Qingqing Zhu

The growth arrest-specific transcript 5 (GAS5): a pivotal tumor suppressor long noncoding RNA in human cancers

Long noncoding RNAs (lncRNAs), which refer to a group of RNAs with length more than 200 nucleotides and limited protein-coding potential, play a widespread role in regulating biological processes, such as cell differentiation, proliferation, apoptosis, and migration. LncRNAs are dysregulated in multiple cancers, playing an either oncogenic or tumor-suppressive role. LncRNA GAS5 is a recently identified tumor suppressor involved in several cancers, like breast cancer, prostate cancer, lung cancer, and colorectal cancer. The low-expression pattern confers tumor cells elevated capacity of proliferation and predicts poorer prognosis. Existing studies mirror that lncRNA GAS5 promises to be a novel diagnostic biomarker, therapy target, as well as prognostic biomarker. In this review, we will summarize the current knowledge about this vital lncRNA, from its discovery, characteristics, and biological function to molecular mechanism in various neoplasms.

The role of TWIST1 in epithelial-mesenchymal transition and cancers

TWIST1 is a basic helix-loop-helix (bHLH) transcription factor which plays essential and pivotal roles in multiple stages of embryonic development, and significantly contributes to tumor metastasis, even tumor initiation and primary tumor growth. It is well recognized that TWIST1 is overexpressed in a variety of tumors. Overexpression of TWIST1 induces epithelial-mesenchymal transition (EMT), a key process in the metastases formation of cancer. TWIST1 also promotes the formation of cancer stem cells and facilitates the process of tumorigenesis. Numerous studies have shown that targeting TWIST1 or TWIST1-related molecules significantly inhibits tumor growth, restricts tumor metastasis, reverses drug resistance, and thus improves the survival of cancer patients. Therefore, it is important to provide a better understanding of the context-dependent regulation of TWIST1 in each individual epithelial tumor, which might reveal new therapeutic targets in cancer treatment.

Circulating long noncoding RNA GAS5 is a novel biomarker for the diagnosis of nonsmall cell lung cancer.

Abstract The recently discovered long noncoding RNAs have the potential to regulate many biological processes, which are aberrantly expressed in many tumor types. Our previous study showed that the long noncoding RNA-growth arrest-specific transcript 5 (GAS5) was decreased in lung cancer tissue, which contributed to the proliferation and apoptosis of nonsmall cell lung cancer (NSCLC). GAS5 was also associated with the prognosis of lung cancer patients. These results suggest that GAS5 may represent a novel prognostic indicator and a target for gene therapy in NSCLC. However, the expression and diagnosis significance of GAS5 in the plasma of NSCLC patients was unknown. The plasma samples were more readily available than the tissue samples in clinical, so we designed the study to investigate the diagnosis value of GAS5 in blood samples. In our study, 90 patients with NSCLC and 33 healthy controls were included. Blood samples were collected before surgery and therapy. We extracted the free RNA in the plasma and analyzed the expression of GAS5 with quantitative reverse transcription PCR. Suitable statistics methods were used to compare the plasma GAS5 levels of preoperative and postoperative plasma samples between the NSCLC patients and healthy controls. Receiver-operating characteristic curve analysis was used to evaluate the diagnostic sensitivity and specificity of plasma GAS5 in NSCLC. The results showed that GAS5 was detectable and stable in the plasma of NSCLC patients. Furthermore, the plasma levels of GAS5 were significantly down-regulated in NSCLC patients compared with healthy controls (P = 0.000). Moreover, GAS5 levels increased markedly on the seventh day after surgery compared with preoperative GAS5 levels in NSCLC patients (P = 0.003). GAS5 expression levels could be used to distinguish NSCLC patients from control patients with an area under the curve of 0.832 (P < 0.0001; sensitivity, 82.2%; specificity, 72.7%). The combination of the GAS5 and carcinoembryonic antigen could produce an area of 0.909 under the receiver-operating characteristic curve in distinguishing NSCLC patients from control subjects (95% confidence interval 0.857–0.962, P = 0.000). We have demonstrated that GAS5 expression was decreased in NSCLC Plasma. Plasma samples were more accessible than tissue samples in clinical; therefore, GAS5 could be an ideal biomarker for the diagnosis of NSCLC.

Upregulation of long intergenic noncoding RNA 00673 promotes tumor proliferation via LSD1 interaction and repression of NCALD in non-small-cell lung cancer

Despite improvements in diagnostics and treatment of non-small cell lung cancer (NSCLC), it remains the leading causes of cancer-related mortality worldwide. In more recent years, mutiple lines of evidence have highlighted long noncoding RNAs (lncRNAs) serve as novel class of regulators of cancer biological processes, including proliferation, apoptosis and metastasis. LncRNAs serve as a novel class of regulators of cancer biological processes in cancer, but little is known of their expression and potential functions in NSCLC. We identified an oncogene, linc00673, whose expression level was upregulated by bioinformatics analyses and qRT-PCR analyses in NSCLC. The effects of linc00673 on tumor progression were investigated in vitro and in vivo. Linc00673 knockdown significantly inhibited cell proliferation and colony-forming ability, and suppressed S-phase entry in vitro and shRNA linc00673 mediated knockdown significantly inhibit tumor growth in vivo, meanwhile, linc00673 overexpression increased tumor cell growth. Analysis of RNAseq data revealed linc00673 could modulate the transcription of a large amount of genes including oncogene and tumor suppressor gene, so we investigated the role and regulatory mechanism of linc00673 in NSCLC proliferation. Further mechanistic analyses indicated that the oncogenic activity of linc00673 is partially attributable to its repression of NCALD through association with the epigenetic repressor LSD1. Taken together, these findings suggested that linc00673 could play crucial role in NSCLC progression and might be a potential therapeutic target for patients with NSCLC.

Clinicopathologic characteristics of patients with ROS1 fusion gene in non-small cell lung cancer: a meta-analysis

BACKGROUND The receptor tyrosine kinase ROS1 is a driver gene in the non-small cell lung cancer (NSCLC) with promising target treatment potential. The clinical features of NSCLC patients harboring ROS1 fusion gene were not fully understood due to small-to-modest sample sizes of these association studies. METHODS We systematically searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from their inception to March 31, 2015. We analyzed the association between ROS1 fusion genes and four common clinical variables, i.e., gender, smoking status, pathological type and clinical stage. RESULTS Eighteen studies consisting of 9,898 NSCLC patients were included in this meta-analysis. Pooled results showed that significantly higher rate of ROS1 fusion gene was detected in female NSCLC patients (OR =1.54, 95% CI: 1.02-2.34, P=0.042), patients without a smoking history (OR =3.27, 95% CI: 1.44-7.45, P=0.005), patients with adenocarcinomas NSCLC (OR =10.24, 95% CI: 5.13-20.40, P<0.001), and patients with an advanced clinical stages III-IV (OR =2.57, 95% CI: 1.78-3.71, P<0.001). The pooled prevalence of ROS1 fusion gene was 2.4% (95% CI: 1.8-3.1%) in adenocarcinoma and a significantly lower (0.2%) in non-adenocarcinoma tumors. CONCLUSIONS ROS1 rearrangement was more prevalent in female patients, patients without a smoking history, patients with adenocarcinoma, and patients on more advanced stages (stages III to IV).

Long non‐coding RNA 00312 regulated by HOXA5 inhibits tumour proliferation and promotes apoptosis in Non‐small cell lung cancer

Non‐small cell lung cancer (NSCLC) is the most prevalent type of lung cancer. The abnormal expression of many long non‐coding RNAs (lncRNAs) has been reported involved in the progression of various tumours, which can be used as diagnostic indicators or antitumour targets. Here, we found that the long non‐coding RNA 00312 was down‐regulated in paired NSCLC tissues and correlated with poor clinical outcome; decreased linc00312 expression in NSCLC was associated with larger and later stage tumours. Functional experiments showed that linc00312 could inhibit cell proliferation and promote apoptosis in vitro and in vivo. Furthermore, we found that HOXA5 could bind in the promoter of linc00312 and up‐regulated the expression of it. Moreover, linc00312 was down‐regulated in the plasma of NSCLC patients compared with that of healthy volunteers or other pulmonary diseases patients. Taken together, our findings indicated that linc00312 could be a novel diagnosis biomarker and a promising therapeutic target for NSCLC.

PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/β-catenin signaling pathway

BackgroundProtein regulator of cytokinesis-1 (PRC1) belongs to the microtubule-associated proteins (MAPs) family, and is involved in cytokinesis. Recent investigations suggest PRC1 involvement in human carcinogenesis, including breast carcinoma, hepatocellular carcinoma and etc. However, whether PRC1 contributes to lung adenocarcinoma tumorigenesis remains unknown.MethodsQuantitative reverse-transcription polymerase chain reaction (qRT-PCR), Western blotting and Immunohistochemical staining (IHC) were used to evaluate and contrast the PRC1 expression profile in lung adenocarcinoma and adjacent normal lung tissues. We examined the clinical use of PRC1 in lung adenocarcinoma prognosis. Additionally, the tumorigenesis impact of PRC1 in lung adenocarcinoma cells was verified via in vitro and in vivo metastasis and tumorigenesis assays. Notably, Next Generation Sequencing (NGS) was performed to investigate the molecular mechanism underlying the oncogenic role of PRC1 in lung adenocarcinoma.ResultsPRC1 mRNA and protein expressions were upregulated in lung adenocarcinoma tissues compared to adjacent normal lung tissues. PRC1 protein overexpression correlated with lymph node metastasis and was an independent poor prognostic factor for lung adenocarcinoma patients. Our data implied that PRC1 depletion limited the proliferation and invasion of lung adenocarcinoma cells in vitro and lowered tumor development and lung metastasis in vivo. Remarkably, limiting PRC1 substantially prompted G2/M phase cell cycle arrest and apoptosis. Mechanistically, by conducting NGS on PRC1-depleted A549 cells and control cells, we discovered that PRC1 expression was significantly correlated with the Wnt signaling pathway.ConclusionsThis investigation offers confirmation that PRC1 is a prognostic and promising therapeutic biomarker for people with lung adenocarcinoma and takes on a key part in the activation of the Wnt/β-catenin pathway in lung adenocarcinoma development.

Long intergenic noncoding RNA 00673 promotes non-small-cell lung cancer metastasis by binding with EZH2 and causing epigenetic silencing of HOXA5

Metastasis of cancer cells is a key impediment to favorable outcomes of cancer treatment. Functional roles of long noncoding RNAs in several biological processes, including metastasis, have recently been discovered. In our previous work, we reported a positive correlation of increased expression of linc00673 in NSCLC tissues with tumor size, lymph node metastasis, TNM stage, and increased proliferation of NSCLC cells, both, in vitro and in vivo. In this study, we demonstrate that ectopic expression of linc00673 promotes migration and invasion of NSCLC cells. Furthermore, our results indicate that linc00673 could silence HOXA5 expression by recruiting epigenetic repressor, EZH2, at its promoter regions. HOXA5 was identified as a tumor suppressor gene, which inhibited NSCLC cell metastasis by regulating cytoskeletal remodeling. To summarize, we for the first time identified the role of lin00673 in promoting invasion and migration of NSCLC cells. Insights from this study may help to identify novel therapeutic targets for NSCLC.

NCAPG2 promotes tumour proliferation by regulating G2/M phase and associates with poor prognosis in lung adenocarcinoma.

NCAPG2 is a component of the condensin II complex and contributes to chromosome segregation via microtubule–kinetochore attachment during mitosis. It is well known that NCAPG2 plays a critical role in cell mitosis; however, the role of altered NCAPG2 expression and its transcriptional regulatory function in cancer development remains mostly unknown. Here, for the first time we reported that NCAPG2 was evidently increased in non‐small cell lung cancer tissues compared to adjacent normal lung tissues. Clinicopathological data analysis showed that NCAPG2 overexpression was significantly correlated with lymph node metastasis and pathologic‐Tumour Nodes Metastasen stages, and was an independent prognostic factor in lung adenocarcinoma patients. Moreover, siRNA‐mediated knockdown of NCAPG2 could inhibit tumour cell growth of lung adenocarcinoma cells (A549 and H1299) in vitro and could significantly lead to cell cycle arrest in the G2 phase. Furthermore, we found that NCAPG2 silencing significantly decreased the expression levels of G2/M phase cell cycle‐related protein expressions (Cyclin B1, Cdc2) and increased the expression levels of p27 and p21 through Western blot analysis. Taken together, we demonstrated that increased NCAPG2 expression could regulate cell proliferation and identified as a poor prognostic biomarker in lung adenocarcinoma.

Prognostic value of the expression of estrogen receptor β in patients with non-small cell lung cancer: a meta-analysis

BACKGROUND Lung cancer remains the leading cause of cancer-related deaths in men and the second leading cause in women worldwide. It is becoming increasingly clear that estrogen and estrogen receptors are involved in the pathogenesis and development of lung cancer. However, observational studies on the prognostic role of estrogen receptor β (ERβ) in non-small cell lung cancer (NSCLC) are controversial. METHODS To clarify the impact of ERβ in NSCLC survival, we performed this meta-analysis that included eligible studies. The combined hazard ratios (HR) and their corresponding 95% confidence intervals (CIs) were calculated in terms of overall survival. RESULTS A total of eleven studies with 3,300 patients were evaluable for this meta-analysis. Our results suggested that ERβ overexpression had no relationship on survival of patients with NSCLC, the HR (95% CI) was 1.000 (0.954-1.047) overall. Moreover, there was no heterogeneity between the studies. CONCLUSIONS ERβ overexpression indicates no relationship of prognosis for patients with NSCLC.