiifcantly lower EYA4 mRNA and protein levels compared with adjacent non?tumoral tis?sues (both P<0.001). Univariate and multivariate analyses showed that EYA4 protein level, tumor number, adjacent organ invasion, lymph node metastasis, and tumor differentiation were independent prognostic factors for disease?free survival and overall survival (all P<0.05). In vitro, EYA4 overexpression inhibited tumor cell growth, foci formation, and cell invasiveness. In vivo, intra?tumoral injection of EYA4?expressing plasmids signiifcantly inhibited ICC growth in the murine xenograft model compared with the control group (P<0.05). Conclusion: EYA4 gene functioned as a molecular prognostic marker in ICC, and its overexpression inhibited tumor growth in vitro and in vivo.     

p27 Labeling index and proliferation in gastrointestinal stromal tumors: correlations with clinicopathologic factors and recurrence

BACKGROUND: Low expression of p27, a cyclin-dependent kinase inhibitor, has recently been reported to be associated with poor prognosis of many tumors. Moreover, an inverse relationship between p27 expression and proliferation was also noted. Although accumulating data indicate a correlation between high proliferation rate and aggressive behavior of gastrointestinal stromal tumors, no conclusive correlation between p27 expression and either tumor recurrence or proliferation has been established yet in this disease. The aim of this study was to immunohistochemically investigate the association of p27 expression (as measured by the p27 labeling index: p27LI) with recurrence and proliferation (as measured by the Ki-67 labeling index: KLI) in gastrointestinal stromal tumors. METHODS: p27LI and KLI were investigated in tumor specimens from 50 patients diagnosed with gastrointestinal stromal tumors. Quantitative evaluations of p27LI and KLI were performed on tissue sections stained immunohistochemically with anti-p27 and anti-Ki-67 monoclonal antibodies. RESULTS: Both p27LI and KLI were associated with the presence of recurrence and high mitotic index. A significant inverse correlation was noted between p27LI and KLI (r = -0.82). The recurrence-free survival time was significantly shorter in patients with high KLI (> or = 10%), low p27LI (<18%), mitosis (> or = 4), and larger tumor size (> or = 5.2 cm). Multivariate analysis indicated that p27LI, KLI, and mitosis were independent predictors of recurrence-free survival. CONCLUSIONS: These findings support the view that p27LI is a reliable marker in predicting recurrence and recurrence-free survival in gastrointestinal stromal tumors. Moreover, the concordance of high KLI together with low p27LI, and vice versa, might allow us to measure the aggressiveness of these tumors.     

The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

BACKGROUND: Loss of the cell-cycle inhibitory protein p27Kip1 is associated with poor prognosis in colorectal carcinoma. The decrease in p27Kip1 levels is the result of increased proteasome-dependent degradation, mediated and rate-limited by its specific ubiquitin ligase subunits S-phase kinase protein (Skp) 2 and cyclin-dependent kinase subunit (Cks) 1. Recently, Skp2 and Cks1 expression were found to be increased in some colorectal carcinomas, but their potential role as prognostic markers for survival is unknown. The present study was undertaken to assess the prognostic value of both Skp2 and Cks1 in colorectal carcinoma. MATERIALS AND METHODS: The expression of Skp2, Cks1, and p27Kip1 was examined by immunohistochemistry using highly specific antibodies on formalin-fixed, paraffin-embedded tissue sections from 80 patients with colorectal carcinoma. RESULTS: Overexpression of Skp2 and Cks1 strongly correlated with loss of p27Kip1 and loss of tumor differentiation. A significant decrease in overall survival was observed in patients expressing high Skp2 or Cks1 levels, and in particular, patients with Stage II and III disease. Each protein provided significant additional prognostic information to that given by disease stage, tumor grade, or p27Kip1 expression. CONCLUSIONS: Results suggest that overexpression of Skp2 or Cks1 is strongly associated with poor prognosis and may thus be used as prognostic markers for overall survival in colorectal carcinoma.