Pin1、β-连接素和细胞周期素D1在老年肺癌组织中的表达及临床意义

Objective:To investigate the expressions and correlations of Pin1,β-catenin and cyclin D1 in elderly lung carcinomas.Methods:The expressions of Pin1,β-catenin and cyclin D1 were examined in the specimens of 92 elderly lung carcinomas and 10 normal lung tissues by immunohistochemistry and explored the relationship between the expression levels and clinicopathological factors.Results:(1) The overexpression of Pin1 and cyclin D1 in lung carcinomas was 46 (50%)cases and 60 (65.22%) cases respectively and 56 (60.82%) cases showed positive immunoreactivity for β-catenin in the nuclear and (or) cytoplasmic fraction in tumor tissues,In normal tissue,the expressions of Pin1 and cyclin D1 were negative,the expression of β-catenin was lied in cell membrane.(2) In lung carcinomas the expressions of Pin1,β-catenin and cyclin D1 correlated with tumor differentiation (P＜0.05).The pesitive expression rate and intensity of Pin1 correlated with tumor stage (P=0.032) and lymph node positive disease (P=0.041).The expression of β-catenin correlated with lymph node positive disease (P=0.012).(3) High expression levels of Pin1 correlated with aberrant β-catenin expression (P=0.000) but did not show a correlation with cyclin D1 (P=0.157).Conclusion:In elderly lung carcinomas,the positive expression of Pin1 causes abnormal accumulation of β-catenin and actives its target gene,however,this target gene was not cyclin DI.The detection of Pin1 expression had some clinical significance in estimating prognosis of elderly patient with lung carcinomas.     

Expression of Cyclin E and Its Relationship with the Prognosis of Patients with Breast Cancer

Objective： To investigate the expression of cyclin E in breast cancer tissues and its relationship with prognosis of the patients with breast cancer. Methods： The expression of cyclin E, HER-2/neu, nm23-H1 and actin was detected in 80 breast cancer tissues and 18 benign breast tumor tissues by immunohistochemical methods. The relationship between cyclin E and the remaining genes or the clinical data of the patients with breast cancer was analyzed. Results： The over expression rate of cyclin E in malignant tissues was obviously higher than that in benign tumor tissues （P〈0.01）. The over expression of cyclin E in later stage of disease was higher than that in early stage of disease （P〈0.05）. The expression of cyclin E in ER positive tissues was lower than that in ER negative tissues （P〈0.05）. The expression of cyclin E in PR positive tissues and PR negative tissues had no significant difference （P〉0.05）. The expression of cyclin E in HER-2/neu positive tissues was higher than that in HER-2/neu negative tissues （P〈0.05）. And the expression of cyclin E in ER, PR and HER-2/neu all positive tissues was much higher （P〈0.01）. There was no significant difference in the expression of cyclin E between nm23-H1 positive tissues and nm23-H1 negative tissues （P〉0.05）. The expression of cyclin E in actin positive and continuous distribution tissues was lower than that in actin negative or discontinuous distribution tissues （P〈0.05）. Conclusion： The expression of cyclin E has a strong correlation to the prognosis of the patients with breast cancer.     

The prognostic value of C-X-C motif chemokine receptor 4 in patients with sporadic malignant peripheral nerve sheath tumors

Background: Recent studies indicate that C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibroma-tosis 1-associated malignant peripheral nerve sheath tumor (MPNST) cells and promote their proliferation. In this study, we measured the expression of CXCR4, CXCL12, and Cyclin D1 proteins in sporadic MPNST tissues from Chinese patients and investigated their prognostic values. Methods: CXCR4, CXCL12, and Cyclin D1 protein expression in samples from 58 Chinese patients with sporadic MPNST was assessed with immunohistochemical staining. Their prognostic values were evaluated with Kaplan–Meier analysis and a log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors. Results: High expression of CXCR4, CXCL12, and Cyclin D1 was observed in 19 (32.8％), 32 (55.2％), and 16 (27.6％) samples, respectively. CXCR4 expression was positively correlated with CXCL12 expression (r= 0.334,P= 0.010) and Cyclin D1 expression (r= 0.309,P= 0.018). Patients with high CXCR4 expression showed longer overall survival than those with low CXCR4 expression (χ2= 4.642,P= 0.031). Conclusion: High CXCR4 expression may define a specific subtype of sporadic MPNST with favorable prognosis.     

Expression of heparanase and its clinical significance in human non-small cell lung cancer

Objective： To explore the expression and significance of heparanase in non-small cell lung cancer （NSCLC） regarding prognosis and clinicopathological parameters. Methods： The expression of heparanase was assessed using immunohistochemistry staining and Western blot in 122 paraffin-embedded specimens and 38 freshly taken tissues. The relationship between heparanase expression and the clinicopathological factors was analyzed by Chi-square test, multivariate analysis and Kaplan-Meier method. Results： In the immunoreactive cells, staining was mainly located in cytoplasma and membrane. Human heparanase was highly expressed in lung cancer tissue （78.7%, 96/122） while negative in epithelia of normal lung tissues. The level of heparanase was remarkably higher in NSCLC than that in normal tissue （P=0.043）. Expression of heparanase significantly correlated with TNM stage （P=0.025）, lymphatic metastasis （P=0.002） and vascular invasion （P=0.0003）. The patients with positive heparanase expression had a significantly shorter survival than those with negative heparanase expression （P=0.0006）. In multivariate analysis, only p-TNM stage, lymphatic metastasis and vascular invasion could be considered as prognostic factors. Conclusion： Elevated level of heparanase in human non-small cell lung cancer tissues correlates with the TNM stage, invasion, metastasis and prognosis. However, heparanase expression is not an independent prognostic factor.     

Over-expression of metastasis-associated in colon cancer-1 (MACC1) associates with better prognosis of gastric cancer patients

Objective: The aim of this study was to detect metastasis-associated in colon cancer-1 (MACC1) expression in Chinese gastric cancer and analyze the relationship between MACC1 expression and postoperative survival. Methods: The expression of MACC1 and c-MET protein in a sample of 128 gastric cancer tissues was detected by immunohistochemistry. A retrospective cohort study on the prognosis was carried out and data were collected from medical records. Results: The positive rate of MACC1 protein expression in gastric cancer was 47.66%, higher than that in adjacent noncancerous mucosa (P<0.001). MACC1 protein expression was not related to the clinicopathological variables involved. Kaplan-Meier analysis revealed that the survival of MACC1 positive group tended to be better than that of MACC1 negative group, particularly in patients with stage III carcinoma (P=0.032). Cox regression analysis revealed that MACC1 protein over-expression in gastric cancer tended to be a protective factor with hazard ratio of 0.621 (P=0.057). Immunohistochemical analysis showed that the positive rate of c-MET protein expression was much higher in cases with positive MACC1 expression in gastric cancer (P=0.002), but P53 expression was not associated with MACC1 expression. Conclusion: MACC1 over-expression implies better survival and may be an independent prognostic factor for gastric cancer in Chinese patients.     

Aurora-A is a novel predictor of poor prognosis in patients with resected lung adenocarcinoma

Background： The Aurora-A （AurA） gene, a key regulator of mitosis, has been proved as an oncogene in a variety of cancers. The Aur-A overexpression has been proved correlated with aggressiveness of cancer cells. However, the frequency of Aur-A protein overexpression, as well as its association with clinicopathologic parameters and prognosis remain unclear in lung adenocarcinoma （ADC）. This study tried to clarify the clinical significance of Aur-A in patients with resected lung ADC. Patients and methods： A total of 142 informative patients with surgically resected lung ADC and 20 normal lung tissues were enrolled. Western blot and immunohistochemistry （IHC） were utilized to assess protein expression of Aur-A. Result： The expression of Aur-A was elevated in most of tumor tissues compared with the adjacent tissues by western blot. The IHC results showed that Aur-A protein was over-expressed in 98 of 142 （69.0%） tumor sections, while Aur-A was low-expressed in all normal lung sections. A positive correlation between Aur-A overexpression rate and ascending pathologic stages was observed （P〈0.05）. Kaplan-Meier analysis demonstrated that patients with Aur-A high expression had significantly inferior survival compared to those with Aur-A low expression. Both overall survival （OS） and disease-free survival （DFS） of positive overexpression patients were shorter than the negative group （P=0.036, P=0.041, respectively）. Multivariate analysis confirmed that Aur-A expression, as an independent and significant factor for both DFS and OS, could predict a poor prognosis in patients with resected lung ADC （P=0.022, P=0.049, respectively）. Conclusions： Aur-A was overexpressed in lung ADC and overexpression of Aur-A might be a novel predictor for poor prognosis and potential therapeutic target in lung ADC.     

DETECTING EXPRESSION OF MRP-1/CD9 mRNA IN LUNG CANCERS USING TISSUE MICROARRAYS AND FLUORESCENCE IN SITU HYBRIDIZATION METHODS

Objective： The aim of this study was to investigate the MRP-1/CD9mRNA expression in lung cancer and normal lung tissues and the relationship between its expression and pathologic grades, clinical stages, metastasis and prognosis. Methods： To observe MRP-1/C9mRNA expression, tissue microarray （TMA） containing 54 lung cancers and 10 normal lung tissues was prepared and Fluorescence in situ hybridization was used. Results： The positive rate of MRP-1/CD9 expression was 48.1% in lung cancer, lower than that of normal lung tissues. The statistical difference was significant （P〈0.05）. Its protein expression had no relationship with the patients＇ ages, sex and the macroscopic type of tumor, but had relationships with the histological type, clinical stage, differentiated degree and metastasis. The expression in non-small cell lung cancer （NSCLC） was higher than that in small cell lung cancer （SCLC）; in well-moderately differentiated group was higher than that in poorly differentiated group; Earlier period group （I＋II） was higher than in later period group （Ⅲ＋Ⅳ）; and in group without lymphoid metastasis was higher than in patients with lymphoid metastasis. Conclusion： The progression of the lung cancer maybe related with the descended MRP-1/Cd9 expression, which may be useful in evaluating the prognosis of cancer patients.     

Expressions of cyclin D1 and p27^kip1 in carcinogenesis of stomach mucosa

Objective: To evaluate the relationship between the expressions of cyclin D1 and p27kipl in the canceration course of the stomach.Methods: The immunohistochemical staining technique (SP method) was used to detect the expressions of cyclin D1, p27kip1 in chronic superficial gastritis (CSG), chronic atrophic gastritis (CAG), intestinal metaplasia (IM), dysplasia (DYS), gastric carcinoma (GCA) biopsy specimens.Results: The positive cyclin D1 expression rates increased with the progressing from CAG→IM→DYS→GCA respectively, and those in IM, DYS and GCA were different from those in CSG, P＜0.05, while DYS group was indifferent from GCA group, P＞0.05.The positive p27k'pl expression rates decreased with the mucosa progressing from CAG→IM→DYS→GCA.There was a negative correlation between the expression cyclin D1 and p27kip1 (y=-0.53, P=0.000).Conclusion: Expression rates of cyclin D1 in the canceration course of the stomach mucosa trend were increased and those of p27kip1 were decreased; the abnormal expressions of them were found in the early term of the canceration course of the stomach mucosa, and the inverse expression suggests there may be a negative feedback regulatory loop between cyclin D1 and p27kip1.     

HRCT Scans of Peripheral Non-Small Cell Lung Cancers and their Relationship with Cyclin D1 Expression: a Longitudinal Study

OBJECTIVE To investigate cyclin D1 expression in peripheral lung cancers and its relationship with CT signs and prognosis.METHODS Cyclin D1 expression in peripheral lung cancers and its relationship with the CT imaging and prognosis were analyzed retrospectively by means of SP immunohistochemistrv and spiral CT scanning in 92 patients with peripheral lung cancer verified by pathology.RESULTS Cyclin D1 expression was related to deep lobulafion,spiculate protuberance,short thin spinules sign and mediastina lymph node metastasis.Cyclin D1 expression was not related to tumor size,cavity,pleural indentation,histological type,djfferentiation,tumor TNM stage,age or sex.Cyclin D1 was a negative prognostic factor whose over-expression indicated a poor prognosis.CONCLUSION Cyclin D1 expression may play an important role in the occurrence,progress and CT scan results of lung cancers.Cyclin D1 was a negative factor whose over-expression implied a poor prognosis.Detection of the cyclin D1 and observation of the CT scan can be considered as indexes of clinical diagnosis and prognostic evaluation.     

Prognostic Significance of Cyclin D1 and E-cadherin Expression in Laryngeal Squamous Cell Carcinoma

Cyclin D1 and E-cadherin are important factors in the progression and metastasis of cancers. Their role in laryngeal carcinoma has been studied with conflicting results. To define the frequency of cyclin D1 and E-cadherin expression and its correlation with both the clinicopathological characteristics and prognosis of patients with laryngeal squamous cell carcinoma (LSCC). Tumor tissue samples from 75 patients with laryngeal squamous cell carcinoma were examined for cyclin D1 and E-cadherin expression by immunohistochemistry. The relationship between the expression of both molecules and the age and sex of the patient, tumor site, tumor differentiation, lymph node metastasis, tumor invasiveness, TNM stages, tumor recurrence and overall survival was analyzed. Cyclin D1 was found to be a significant independent prognostic factor of lymph node metastasis (p?=?0.000). The multivariate analysis revealed that cyclin D1 and E-cadherin expression wasn’t an independent prognostic factor of local recurrence free survival (LRFS) in patients with LSCC (P?=?0.56 and 0.28) respectively. However, the univariate analysis revealed a significant association between them and LRFS (p?=?0.003 and 0.000) respectively. Also, the group of high cyclin D1 /low E-cadherin expression had the poorest prognosis, so they might serve as potential predictors of the prognosis of the patients with LSCC. E-cadherin was found to affect the overall survival (OAS) significantly by the univariate analysis (p?=?0.01). However, by the multivariate analysis the TNM stage was the only independent prognostic factor of OAS (p?<?0.05). Cyclin D1 can be used as an independent prognostic marker of lymph node metastasis in patients with LSCC and can help to identify those patients with clinically negative lymph nodes but with considerable risk for occult metastasis. Detection of cyclin D1 and E-cadherin status in LSCC may contribute to the identification of patients with high risk factors of local recurrence. However, they don’t appear to be better prognostic predictors than other established markers in LSCC.     

CyclinD1和VEGF在非小细胞肺癌组织中的表达及其与预后的关系

背景与目的:肿瘤的发生与发展由癌基因、抑癌基因及转移相关基因的特性所决定。细胞周期蛋白D1(CyclinD1)为癌基因CCND1的表达产物,血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)可调节肿瘤新生血管的形成,有助于肿瘤侵袭转移。本研究探讨非小细胞肺癌(non-smallcelllungcancer,NSCLC)病理组织中CyclinD1、VEGF的表达及与患者预后的关系。方法:采用免疫组织化学方法测定55例NSCLC和10例肺部非恶性病变病理切片中CyclinD1和VEGF的表达,并对55例NSCLC组织中CyclinD1和VEGF的表达与患者的年龄、性别、吸烟情况、瘤体大小、病理类型、组织分化程度、临床分期、淋巴结转移情况及生存时间进行统计分析。结果:55例肺癌病理组织中,CyclinD1和VEGF表达的阳性率分别是61.82%和74.55%;10例肺部非恶性病变标本中CyclinD1表达均为“-”,VEGF表达均为“-”。CyclinD1和VEGF表达:在不同年龄、性别,吸烟情况,瘤体大小,腺癌和鳞癌,不同组织分化程度,不同临床分期差异均无统计学意义;在有无淋巴结转移分组比较中差异均有统计学意义;表达阳性与阴性组生存分析差异均有统计学意义,提示CyclinD1与VEGF均有负性预后意义。结论:CyclinD1和VEGF在60%以上NSCLC中有表达,两者均可能影响NSCLC的生物学行为和预后。     

Prognostic significance of p21waf1, cyclin D1 and retinoblastoma expression detected by immunohistochemistry in non-small cell lung cancer.

p21waf1 is a downstream effector of p53, and mediates growth arrest by inhibiting the action of G1 cyclin-dependent kinases. Cyclin D1 is a cell-cycle regulator essential for G1 phases progression and a candidate proto-oncogene implicated in the pathogenesis of several human tumor types. Cyclin D1 overexpression and the absence of retinoblastoma (Rb) protein have been frequently seen in various types of cancer, including lung cancer. The aim of this study was to clarify the relationship between the expressions of p21waf1, cyclin D1, and Rb protein, and to investigate the correlation between these protein expressions and the clinical features of the patients, and their prognoses. We immunohistochemically examined 92 samples of resected non-small cell lung cancer for p21waf1, cyclin D1, and Rb expression. Of the 92 specimens examined, 43 cases (46.7%) showed p21waf1 expression, 23 cases (25.0%) showed cyclin D1 overexpression, and 61 cases (66.3%) showed Rb expression. No correlation was observed between the expressions of p21waf1, cyclin D1, and Rb. There was no association of p21waf1 and cyclin D1 immunoreactivity with gender, disease stage, or histological types of the tumor. Regarding the prognosis in 79 cases with complete resection, no statistical differences were observed according to the degree of expression of these three factors. However, when unfavorable prognostic factors were considered to be the positive expression of p21waf1, positive of cyclin D1, and negative of Rb, the 5-year disease-free survival rate in the group with 2 or 3 unfavorable prognostic factors was 21.1%, which was statistically poorer than the 45.4% in the group with 0 or 1 unfavorable prognostic factor (p=0.0138). We conclude that examination of the expression of cell cycle regulators, such as p21waf1, cyclin D1, and Rb, is useful as a prognostic indicator, when these proteins' expression is analyzed in combination.     

Prognostic Significance of Cyclin D1 Over-expression in Colorectal Cancer: An Experience from Madinah,Saudi Arabia

Background and study aim: Cyclin D1 is a key regulatory protein in the cell cycle and is over-expressed inmany tumors, including endometrial, thyroid, urothelial, breast, brain gliomas, and esophageal cancers. The mainaim of the present study is to examine the expression pattern of cyclin D1 and its correlation with the differentclinicopathological features in patients with colorectal camcer (CRC) from the Madinah region of Saudi Arabia.Patients and methods: The archival tumor blocks were analyzed using immunohistochemistry for Cyclin D1over-expression in 324 CRC patients diagnosed from January 2006 to December 2017, at the Department of Pathology,King Fahad Hospital, Madinah, Saudi Arabia. Results: Cyclin D1 over-expression was absent in normal mucosa, while15% cases of adenoma showed its over-expression. In CRC, Cyclin D1 was expressed at high levels in 24.1% of case.No significant correlation was observed between Cyclin D1 over-expression and age, gender, tumor size, type andlocation. However, Cyclin D1 over-expression exhibited a significant correlation with tumor differentiation (p=0.04),lymph node involvement (p=0.001), lymphovascular invasion (p=0.001), distant metastasis (p=0.006) and AJCC staging(p=0.001). The Kaplan-Meir analysis revealed a shorter period of survival with Cyclin D1 over-expression (p=0.000).The Cox-regression model analysis showed that Cyclin D1 over-expression was an independent prognostic markerin CRC (p=0.000). Conclusion: Cyclin D1 over-expression increases during normal-adenoma-carcinoma sequence.The significant association observed between Cyclin D1 over-expression, advanced tumor stage and short survivalperiod clearly suggest the role of Cyclin D1 in the carcinogenesis and progression of CRC.     

Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma.

PURPOSE: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. EXPERIMENTAL DESIGN: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. RESULTS: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21(Waf1) overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively). CONCLUSIONS: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.     

High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients

Cyclin E is an important regulator of entry into the S phase of the cell cycle. p27/Kip1 (p27) binds to cyclin E/Cdk2 complex and negatively regulates cell proliferation. We immunohistochemically examined the expression of cyclin E and p27 in 98 cases of resected lung adenocarcinoma to evaluate the prognostic significance of cyclin E and p27. Cyclin E was expressed in 16 cases (16%), and p27 was expressed in 41 cases (42%). Using Kaplan-Meier survival analysis, patients with cyclin E positive (P=0.0017) and p27 negative (P=0.011), both individually and in combination (P<0.0001), had a worse prognosis. We also analyzed the relationship of these findings to clinicopathological parameters, which revealed that cyclin E-positive, p27-negative cases had a higher Ki67 expression (P=0.012) and a higher rate of lymph node metastasis (P=0.0078) than other groups. Our results suggested that cyclin E over expression, in association with p27 reduction in particular, may potentially be a poor prognostic factor in lung adenocarcinoma patients. However, to verify the prognostic significance of these factors, a multivariate analysis of a larger number of patients should be undertaken.     

Cyclin A在非小细胞肺癌中的表达及临床意义

目的 :观察细胞周期因子CyclinA在非小细胞肺癌 (NSCLS)中的表达 ,探讨其临床意义。方法 :采用免疫组化SP法 ,观察 66例非小细胞肺癌患者及 12例正常肺组织中细胞周期因子CyclinA的表达 ,并对其与临床预后关系进行了相关分析。结果 :在 66例非小细胞肺癌病例中 ,CyclinA表达阳性率分别为 90 9%。CyclinA与肿块大小、病理分级和TNM分期间显著相关 ,P <0 0 5 ,与年龄、性别、组织学类型及淋巴结转移间无显著相关 ,P >0 0 5。与阴性患者相比 ,CyclinA阳性患者生存时间明显缩短 ,P =0 0 0 6,估计增加相对风险为 3 6;分析显示 ,CyclinA给出最佳预后诊断信息。LN/CyclinA ,P=0 0 0 12 ,两因子协同的预后判断价值优于最佳单个因子。结论 :CyclinA过表达与非小细胞肺癌不良预后有关     

Cyclin D1 in Breast Cancer

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over- expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c- erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over- expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over- expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.     

A risk-stratification model of non-small cell lung cancers using cyclin E, Ki-67, and ras p21: different roles of G1 cyclins in cell proliferation and prognosis

A large number of biological factors that seem to have important prognostic significance have been identified in non-small cell lung cancers (NSCLCs). In the present study, we have characterized expression of cyclin D1 and cyclin E in a cohort of 217 resected NSCLCs from a single institution by immunohistochemistry to analyze their expression in relation to the growth fraction determined by Ki-67 and to prognosis, and then we have constructed a risk-stratification model of cancer death by multiple biological factors in p-stage I NSCLCs. The cyclin E labeling index (LI) was significantly associated with the Ki-67 LI (r = 0.45; P < 0.001). Tumors having high-level cyclin E expression (cyclin E LI > or =30%) showed a significantly higher Ki-67 LI than tumors having low-level cyclin E expression (cyclin E LI <30%; P < 0.001), whereas positive or negative cyclin D1 expression was not associated with the Ki-67 LI (P = 0.1). Cyclin E expression was a significant and independent unfavorable prognostic factor (hazards ratio = 2.09; P = 0.03), as reported previously (Clin. Cancer Res., 6: 11-16, 2000), whereas cyclin D1 expression was not. These findings indicate different roles of cyclin D1 and cyclin E in cell proliferation and in the prognosis of NSCLCs. Furthermore, we stratified this cohort of p-stage I NSCLCs into different survival groups by using biological factors, including cyclin E, Ki-67, and ras p21, which previously we have found to be independent prognostic factors among 10 factors studied in p-stage I NSCLCs. Four groups of patients with markedly different survivals were identified with 5-year survival rates that ranged from 96% for patients with no factors altered to 41% for patients with all three factors altered (P < 0.001). This combination of biological factors was a significant and independent prognostic factor (hazards ratio = 7.94; P = 0.001).