The interactive effect of Ras, HER2, P53 and Bcl-2 expression in predicting the survival of non-small cell lung cancer patients

In patients with non-small cell lung cancer (NSCLC), tumor expression of P21-Ras, HER2, P53, and Bcl-2 has been reported as independent predictors of prognosis. However, the prognostic information carried by these proteins has usually been determined separately, and their potential interaction has not been taken into account. We conducted immunostaining for P21-Ras, HER2, P53 and Bcl-2 on 238 cases of NSCLC in a Korean population with 203 squamous cell carcinomas, and 35 adenocarcinomas. P21-Ras, HER2, P53 or Bcl-2 was expressed at high levels in 54.6, 42.0, 18.1 and 71.8% of the NSCLC studied, respectively. A total of 59 tumors (24.8%) expressed only one protein, while 70 (29.4%) expressed two, 59 (24.8) expressed three, and 17 tumors (7.1%) expressed all four proteins. Univariate analysis testing the association of marker expression with survival found Bcl-2 expression to be significantly associated with a poor prognosis, as well as the co-expression of Bcl-2 + HER2, Bcl-2 + HER2 + P53, and Bcl-2 + HER2 + P53 + P21-ras with an increasing hazard ratio. By multivariate analysis controlling for age, tumor stage and tumor type, only the combination of Bcl-2 + HER2 expression was an independent marker of poor prognosis (hazard ratio = 1.91, P = 0.003). Thus, a prospective analysis of the co-expression of Bcl-2 + HER2 in NSCLC patients may identify patients with a poor prognosis who may benefit from more aggressive therapy.     

Increased expression levels of p53 correlate with good response to cisplatin-based chemotherapy in non-small cell lung cancer

In order to determine whether expression of the tumor suppressor gene p53 in non-small cell lung cancer (NSCLC) correlates with chemotherapeutic response, resected tumors from 18 patients with recurrent lung cancer who had undergone complete resection and received chemotherapy after the initial tumor recurrence were subjected to p53 immunostaining. Histological examination of the resected tumors revealed 11 adenocarcinomas, 6 squamous cell carcinomas and one adenosquamous cell carcinoma. Group 1 was 50% (n=9) p53-immunopositive. All patients received cisplatin-based chemotherapy after recurrence. No patient in group 1 achieved response to chemotherapy whereas 2 and 3 in group 2 achieved complete and partial responses, respectively. The chemotherapy response rate of group 2 (56%) was significantly higher than that of group 1 (0%, p=0.009). The times to reoccurrence after tumor resection of group 2 was significantly better than that of group 1 (log-rank p=0.019, Wilcoxon p=0.042), and survival after chemotherapy of group 2 was also significantly better than that of group 1 (log-rank p=0.023, Wilcoxon p=0.034). It is suggested that high p53 expression levels in tumors correlate with both good response to cisplatin-based chemotherapy and good survival of patients with advanced NSCLC.     

Clinical significance of insulin receptor substrate-I down-regulation in non-small cell lung cancer

Insulin receptor substrate-1 (IRS-1) is an adaptor protein for insulin-like growth factor (IGF) signaling and it is presumed associated with cancer development, progression or clinical outcome of patients harboring solid tumors. Therefore, we investigated by immunohistochemistry, the expression of IRS-1 in the tumor tissues from 94 patients who were diagnosed as stage I non-small cell lung cancer (NSCLC) and had undergone a curative lung resection. The relationships between its intratumoral expression and various clinical parameters were explored. IRS-1 is consistently expressed in the cytoplasm of intrapulmonary bronchial and bronchiolar epithelial cells comprising normal appearing adjacent lung tissues. Forty-one (43.6%) of 94 specimens showed loss of IRS-1 expression. In a subset analysis, IRS-1 was more frequently lost in stage IB than in IA tumors (50.0 vs. 22.7%, p=0.024, chi(2) test), which was reflected by the facts that tumors which showed down-regulation of IRS-1 had larger area than those with IRS-1 expression (18.1 vs. 12.1 cm(2), p=0.044, t-test). Down-regulation of IRS-1 is more frequently observed in squamous cell carcinoma than other cell type lung cancer (p=0.002, chi(2) test) and its expression was not affected by histological grade of differentiation. Comparing pack-years (P.Y.) between groups of smokers whose tumor expressed IRS-1 and those that did not, smokers whose tumor showed loss of IRS-1 expression had higher P.Y. than those whose tumor did express IRS-1 (39.2+/-23.67 vs. 25.6+/-26.61 P.Y., p=0.034, t-test). Intratumoral expression of IRS-1 did not influence disease-free survival, disease-specific survival or overall survival of stage I NSCLC patients, whose median follow-up duration is 7.5 years (95% CI; 7.21-7.86 years). These results suggest that loss of IRS-1 might rather be an early event in NSCLC development than a prognostic factor and that it is more strongly related with squamous cell carcinoma and with smoking.     

P2RY6在非小细胞肺癌中的表达和临床意义分析

  目的  探讨P2RY6在非小细胞肺癌（non-small cell lung cancer,NSCLC）患者中的表达及临床意义。  方法  在基因表达集（Gene Expression Omnibus,GEO）和癌症基因组图谱计划（The Cancer Genome Atlas Program,TCGA）数据库中获取多个NSCLC、肺腺癌和肺鳞癌的基因表达以及临床信息数据集。使用非参数检验分析癌组织与邻近正常组织的P2RY6表达水平差异,并且通过免疫组织化学研究肺鳞癌及肺腺癌组织和正常组织的P2RY6蛋白表达情况。使用χ2检验分析P2RY6表达与肺腺癌、肺鳞癌患者临床特征之间的相关性。使用Kaplan-Meier方法和Log-rank检验评估肺腺癌和肺鳞癌P2RY6表达水平与总生存期和无进展生存期之间的关系。使用Cox比例风险回归模型进一步评估P2RY6表达量对肺鳞癌患者总生存期和无进展生存期的预测效能。  结果  P2RY6在NSCLC、肺腺癌和肺鳞癌中均高表达。在肺腺癌患者中,P2RY6表达与生存无关,而与性别有关。在P2RY6高表达的肺鳞癌患者中,总生存期和无进展生存期较短,P2RY6高表达是独立危险因素。  结论  P2RY6与肺鳞癌患者的生存相关,P2RY6高表达预示着肺鳞癌患者总生存期与无进展生存期较短,是预后不良的独立危险因素。      

Maspin gene expression is a significant prognostic factor in resected non-small cell lung cancer (NSCLC). Maspin in NSCLC

Maspin is a member of the serpin (serine protease inhibitor) superfamily, and some experimental studies revealed a potential tumor suppressor activity of maspin. To reveal clinical significance of maspin status in non-small cell lung cancer (NSCLC), we quantitatively evaluated maspin gene expression in lung primary tumors cut from a total of 55 resected NSCLC patients. Maspin expression in squamous cell carcinoma (Sq) was significantly higher than that in adenocarcinoma (Ad, p=0.011). Five-year overall survival rates of maspin-high and maspin-low patients were 67.7 and 41.4%, respectively, demonstrating a significant favorable prognosis of maspin-high patients (log-rank, p=0.042). A multivariate analysis confirmed that high maspin expression was an independent and significant factor to predict a favorable overall survival (p=0.031). These results suggested that maspin expression was significantly increased in Sq than in Ad, and that increased maspin expression was a significant factor to predict a favorable prognosis in resected NSCLC.     

人非小细胞肺癌CD46分子的表达及临床意义研究

目的:研究人非小细胞肺癌组织中CD46的表达水平及意义。方法:免疫组织化学检测人非小细胞肺癌组织中CD46的表达水平,分析其与肿瘤发生发展的相关性。结果:检测66例非小细胞肺癌组织样本,24例鳞癌中14例CD46表达阳性(71.4%),42例腺癌中37例CD46表达阳性(88.1%);66例标本中40例TNM早期患者有32例CD46表达阳性(80.0%),26例TNM中晚期患者有19例CD46表达阳性(73.8%);此外,20例正常肺支气管上皮细胞CD46表达均为阳性,19例正常肺泡上皮细胞CD46表达均为阴性。结论:CD46表达与非小细胞肺癌的病理组织类型及肿瘤细胞的起源有关,与肺癌的TNM分期无关。     

ABCB5与V-ATPase在非小细胞肺癌中的表达及意义

目的 检测ABCB5和空泡型ATP酶（V-ATPase）在非小细胞肺癌（NSCLC）中的表达,分析其在不同病理类型、分级、分期之间表达的差异及相关性。方法 采用免疫组化En Vinsion法检测ABCB5和V-ATPase在72例NSCLC组织中的表达情况,分析其在不同病理类型、病理分级和TNM分期NSCLC中的表达差异及两者表达的相关性。结果 ABCB5在肺鳞癌或腺癌中的阳性表达率分别为75.7％和80.0％,差异有统计学意义（P=0.012）;ABCB5表达在鳞癌或腺癌不同病理分级之间差异显著（P=0.030,P=0.036）,但在不同TNM分期之间的表达无显著差异（P=0.179,P=0.844）。V-ATPase在鳞癌或腺癌中的阳性表达率分别为64.9％和82.9％,差异有统计学意义（P=0.000）;V-ATPase在鳞癌或腺癌不同病理分级之间差异显著（P=0.040,P=0.010）,但在不同TNM分期之间的表达无显著差异（P=0.918,P=0.545）。ABCB5和V-ATPase蛋白表达在NSCLC、腺癌或鳞癌中均呈正相关（P＜0.05）。结论 ABCB5和V-ATPase在NSCLC中高表达,其与病理分级有关;两者在NSCLC中的表达存在正相关性,提示可能存在相互促进作用,这为研究ABCB5和V-ATPase在肿瘤中可能的耐药作用提供了依据。     

Expression of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ) in Human Non-small Cell Lung Carcinoma: Correlation with Clinicopathological Parameters, Proliferation and Apoptosis Related Molecules and Patients’ Survival

Peroxisome proliferator-activated receptor-γ (PPAR-γ) has currently been considered as molecular target for the treatment of human metabolic disorders. PPAR-γ has also been implicated in the pathogenesis and progression of several types of cancer, being associated with cell differentiation, growth and apoptosis. The present study aimed to evaluate the clinical significance of PPAR-γ expression in non-small cell lung carcinoma (NSCLC). PPAR-γ protein expression was assessed immunohistochemically in tumoral samples of 67 NSCLC patients and was statistically analyzed in relation to clinicopathological parameters, proliferation and apoptosis related molecules and patients' survival. Positive PPAR-γ expression was prominent in 30 (45?%) out of 67 NSCLC cases. PPAR-γ positivity was more frequently observed in squamous cell lung carcinoma cases compared to lung adenocarcinoma ones (p?=?0.048). PPAR-γ positivity was significantly associated with bcl-2 positivity (p?=?0.016) and borderline with c-myc positivity (p?=?0.052), whereas non associations with grade of differentiation, TNM stage, Ki-67, p53, bax proteins' expression and patients' survival were noted. In the subgroup of squamous cell lung carcinoma cases, PPAR-γ positivity was significantly associated with tumor size (p?=?0.038), while in lung adenocarcinoma ones with histopathological grade of differentiation (p?=?0.026). The present study supported evidence for possible participation of PPAR-γ in the biological mechanisms underlying the carcinogenic evolution of the lung. Although the survival prediction using PPAR-γ expression as a marker seems uncertain, the observed correlation with apoptosis related proteins reinforces the potential utility of PPAR-γ ligands as cell cycle modulators in future therapeutic approaches in lung cancer.     

SPARC expression and prognostic value in non-small cell lung cancer

Secreted protein,acidic and rich in cysteine(SPARC) is expressed in numerous types of tumors and is suggested to have prognostic value.Moreover,because of its strong affinity for albumin,and hence albumin-bound drugs,SPARC has increasingly become a focus for research.In this study,we aimed to determine SPARC expression in patients with non-small cell lung cancer(NSCLC) and investigate the association of SPARC with disease prognosis.Tissue microarrays were constructed with specimens from 105 patients with NSCLC treated at Sun Yat-sen University Cancer Center,and immunohistochemical analysis was performed on these tissue microarrays to assess SPARC expression.Our results showed that SPARC expression status did not significantly relate with age,gender,and tumor stage.However,SPARC was expressed more frequently in squamous cell carcinoma than in adenocarcinoma(75% vs.43.5%,P = 0.004).Patients with smoking history had higher SPARC expression than non-smokers(68.2% vs.33.3%,P = 0.002).In both univariate and multivariate analyses,SPARC was a prognostic factor of overall survival(HR = 0.32;95% CI:0.16-0.65) but not disease-free survival.Our study indicates that SPARC expression is higher in squamous cell carcinoma than in adenocarcinoma in NSCLC.Most notably,SPARC can be used as a prognostic factor for NSCLC.