Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis and correlates with improved patient survival in non-small cell lung cancer

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. The role of BRMS1 in non-small cell lung cancer (NSCLC) is not well established. To assess in vitro and in vivo metastatic behavior H1299 NSCLC cells stably expressing BRMS1 or a vector control were created. BRMS1 expression significantly decreases both migration and invasion of NSCLC cells in vitro. Importantly, in flank xenografts, BRMS1 suppresses the formation of pulmonary and hepatic metastases but does not significantly affect primary tumor growth. To evaluate whether BRMS1 is related to the progression of NSCLC, we examined BRMS1 expression in human NSCLC. Both BRMS1 mRNA and protein levels are diminished in NSCLC compared to adjacent non-cancerous lung. BRMS1 expression is also lower in squamous cell carcinoma compared to adenocarcinoma. Moreover, preservation of tumor BRMS1 expression is associated with improved patient survival. Thus, BRMS1 functions as a metastasis suppressor and may be a prognostic indicator for human NSCLC.     

ARID1A is downregulated in non-small cell lung cancer and regulates cell proliferation and apoptosis

ARID1A (AT-rich interactive domain 1A) is a key member of the SWI/SNF chromatin-modeling complex, and the gene has emerged as a tumor suppressor in various human cancers. In the present study, we investigated the expression and clinical significance of ARID1A in non-small cell lung cancer (NSCLC). We found that ARID1A expression was decreased in NSCLC tissues compared with normal bronchial epithelium and was significantly correlated with nodal metastasis, tumor, node, metastasis (TNM) stage, and poor differentiation. ARID1A expression was lower in lung cancer cell lines than normal bronchial epithelial HBE cell line. We also explored the involvement of ARID1A in biological behavior of lung cancer cell lines. ARID1A depletion by small interfering RNA (siRNA) in H460 and H1299 cell lines promoted proliferation, colony formation ability, and inhibited paclitaxel-induced apoptosis. Furthermore, we identified that ARID1A regulated several cell cycle and apoptosis-related targets such as cyclin D1 and Bcl-2. In addition, the activity of Akt phosphorylation was also enhanced after ARID1A depletion. In conclusion, our data suggested that ARID1A may serve as an important tumor suppressor in NSCLC.     

MCM5在非小细胞肺癌中的表达及其临床意义

目的探讨MCM5在非小细胞肺癌（non-small cell lung cancer,NSCLC）中的表达及与其临床病理特征的关系。方法采用免疫组织化学SP法,检测78例原发性非小细胞肺癌组织、40例正常肺组织中MCM5的表达水平。结果非小细胞肺癌组MCM5阳性率高于正常肺组织组（P=0.000）。Ⅰ、Ⅱ、Ⅲ期非小细胞肺癌组织中MCM5阳性率比较,差异有统计学意义（P=0.031）;淋巴结转移者MCM5表达率与无淋巴结转移者比较也有统计学差异（P=0.015）。结论 MCM5可能参与了非小细胞肺癌的发生和发展过程;可能成为判断非小细胞肺癌发生发展和评价预后的有效参考指标之一,对于非小细胞肺癌的早期预测可能具有重要的临床意义。     

Epigenetic silencing of microRNA-199a-5p promotes the proliferation of non-small cell lung cancer cells by increasing AKAP1 expression

MicroRNA (miR)-199a-5p expression is downregulated in a variety of malignancies, including non-small cell lung cancer (NSCLC), and its low expression is associated with a poor prognosis. However, to the best of our knowledge, the mechanism underlying miR-199a-5p downregulation in NSCLC and its target effectors remain to be elucidated. The present study revealed the downregulation of miR-199a-5p expression in NSCLC tissues and cell lines compared with in para-carcinoma tissues and a lung epithelial cell line. Further experiments indicated that the methylation levels of the miR-199a promoter were markedly higher in NSCLC tissues compared with in para-carcinoma tissues. The DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine markedly increased the expression levels of miR-199a-5p in NSCLC cells. Furthermore, it was identified that miR-199a-5p mimics transfection decreased the expression levels of A-kinase anchoring protein 1 (AKAP1) at both the mRNA and protein levels by targeting the 3′ untranslated region of AKAP1 mRNA. The in vitro experiments demonstrated that miR-199a-5p overexpression inhibited the proliferation and tumorigenicity of NSCLC cells, whereas overexpression of AKAP1 partially recovered the malignant phenotypes, suggesting that AKAP1 may be a downstream effector targeted by miR-199a-5p. Collectively, the present findings indicated that miR-199a-5p may be a novel regulator of AKAP1, and that miR-199a-5p may be a potential tumor suppressor in NSCLC.     

TRIM31 is downregulated in non-small cell lung cancer and serves as a potential tumor suppressor

The present study aims to investigate expression pattern and biological roles of TRIM31 in human non-small cell lung cancer (NSCLC). We examined TRIM31 expression in 116 NSCLC tissues and 20 corresponding normal lung tissues by immumohistochemistry. We found TRIM31 downregulation in 47 out of 116 (40.5 %) cancer samples, which correlated with tumor status (p?=?0.0132), advanced p-TNM stage (p?=?0.001), and nodal metastasis (p?=?0.0382). TRIM31 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TRIM31 plasmid was performed in H157 and H1299 cells. TRIM31 overexpression inhibited cell growth rate and colony formation ability in both cell lines. In addition, expression of cell cycle regulator cyclin D1 and cyclin E were decreased after TRIM31 transfection. In conclusion, TRIM31 might serve as a tumor suppressor in non-small cell lung cancer.     

非小细胞肺癌组织中P-ACC及COX-2的相关性研究

  目的   探讨非小细胞肺癌组织中乙酰辅酶A羧化酶磷酸化后的产物（P-ACC）与环氧合酶-2（COX-2）的表达及其与肿瘤大小、淋巴结转移、临床分期及病理类型的关系,并研究两者的相关性。   方法   以62例非小细胞肺癌患者的肺癌组织作为研究组,20例因其他它原因行肺叶切除患者的正常肺组织作为对照组。应用免疫组织化学SP法检测肺癌组织及正常肺组织中P-ACC、COX-2的表达情况。   结果   P-ACC、COX-2在非小细胞肺癌和正常肺组织中的阳性表达差异有统计学意义（P < 0.05）。在非小细胞肺癌中,P-ACC的阳性表达与肿瘤大小显著相关（P < 0.05）,而与淋巴结转移、临床分期及病理类型无关;COX-2的阳性表达与肿瘤大小、淋巴结转移、临床分期及病理类型无关。P-ACC与COX-2的阳性表达之间呈显著负相关（r=-2.37,P=0.032）。   结论   P-ACC在非小细胞肺癌组织中的阳性表达降低;COX-2在非小细胞肺癌组织中阳性高表达,二者呈显著负相关,提示P-ACC阳性表达降低可能激活COX-2阳性表达,可促进非小细胞肺癌的发生、发展及侵袭转移。      

Characterization of microRNA transcriptome in lung cancer by next-generation deep sequencing

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. Systematically characterizing miRNAs in NSCLC will help develop biomarkers for its diagnosis and subclassification, and identify therapeutic targets for the treatment. We used next-generation deep sequencing to comprehensively characterize miRNA profiles in eight lung tumor tissues consisting of two major types of NSCLC, squamous cell carcinoma (SCC) and adenocarcinoma (AC). We used quantitative PCR (qPCR) to verify the findings in 40 pairs of stage I NSCLC tissues and the paired normal tissues, and 60 NSCLC tissues of different types and stages. We also investigated the function of identified miRNAs in lung tumorigenesis. Deep sequencing identified 896 known miRNAs and 14 novel miRNAs, of which, 24 miRNAs displayed dysregulation with fold change ≥4.5 in either stage I ACs or SCCs or both relative to normal tissues. qPCR validation showed that 14 of 24 miRNAs exhibited consistent changes with deep sequencing data. Seven miRNAs displayed distinctive expressions between SCC and AC, from which, a panel of four miRNAs (miRs-944, 205-3p, 135a-5p, and 577) was identified that cold differentiate SCC from AC with 93.3% sensitivity and 86.7% specificity. Manipulation of miR-944 expression in NSCLC cells affected cell growth, proliferation, and invasion by targeting a tumor suppressor, SOCS4. Evaluating miR-944 in 52 formalin-fixed paraffin-embedded SCC tissues revealed that miR-944 expression was associated with lymph node metastasis. This study presents the earliest use of deep sequencing for profiling miRNAs in lung tumor specimens. The identified miRNA signatures may provide biomarkers for early detection, subclassification, and predicting metastasis, and potential therapeutic targets of NSCLC.     

Overexpression and cytoplasmic accumulation of Hepl is associated with clinicopathological parameters and poor prognosis in non-small cell lung cancer

Hepl, first described in 2008, is the fourth member of the Crk-associated substrate (CAS) family and is specifically expressed in the lung. Compared to other CAS proteins, Hepl has a varying effect on cell migration in different cell types. We speculated that Hepl may play a role in lung cancer invasion and metastasis. We quantified the expression and subcellular localization of Hepl in 143 non-small cell lung cancer (NSCLC) tissues, adjacent noncancerous tissues, and eight lung cancer cell lines using Western blotting, immunohistochemistry, and immunofluorescent staining. Expression of Hepl was correlated with the clinicopathological features of NSCLC. Hepl was overexpressed in 72.3 % (103/143) of the NSCLC tissues, compared to the adjacent noncancerous lung tissues (P?=?0.022). Overexpression of Hepl was associated with lymph node metastasis and high TNM stage (P?=?0.005 and P?=?0.045, respectively). Kaplan–Meier survival curves and the log-rank test indicated that overexpression of Hepl correlated with poorer overall survival in NSCLC (P?<?0.001), and Cox regression analysis demonstrated that overexpression of Hepl was an independent prognostic factor in NSCLC. Furthermore, cytoplasmic accumulation of Hepl was observed in a high metastatic potential lung cancer cell lines (H1299 and BE1), but not in low metastatic potential cell lines (LTE and A549). This study reveals that Hepl is overexpressed in the nucleus and aberrantly accumulates in the cytoplasm of NSCLC cells, and indicates that Hepl may play a role in the progression of lung cancer, including lymph node metastasis and TNM stage. Additionally, Hepl may be a useful prognostic factor in lung cancer.     

KAI1基因在非小细胞肺癌中的表达及意义

 目的 探讨肿瘤转移抑制基因KAI1基因在非小细胞肺癌组织中的表达及其与患者临床病理指标的关系。 方法 采用RT-PCR和Western blot法,检测48例肺癌患者手术切除的新鲜肺癌组织标本和20例同期手术切除的肺部良性病变周围正常组织中KAI1 mRNA、KAI1/CD82,并结合患者的临床病理资料对其结果进行统计分析。 结果 肺癌组织和肺部良性病变组织中KAI1 mRNA的阳性率分别为52%和90%,KAI1/CD82蛋白的阳性率分别为48%和85%,肺癌组KAI1mRNA及KAI1/CD82蛋白表达均低于肺部良性病变组（P<0.01）;KAI1mRNA、KAI1/CD82表达水平与肺癌患者的临床分期、组织分化程度、淋巴结转移有关（P<0.05）,其中KAI1/CD82表达与淋巴结转移状况密切相关(P<0.01),肺癌组织中KAI1 mRNA与KAI1/CD82表达有相关性（P<0.01）。 结论 KAI1基因的低表达可能与非小细胞肺癌的发生、发展和转移有关;其下调的机制可能主要发生在转录水平;KAI1基因的表达可作为一项评估肺癌患者转移潜能的指标。     

OTUD1在非小细胞肺癌中的表达及其与临床病理特征的相关性

目的 探究OTUD1在非小细胞肺癌中的表达及其与临床病理特征的相关性.方法 选取在南阳市第二人民医院经病理确诊的70例非小细胞肺癌患者,采用免疫组织化学法检测肿瘤组织及癌旁组织中OTUD1表达情况,并分析其表达水平与临床病理特征的相关性.结果 肺癌组织的OTUD1高表达率为48.57％,显著高于正常组织的5.71％(P...     

miR-302b在非小细胞肺癌中的表达及意义

目的:探讨miR-302b在人非小细胞肺癌组织中的表达及与临床病理特征的关系。方法:采用实时荧光定量PCR（qRT-PCR）检测65例非小细胞肺癌组织和52例癌旁组织miR-302b的表达,分析其与临床病理特征之间的关系。结果:miR-302b在非小细胞肺癌组织中的表达明显低于癌旁组织（P<0.05）。与患者淋巴转移以及分化程度明显相关（P<0.05）。结论:miR-302b在非小细胞肺癌中低表达,提示其可能发挥抑癌基因的功能。     

Bmi-1 expression modulates non-small cell lung cancer progression

Previous studies indicate that the role of B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is responsible for multiple cancer progression. However, Bmi-1 in controlling gene expression in non-small cell lung cancer (NSCLC) development is not well explored. Here we report that the Bmi-1 level is highly increased in primary NSCLC tissues compared to matched adjacent non-cancerous tissues and required for lung tumor growth in xenograft model. Furthermore, we also demonstrate that Bmi-1 level is lower in matched involved lymph node cancerous tissues than the respective primary NSCLC tissues. We find that Bmi-1 does not affect cell cycle and apoptosis in lung cancer cell lines as it does not affect the expression of p16/p19, Pten, AKT and P-AKT. Mechanistic analyses note that reduction of Bmi-1 expression inversely regulates invasion and metastasis of NSCLC cells in vitro and in vivo, followed by induction of epithelial-mesenchymal transition (EMT). Using genome microarray assays, we find that RNAi-mediated silence of Bmi-1 modulates some important molecular genetics or signaling pathways, potentially associated with NSCLC development. Taken together, our findings disclose for the first time that Bmi-1 level accumulates strongly in early stage and then declines in late stage, which is potentially important for NSCLC cell invasion and metastasis during progression.     

非小细胞肺癌中TRIM29、caspase-8、β-catenin蛋白表达情况及临床意义研究

目的 探讨TRIM29、caspase-8和β-catenin在非小细胞肺癌(NSCLC)组织中的表达及其临床意义.方法 分别通过免疫组织化学法检测254例NSCLC患者肺癌组织(NSCLC组)及其癌旁正常肺组织(对照组)中TRIM29、caspase-8和β-catenin表达情况,并分析其与患者临床特征的关系.结果 NSCLC组中TRIM29的阳性表达率和β-catenin的异常表达率均明显高于对照组,caspase-8的阳性表达率明显低于对照组(P<0.01);肺鳞癌组织中TRIM29阳性表达率高于肺腺癌组织,β-catenin的异常表达率低于肺腺癌组织,而caspase-8在两种组织中的表达无明显差异;TRIM29、caspase-8阳性表达患者的平均生存时间明显低于阴性表达者,β-catenin高表达患者的平均生存时间明显低于低表达患者(P<0.01);Cox多因素分析显示,淋巴结转移、肿瘤分期、TRIM29、caspase-8和β-catenin表达水平是影响患者生存的独立预后因素.结论 TRIM29、caspase-8、β-catenin在NSCLC中均有异常表达,同时与NSCLC患者淋巴结转移、病理分类、临床分期及患者生存期有密切关系,可以作为临床中判断NSCLC患者病理分类、分期及预后的参考依据.     

Cdc42和WAVE1在非小细胞肺癌中的表达及临床病理意义

  目的  探讨Cdc42和WAVE1在非小细胞肺癌（NSCLC）中的表达及其临床意义。  方法  采用免疫组织化学法检测106例经石蜡包埋的NSCLC组织及46例癌旁正常肺组织中Cdc42和WAVE1的表达情况。  结果  Cdc42和WAVE1在NSCLC组织中的表达明显高于正常肺组织。Cdc42的表达强度与肿瘤的分化程度、TNM分期及淋巴结转移情况之间差异有统计学意义（P < 0.05）;WAVE1的表达强度与TNM分期及淋巴结转移情况之间差异有统计学意义（P < 0.05或P < 0.01）。NSCLC组织中Cdc42和WAVE1的表达呈正相关（r=0.469,P < 0.01）。Cdc42高表达组的3年生存率（44.16%）低于低表达组（72.41%）,WAVE1高表达组的3年生存率（39.44%）亦低于低表达组（77.14%）,且差异均有统计学意义（P < 0.01）。淋巴结转移、Cdc42和WAVE1共同高表达是影响NSCLC患者预后的独立因素。  结论  Cdc42和WAVE1在NSCLC组织中异常高表达,且呈现较好的相关性,可能共同参与并促进NSCLC的恶性进程,检测两者的表达会对NSCLC患者的临床病理学特征及预后起一定的提示作用。