Increased expression of integrin-linked kinase is associated with shorter survival in non-small cell lung cancer

Background  

Integrin-linked kinase (ILK) promotes tumor growth and invasion. Increased ILK expression is correlated with progression of several tumor types, but the expression of ILK has not been investigated in patients with non-small cell lung cancers (NSCLCs).     

CHK2 kinase expression is down-regulated due to promoter methylation in non-small cell lung cancer

Background  

CHK2 kinase is a tumor suppressor that plays important role in DNA damage signaling, cell cycle regulation and DNA damage induced apoptosis. CHK2 kinase expression was known to be ubiquitous in mammalian cells. CHK2-/- cells were remarkably resistant to DNA damage induced apoptosis, mimicking the clinical behavior of non-small cell lung cancer to conventional chemo and radiation therapy.     

非小细胞肺癌mRNA的表达谱分析

目的 检测非小细胞肺癌（NSCLC）组织和正常肺组织中mRNA的表达差异,并进行生物信息学分析。方法 采用基因芯片技术对3例NSCLC组织和3例正常肺组织的mRNA进行检测,筛选差异表达基因,进一步对差异表达基因进行Gene Ontoloty（GO）分析和信号通路分析。结果 在20 716条目的基因中共发现两种组织差异表达基因896条,其中593条基因表达增加,303条基因表达降低;生物信息学分析表明上述差异性表达的mRNA参与了NSCLC重要的生物学调节功能和通路。结论 基因芯片技术可以筛选出NSCLC组织和正常肺组织间差异表达的基因,mRNA在NSCLC组织和正常肺组织间的表达水平有明显差异,差异性表达的mRNA参与了NSCLC重要的生物学功能。     

非小细胞肺癌组织中内皮抑素mRNA的转录表达及临床意义

背景与目的肿瘤生长和转移依赖于肿瘤血管形成,抑制其血管形成能够控制其生长和转移.胶原ⅩⅧ/内皮抑素(collagen ⅩⅧ/endostatin)是迄今为止最有效的内源性血管生长抑制剂之一.本研究拟探讨内皮抑素mRNA在非小细胞肺癌组织中的转录表达及其与肺癌临床病理生理特征的关系.方法用RT-PCR法检测46例非小细胞肺癌组织和14例肺良性病变组织中内皮抑素mRNA的转录表达.结果①肺癌组织中内皮抑素mRNA转录表达水平(0.872±0.071)显著高于癌旁肺组织(0.717±0.073)和肺良性病变肺组织(0.611±0.026)(P＜0.001),癌旁肺组织亦显著高于肺良性病变肺组织(P＜0.01).②肺癌组织中内皮抑素mRNA转录表达水平与肺癌原发肿瘤大小、有无远处转移、细胞分化程度和P TNM分期等均有密切关系,而与肺癌原发部位、淋巴结转移状态、组织学类型,患者性别、年龄和吸烟与否等均无明显关系.结论肺癌患者肺癌组织中存在内皮抑素mRNA转录表达水平的升高,这种升高与肺癌的发生、发展、远处转移和细胞分化不良有密切关系,因而有助于预测肺癌的恶性行为.     

Resectable left lower lobe non-small cell lung cancer withlymph node metastasis is related tounfavorable outcomes

Background:Despite numerous previous studies, the consideration of tumor location as a prognostic factor in resectable non–small cell lung cancer (NSCLC) remains controversial. The present study analyzed the association between tumor location and clinical outcome in patients with resectable NSCLC who had undergone lobectomy with systematic lymphadenectomy and who had presented with varying nodal statuses.
Methods:The data from a cohort of 627 eligible patients treated in Sun Yat?sen University Cancer Center between January 2000 and December 2008 were retrospectively collected, and the nodal statuses of patients with different tumor locations were compared. Cox proportional hazards regression model was used to determine the independent factors related to cancer?speciifc survival (CSS).
Results:Multivariate analysis demonstrated that left lower lobe (LLL) tumors [hazard ratio (HR): 1.465, 95% conif?dence interval (CI) 1.090–1.969,P= 0.011], lymph node metastasis (HR: 2.742, 95% CI 2.145–3.507,P < 0.001), and a tumor size of >4cm (HR: 1.474, 95% CI 1.151–1.888,P= 0.002) were three independent prognosticators in patients with resectable NSCLC. However, LLL tumors were associated only with CSS in node?positive patients (HR: 1.528, 95%CI 1.015–2.301,P= 0.042), and a tumor size of >4cm was the only independent risk predictor in the node?negative subgroup (HR: 1.889, 95% CI 1.324–2.696,P < 0.001).
Conclusions:Tumor location is related to the long?term CSS of NSCLC patients with lymph node metastasis. LLL tumors may be upstaged in node?positive patients to facilitate an optimal treatment strategy.     

Clinical significance of RKIP mRNA expression in non-small cell lung cancer

Raf-1 kinase inhibitor protein (RKIP) expression was associated with the onset, development, invasion, and metastasis of numerous tumor types including prostate cancer, melanoma, colorectal cancer, liver cancer, and breast cancer. However, RKIP mRNA expression and the clinical significance in non-small cell lung cancers (NSCLC) remain unresolved. Real-time PCR was performed to detect the expression of RKIP mRNA in 126 pairs of lung tumor tissues (TT) and surrounding normal tissues (sNT). Correlations between RKIP mRNA expression and clinicopathological features were evaluated by statistical analysis. In the 126 patients examined, RKIP mRNA expression was significantly lower in lung TT than the sNT (p?<?0.05). Our results indicated that downregulation of RKIP mRNA expression was associated with a poorer N-stage (p?=?0.019) and poorer pathological TNM stage (p?=?0.015). However, no significant association was observed between the expression status of RKIP mRNA and clinicopathologic factors, such as gender, age, histological type, and the size of the tumor (p?>?0.05). The level of RKIP mRNA expression was found to be significantly downregulated in NSCLC, and the lower mRNA levels correlated with poorer differentiation, advanced pathologic TNM stage in patients with NSCLC.     

Gallbladder metastasis of non-small cell lung cancer

BACKGROUND: Although non-small cell lung cancer is known for its potency to spread to almost any organ of the body, metastasis to the gallbladder with significant clinical manifestation is rarely reported in the literature. CASE REPORT: We report the case of a 45-year-old man with non-small cell lung cancer (NSCLC), who developed symptoms of acute cholecystitis caused by a metastasis of the gallbladder wall. Histological examination showed tumor cell invasion in regional gallbladder lymph nodes. A second primary tumor of the gallbladder was excluded by immunohistochemical methods. CONCLUSION: Our experience showed that acute cholecystitis can occur in association with metastases of lung cancer to the gallbladder.     

Angiostatin expression in non-small cell lung cancer.

Angiostatin, a potent inhibitor of angiogenesis, tumor growth, and metastasis, was examined in a panel of human lung cancer cell lines with Western blot analysis and in 143 primary non-small cell lung carcinomas with immunohistochemistry. Thirty-four of 143 cases (24%) stained positively. Patients with angiostatin-positive tumors survived longer (146 weeks) than patients with angiostatin-negative tumors (77 weeks; log-rank test: P = 0.07; rank-sum test: P = 0.02). To determine whether combining stimulating and inhibiting factors might improve the prognostic capability, both angiostatin and vascular endothelial growth factor (VEGF) were analyzed together with respect to patient survival. The median survival time of patients with angiostatin-positive/VEGF-negative carcinomas was 184 weeks, whereas the median survival time of patients with angiostatin-negative/VEGF-positive tumors was only 52 weeks. The angiostatin-positive tumors exhibited an increased incidence of apoptosis and a reduced capability to be transplanted into nude mice, but these differences did not reach or were only of borderline statistical significance.     

Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation.

PURPOSE: The PTEN gene at chromosome 10q23.3 is a tumor-suppressor genethat is inactivated in several types of human tumors. Althoughmutation and homozygous deletion are the most commonmechanisms of PTEN inactivation, promoter methylation and translational modification can also account for PTEN silencing. The aim of this study was to investigate the expression of PTEN protein in primary non-small cell lung cancer (NSCLC) samples and to investigate the promoter methylation status of the gene in a panel of NSCLC cell lines as well as primary tumors. EXPERIMENTAL DESIGN: We analyzed PTEN expression by immunohistochemistry in tissue samples from 125 patients with early-stage NSCLC. We also evaluated PTEN promoter methylation status by methylation-specific PCR in 20 microdissected PTEN-negative primary tumors from among the last specimens as well as in a panel of 16 NSCLC cell lines. Western and Northern blotting were performed in the same panel of NSCLC cell lines. RESULTS: Thirty (24%) of the 125 specimens showed a lack of staining for PTEN. PTEN methylation was detected in 7 (35%) of the 20 PTEN-negative NSCLC samples and in none of the 10 PTEN-positive NSCLC samples that were microdissected. Furthermore, PTEN methylation was observed in 11 (69%) of the 16 NSCLC cell lines tested. PTEN mRNA expression was increased in the NCI-H1299 cell line by in vitro treatment with the demethylating agent 5-aza-2'-deoxycytidine. PTEN methylation was well correlated with PTEN expression in NSCLC cell lines by Western and Northern blot (P = 0.025). CONCLUSIONS: Although genetic alterations of the PTEN gene are rare in NSCLC, loss of PTEN protein is not an uncommon event in early-stage NSCLC. Lack of PTEN expression may be partially explained by promoter methylation.     

非小细胞肺癌EGFR启动子区甲基化和mRNA表达临床意义的探讨

目的:研究表皮生长因子受体(EGFR)的表达与非小细胞肺癌(NSCLC)组织学类型和淋巴结转移的关系,分析EGFR启动子区甲基化与其mRNA表达的关系.方法:应用免疫组织化学法检测60例非小细胞肺癌组织中EGFR的表达,统计EGFR与病理类型及淋巴结转移的关系.用实时定量PCR方法检测其中30例非小细胞肺癌组织和对应的癌旁组织中EGFR mRNA的表达,用甲基化特异性PCR(MSP)方法检测EGFR启动子区的甲基化状态.结果:鳞癌中EGFR阳性率为38.5％(10/26),明显低于腺癌中EGFR阳性率76.5％ (26/34),差异有统计学意义,x2=8.87,P=0.002 9;且有淋巴结转移的NSCLC中EGFR的阳性率为73.7％(28/38),而无淋巴结转移的NSCLC中EGFR的阳性率为45.5％(10/22),差异有统计学意义,x2=4.78,P=0.028.30例有癌旁组织的标本中,11例患者肿瘤组织EGFR的表达高于其癌旁组织;12例标本中存在肿瘤组织EGFR基因启动子区甲基化水平与EGFR mRNA表达呈负调节关系.结论:EGFR的表达与NSCLC的病理类型及淋巴结转移相关,部分NSCLC患者中存在EGFR基因启动子区甲基化水平与EGFR基因mRNA表达呈负调节关系.     

整合素连接激酶mRNA在非小细胞肺癌组织中的表达和意义

目的:比较整合素连接激酶(ILK)mRNA在非小细胞肺癌(NSCLC)组织及正常肺组织的表达差异,分析ILKmRNA的表达与NSCLC的恶性表型、侵袭程度、淋巴转移、远处转移、临床分期之间的关系。方法:取NSCLC患者及肺部良性病变手术切除标本,液氮及超低温冰箱保存,TRIzol法提取总RNA,RTPCR扩增ILKmRNA后对扩增产物进行电泳及图像分析。结果:35例肺癌、30例癌旁组织、29例正常肺及10例肺部良性病变组织ILKmRNA定性表达阳性率分别为82.9%(29/35)、76.7%(23/30)、55.2%(16/29)和60%(6/10),癌组织与正常肺组织之间ILKmRNA阳性率比较有显著性差异(P=0.027)。ILKmRNA定量表达为肺癌组1.67±0.349,癌旁组0.86±0.185,正常组0.43±0.102,肺部良性病变组0.78±0.201,除癌旁组织和肺部良性病变组织差别无统计学意义外,其余差异均有显著性(P<0.01)。NSCLC组织ILKmRNA定量表达的均值随细胞恶性程度、淋巴转移和远处转移及临床分期递增而随之递增(P<0.05)。结论:ILKmRNA在NSCLC组织中表达量高于癌旁组织、正常肺及肺部良性病变组织。高表达的ILKmRNA预示着NSCLC的高度恶性、高侵袭性、高转移性和预后不良,ILKmRNA可作为反映NSCLC恶性表型、转移和侵袭特性的分子标记物。     

Prognostic significance of sphingosine kinase 2 expression in non-small cell lung cancer

Sphingosine kinase 2 (SphK2) as a conserved lipid kinase has not been thoroughly elucidated in non-small cell lung cancer (NSCLC). The aim of the present study was to evaluate the expression of SphK2 in NSCLC tissues and to determine its correlation with clinicopathologic characteristics and its impact on patient prognosis. We assessed the expression of SphK2 and proliferating cell nuclear antigen (PCNA) (as a proliferative index) by immunohistochemistry in 180 NSCLC patient's formalin-fixed paraffin-embedded tissue blocks. Relationship between the expression of SphK2 and PCNA and various clinicopathological features in these patients was evaluated. We detected that expression of SphK2 was gradually upregulated from normal, metaplasia/dysplasia tissues to NSCLC tissues. At the same time, PCNA expression followed a similar pattern. Statistical analysis showed that expression of SphK2 in NSCLC tissues was strongly associated with PCNA expression, histology grade, live vaccine strain invasion, lymph node status, clinical stage, tumors size, and histology type. Patients with SphK2 overexpression in their tissues had lower overall survival (OS) and disease-free survival (DFS) rates than those with low SphK2 expression. Using uni- and multivariate analysis, we found that SphK2 overexpression was an independent prognostic factor for both OS and DFS. The expression of SphK2 parallels the progression of NSCLC, and SphK2 overexpression may represent a novel and potentially independent biomarker for the prognosis of patients with NSCLC.     

The P21-activated kinase expression pattern is different in non-small cell lung cancer and affects lung cancer cell sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors

Exploring methods for increasing epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sensitivity has become a major focus in non-small cell lung cancer (NSCLC). Major downstream effectors of the Rho family small guanosine triphosphatases, P21-activated kinases (PAKs) activate the main signaling pathways downstream of EGFR and thus promote tumor cell proliferation. In this study, we explored the expression pattern of phosphorylated PAKs in NSCLC and their potential value as drug targets for treating cancer. The expression and prognostic significance of phosphorylated group I and II PAKs were evaluated in 182 patients with NSCLC. Immunohistochemical analysis revealed low group I PAK expression in normal lung tissues and increased expressed in the cytoplasm, particularly in lung squamous cell carcinoma. Abnormal group I PAK expression was associated with lymph node metastases and high tumor-node-metastases (TNM) stage in NSCLC patients and correlated with poor prognosis. We used group I PAK inhibitor (IPA3) to specifically decrease group I PAK activity in human lung cancer cell lines. Decreased group I PAK activity inhibited cell proliferation and combined IPA3 and EGFR-TKI (gefitinib) treatment inhibited cell proliferation in an obvious manner. Together, our results revealed the PAK expression pattern in NSCLC, and a role for group I PAK in cell proliferation, which provides evidence that decreased PAK activity may have a potential application as a molecular targeted therapy in advanced NSCLC.     

Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate with good responses to platinum-based chemotherapy in non-small cell lung cancer

In order to determine whether expression of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer (NSCLC) correlates with chemotherapeutic response, resected tumors from 22 patients with recurrent lung cancer who had undergone complete resection and received chemotherapy after the initial tumor recurrence were subjected to p27 immunostaining. Histological examination of the resected tumors revealed 14 adenocarcinomas, 7 squamous cell carcinomas and one adenosquamous cell carcinoma. Fifty percent or less and over 50% of the cells in the resected tumors of 11 patients each (groups 1 and 2, respectively) were p27-immunopositive. All but one patient received platinum-based chemotherapy after recurrence. Only one in group 1 achieved a partial response (PR) in chemotherapy whereas 2 and 4 in group 2 achieved complete and PRs, respectively. The chemotherapy response rate of group 2 (54%) was significantly higher than that of group 1 (9%, p=0.022). The times to recurrence after tumor resection of the 2 groups did not differ significantly (log-rank p=0.23, Wilcoxon p=0. 32), but survival after chemotherapy of group 2 was significantly better than that of group 1 (log-rank p=0.045, Wilcoxon p=0.028). It is suggested that high p27 expression levels in tumors may predict the good responses to platinum-based chemotherapy for NSCLC.     

吉非替尼(Gefitinib)对非小细胞肺癌的脑部转移具有疗效

目的 比较分析吉非替尼对不同体能表现、既往不同化疗次数、有或无脑部转移病灶的非小细胞肺癌患者的治疗结果。方法 总共有76例患者参加试验。结果 患者的疾病控制率为63．2％(95％CI为52．1％～74．3％)．无疾病恶化牛存期的中位数为5．0个月(95％CI为3．5～6．6个月)，整体生存期的中位数为9．9个月(95％CI为4．9～14．8个月)。其中具有可测量病灶的57例患者的客观反应率为33．3％(95％CI为20．7％～46．0％)。76例患者中有21例患者同时具有可评估的颅内及颅外病灶，其中17例(81．0％)对吉非替尼有相同的颅内及颅外肿瘤反应．而出现脑部转移并不影响患者的生存期。药物引起的副作用大部分是中等反应．仅5例患者发生不可耐受的毒性，其中1例(5．8％)为间质性肺炎。结论 吉非替尼对非小细胞肺癌的脑部转移有疗效．值得进一步没计随机临床试验观察单剂吉非替尼治疗或加上其它形式的治疗在脑部转移的非小细胞肺癌患者中所扮演的角色。     

Increased Midkine and Estrogen Receptor-β Expression in Human Non-Small Cell Lung Cancer

Objective  

Midkine (MK), a new member of the heparin-binding growth factor family, has been found recently to have a high expression level in many tumor specimens including lung carcinoma. Estrogens may be involved in lung carcinogenesis, and estrogen receptors, mainly estrogen receptor-β (ER-β), are present and functional in normal lung and tumor cell lines and tissues. In addition, estrogens and growth factors may promote the progression of human non-small cell lung cancer (NSCLC). Previously, we have immunohistochemically demonstrated that MK and ER-β proteins were overexpressed in NSCLC and their expression levels were both significantly negatively correlated with the pathological classification. The purpose of this study was to further verify their expression and its correlation with NSCLC.     

Glypican-5 is a novel metastasis suppressor gene in non-small cell lung cancer

Glypican-5 (GPC5) may be a potential tumor suppressor gene in non-small cell lung cancer (NSCLC). The present study aimed to clarify the GPC5 expression pattern and to explore its potential functions in NSCLC. The expression of GPC5 gene was lower in lung cancer tissues compared with adjacent noncancerous tissues. The GPC5 gene expression in the lymph node metastasis group was remarkably lower than that in the non-metastasis group. The tissue microarray (TMA) study found that the overall survival rate of GPC5-positive group was significantly higher than that of GPC5-negative group in AC subgroup. Overexpressing GPC5 in NSCLC cell lines significantly suppressed their migration, invasion, and proliferation activities and also induced G1/S phase arrest of the cells in vitro. Our data suggest that GPC5 is a novel metastasis suppressor gene in NSCLC and may be a potential biomarker that predicts NSCLC metastasis.