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Since 2012, China has pursued an "ecological civilization" policy to promote green energy, increase environmental protection, and transition to more sustainable growth models. The complicated positive trends in energy consumption, more sustainable economic growth, and ecological management are obscured by China's persistent, significant dependence on fossil fuels, particularly coal. The study aims to analyze how renewable energy use in China affects carbon dioxide emissions and how those impacts change over time, as well as urbanization, industrialization, tourism, and green supply chain management. The DOLS dynamic system method used historical data from 1995 to 2022. The DOLS results show a positive and statistically significant economic growth coefficient in the long term, suggesting that an increase of only one percent in CO₂ emissions rise would be proportional to a surge in economic growth. Furthermore, using renewable energy sources correlates with long-term sustainability negatively and significantly. The results show reducing CO₂ emissions and boosting renewable energy use by 1 %. Furthermore, the long-run coefficients for industrialization and urbanization are positive and statistically significant, indicating that a 1 % increase in either component results in a comparable increase in CO₂ emissions. Sustainable logistics and tourism have negative and statistically significant coefficients, meaning that a one percent increase will gradually decrease carbon dioxide emissions. The estimated findings hold up when using other estimators, such as the commonly used co-integrating regression (CCR) strategy and fully modified least squares (FMOLS). When Granger causality is coupled, the test also catches the variables' causal link. test. To achieve environmental sustainability, the essay suggests using robust regulatory policy tools to curb ecological deterioration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background: LIN28B plays a critical role in the Warburg effect. However, its underlying mechanism remains elusive. Recently, it has been reported that LIN28B could collaborate with IGF2BP3, which can bind to m6A-modified c-MYC transcripts. Therefore, this study investigated if LIN28B recognises methylated c-MYC mRNA to promote the Warburg effect in gastric cancer., Methods: Effects of LIN28B on gastric cancer were confirmed in vitro and in vivo. On the basis of bioinformatics analysis, the association between LIN28B and c-MYC mRNA was shown using RNA immunoprecipitation (RIP) and luciferase reporter assays. The role of m6A was identified by RNA pull-down assays. We further performed RIP-seq to search for long non-coding RNAs (lncRNAs) participating in the LIN28B binding process. Chromatin immunoprecipitation was used to show the impact of c-MYC on transcription of LIN28B and lncRNAs., Results: LIN28B was identified to stabilize c-MYC mRNA by recognizing m6A. Furthermore, the interaction between c-MYC mRNA and LIN28B is speculated to be supported by LOC101929709, which binds to both LIN28B and IGF2BP3. Functional experiments revealed that LOC101929709 promotes the proliferation, migration and glycolysis of gastric cancer. Mechanistically, LOC101929709 enriched in the cytoplasm helps LIN28B stabilize c-MYC mRNA. Moreover, c-MYC promoted the transcription of both LOC101929709 and LIN28B. Additionally, LOC101929709 also activated the PI3K/AKT pathway., Conclusions: The c-MYC/LOC101929709/LIN28B axis promotes aerobic glycolysis and tumour progression. Thus, LOC101929709 can be a novel potential target for gastric cancer treatment., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

It was found in this study that long intergenic non-protein coding RNA 346 (LINC00346) was an lncRNA aberrantly expressed in gastric cancer (GC) based on multiple Gene Expression Omnibus (GEO) databases of GC cohorts. The LINC00346 gene was recurrently amplified and upregulated in GC, and its expression was positively correlated with poor pathologic stage, large tumor size, and poor prognosis. In addition, the oncogenic transcription factors KLF5 and MYC could bind to the LINC00346 promoter and enhance its expression. Gene Set Enrichment Analysis (GSEA) in the GEO datasets revealed that cell cycle and focal adhesion genes were enriched in patients with high LINC00346 expression. In vitro and in vivo assays of LINC00346 alterations revealed a complex integrated phenotype affecting cell growth, migration and invasion. Strikingly, high-throughput sequencing analysis after LINC00346 alterations highlighted alterations in cell cycle and focal adhesion pathways in GC cells. Mechanistically, argonaute 2 (Ago2) was recruited by LINC00346, which functioned as a molecular sponge for miR-34a-5p by antagonizing its ability to repress CD44, NOTCH1, and AXL protein translation. Taken together, our findings support a model in which the KLF5, MYC/LINC00346/miR-34a-5p cross-talk served as critical effectors in GC tumorigenesis and progression, suggesting a new therapeutic direction in the treatment of GC.

EphB3 is a member of the EPH family of receptors and has been found to play a role in the carcinogenesis of some human cancers. However, its expression and clinical significance in gastric cancer (GC) have not been well documented. In the present study, we detected the expression of EphB3 in GC and adjacent noncancerous tissues and explored its relationships with the clinicopathological features and prognosis of GC patients. It was found that EphB3 silenced GC cells epigenetically by direct transcriptional repression of GC cells via polycomb group protein EZH2 mediation. EphB3 was downregulated in GC cells and tissues, and EphB3 depletion promoted GC cell growth and invasion, while ectopic overexpression of EphB3 produced a significant anti-tumor effect. EphB3 was found to be involved in epithelial-mesenchymal transition by regulating E-cadherin and vimentin expression. In addition, patients with reduced EphB3 expression had shorter disease-free survival (DFS), indicating that EphB3 may prove to be a biomarker for prognosis of GC. These results demonstrated that EphB3 functioned as a tumor-suppressor and prognostic biomarker in GC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.

It is widely reported that long non‑coding RNAs (lncRNAs) are involved in regulating cell differentiation, proliferation, apoptosis and other biological processes. Certain lncRNAs have been found to be crucial in various types of tumor. Taurine‑upregulated gene 1 (TUG1) has been shown to be expressed in a tissue‑specific pattern and exert oncogenic or tumor suppressive functions in different types of cancer in humans. According to previous studies, TUG1 is predominantly located in the nucleus and may regulate gene expression at the transcriptional level. It mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Although the mechanisms of how TUG1 affects the tumor genesis process remain to be fully elucidated, increasing studies have suggested that TUG1 offers potential as a diagnostic and prognostic biomarker, and as a therapeutic target in certain types of tumor. This review aims to summarize current evidence concerning the characteristics, mechanisms and associations with cancer of TUG1.

Recent evidence indicates that E2F1 transcription factor have pivotal roles in the regulation of cellular processes, and is found to be dysregulated in a variety of cancers. Long non-coding RNAs (lncRNAs) are also reported to exert important effect on tumorigenesis. E2F1 is aberrantly expressed in gastric cancer (GC), and biology functions of E2F1 in GC are controversial. The biological characteristics of E2F1 and correlation between E2F1 and lncRNAs in GC remain to be found. In this study, integrated analysis revealed that E2F1 expression was significantly increased in GC cases and its expression was positively correlated with the poor pathologic stage, large tumor size and poor prognosis. Forced E2F1 expression promotes proliferation, whereas loss of E2F1 function decreased cell proliferation by blocking of cell cycle in GC cells. Mechanistic analyses indicated that E2F1 accelerates GC growth partly through induces TINCR transcription. TINCR could bind to STAU1 (staufen1) protein, and influence CDKN2B mRNA stability and expression, thereby affecting the proliferation of GC cells. Together, our findings suggest that E2F1/TINCR/STAU1/CDKN2B signaling axis contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.

Long noncoding RNAs (lncRNA) are a novel class of transcripts with no protein coding capacity, but with diverse functions in cancer cell proliferation, apoptosis, and metastasis. The lncRNA PVT1 is 1,716 nt in length and located in the chr8q24.21 region, which also contains the myelocytomatosis (MYC) oncogene. Previous studies demonstrated that MYC promotes PVT1 expression in primary human cancers. However, the expression pattern and potential biologic function of PVT1 in non-small cell lung cancer (NSCLC) is still unclear. Here, we found that PVT1 was upregulated in 105 human NSCLC tissues compared with normal samples. High expression of PVT1 was associated with a higher tumor-node-metastasis stage and tumor size, as well as poorer overall survival. Functional analysis revealed that knockdown of PVT1 inhibited NSCLC cell proliferation and induced apoptosis both in vitro and in vivo RNA immunoprecipitation and chromatin immunoprecipitation assays demonstrated that PVT1 recruits EZH2 to the large tumor suppressor kinase 2 (LATS2) promoter and represses LATS2 transcription. Furthermore, ectopic expression of LATS2 increased apoptosis and repressed lung adenocarcinoma cell proliferation by regulating the Mdm2-p53 pathway. Taken together, our findings indicated that PVT1/EZH2/LATS2 interactions might serve as new target for lung adenocarcinoma diagnosis and therapy. Mol Cancer Ther; 15(5); 1082-94. ©2016 AACR., (©2016 American Association for Cancer Research.)

Long noncoding RNAs (lncRNAs) play important regulatory roles in several human cancers. Integrated analysis revealed that expression of long intergenic non-coding RNA 152 (LINC00152) was significantly upregulated in gastric cancer (GC). Further analysis in a cohort of 97 GC patients revealed that LINC00152 expression was positively correlated with tumor invasion depth, lymph node metastasis, higher TNM stage, and poor survival. Gene set enrichment analysis revealed that cell proliferation and cell cycle progression were increased in patients with high LINC00152 expression. In both GC cell lines and xenograft systems, LINC00152 overexpression facilitated GC cell proliferation by accelerating the cell cycle, whereas LINC00152 knockdown had the opposite effect. Moreover, by binding to enhancer of zeste homolog 2 (EZH2), LINC00152 promotes GC tumor cell cycle progression by silencing the expression of p15 and p21. These findings suggest that LINC00152 may play contribute to the progression of GC and may be an effective therapeutic target.

Emerging evidences indicate that dysregulated long noncoding RNAs (lncRNAs) are implicated in cancer tumorigenesis and progression and might be used as diagnosis and prognosis biomarker, or potential therapeutic targets. LncRNA H19 has been reported to be upregulated in diverse human cancers; however, its clinical significance in gastric cancer (GC) remains elusive. Expression levels of H19 in 128 pairs of GC and adjacent normal tissues, GC cell lines and GC juices compared to their corresponding controls were detected by real-time quantitative polymerase chain reaction (qPCR) assay. A receiver operating characteristic (ROC) curve and Kaplan-Meier analysis were constructed to evaluate the diagnostic and prognostic values. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis. H19 expression was remarkably increased in GC tissues and cell lines compared with that in the normal control, and its up-regulation was significantly correlated to invasion depth (P < 0.001), advanced TNM stage (P = 0.002) and regional lymph nodes metastasis (P < 0.001) in GC. H19 levels were robust in differentiating GC tissues from controls [area under the curve (AUC) = 0.697; 95% confidence interval (CI) = 0.636-0.752, p<0.01]. Kaplan-Meier analysis demonstrated that increased H19 expression contributed to poor overall survival (P = 0.017) and disease-free survival (P = 0.024) of patients. A multivariate survival analysis also indicated that H19 could be an independent prognostic marker. The levels of H19 in gastric juice from gastric patients were significantly higher than those from normal subjects (P = 0.034). Furthermore, knockdown of H19 expression by siRNA could inhibit cell migration and invasion in GC cells partly via regulating E-cadherin protein expression. H19 might serve as a promising biomarker for early detection and prognosis prediction of GC.

The long noncoding RNA TINCR shows aberrant expression in human squamous carcinomas. However, its expression and function in gastric cancer remain unclear. We report that TINCR is strongly upregulated in human gastric carcinoma (GC), where it was found to contribute to oncogenesis and cancer progression. We also revealed that TINCR overexpression is induced by nuclear transcription factor SP1. Silencing TINCR expression inhibited cell proliferation, colony formation, tumorigenicity and apoptosis promotion, whereas TINCR overexpression promoted cell growth, as documented in the SGC7901 and BGC823 cell lines. Mechanistic analyses indicated that TINCR could bind to STAU1 (staufen1) protein, and influence KLF2 mRNA stability and expression, then KLF2 regulated cyclin-dependent kinase genes CDKN1A/P21 and CDKN2B/P15 transcription and expression, thereby affecting the proliferation and apoptosis of GC cells. Together, our findings suggest that TINCR contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and the biology of this cancer remains poorly understood. Recent evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in a variety of cancers, including HCC. Taurine Up-regulated Gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is found to be disregulated in non-small cell lung carcinoma (NSCLC) and esophageal squamous cell carcinoma (ESCC). However, its clinical significance and potential role in HCC remain unclear., Methods and Results: In this study, expression of TUG1 was analyzed in 77 HCC tissues and matched normal tissues by using quantitative polymerase chain reaction (qPCR). TUG1 expression was up-regulated in HCC tissues and the higher expression of TUG1 was significantly correlated with tumor size and Barcelona Clinic Liver Cancer (BCLC) stage. Moreover, silencing of TUG1 expression inhibited HCC cell proliferation, colony formation, tumorigenicity and induced apoptosis in HCC cell lines. We also found that TUG1 overexpression was induced by nuclear transcription factor SP1 and TUG1 could epigeneticly repress Kruppel-like factor 2 (KLF2) transcription in HCC cells by binding with PRC2 and recruiting it to KLF2 promoter region., Conclusion: Our results suggest that lncRNA TUG1, as a growth regulator, may serve as a new diagnostic biomarker and therapy target for HCC.

lncRNAs play important roles in the epigenetic regulation of carcinogenesis and progression. Previous studies suggest that HOTAIR contributes to gastric cancer (GC) development, and the overexpression of HOTAIR predicts a poor prognosis. In this study, we found that HOTAIR was more highly expressed in diffuse-type GC than in intestinal type (P=0.048). In the diffuse type, there is significant relationship between HOTAIR expression and DFS (P<0.001). CDH1 was downregulated in diffuse-type GC tissues (P=0.0007) and showed a negative relationship with HOTAIR (r(2)=0.154, P=0.0354). In addition, HOTAIR knockdown significantly repressed migration, invasion and metastasis both in vitro and vivo and reversed the epithelial-to-mesenchymal transition in GC cells. We also showed that HOTAIR recruiting and binding to PRC2 epigenetically represses miR34a, which controls the targets C-Met (HGF/C-Met/Snail pathway) and Snail, thus contributing to GC cell-EMT process and accelerating tumor metastasis. Moreover, it is demonstrated that HOTAIR crosstalk with microRNAs during epigenetic regulation. Our results suggest that HOTAIR acts as an EMT regulator and may be a candidate prognostic biomarker and a target for new therapies in GC patients.

SUZ12 is a core component of the polycomb repressive complex 2 (PRC2), which could silence gene transcription by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). Meanwhile, SUZ12 has been found to be overexpressed in multiple cancers; however, the clinical significance and molecular mechanisms of SUZ12 controlling gastric cancer cell proliferation and metastasis are unclear. In this study, we found that SUZ12 expression was significantly increased in 64 gastric tumor tissues compared with normal tissues. Additionally, SUZ12 expression was associated with pathological stage, metastasis distance, and shorter overall survival of gastric cancer patients. Knockdown of SUZ12 expression impaired cell proliferation and invasion in vitro, leading to the inhibition of metastasis in vivo. Upregulation of SUZ12 was found to play a key role in gastric cancer cell proliferation and metastasis through the regulation of EMT and KLF2 expression.

Background: Long noncoding RNAs (lncRNAs) have been recently shown to play important regulatory roles in fundamental biological processes, and many of them are deregulated in several human cancers. LncRNA hypoxia-inducible factor 1alpha antisense RNA-2 (HIF1A-AS2) is overexpressed in nonpapillary clear-cell renal carcinomas and involved in cancer progression., Aim: This study was to evaluate the expression of HIF1A-AS2 in gastric cancer (GC) and further explore its biological function in GC cells., Materials and Methods: Quantitative real-time polymerase chain reaction was used to detect the expression level of HIF1A-AS2 in GC tissues. The correlation of its expression with clinicopathological features was analyzed. Area under receiver operating characteristic curve (ROC(AUC)) was constructed to evaluate the diagnostic value of HIF1A-AS2. Besides, tumor cell proliferation was assessed following knockdown of HIF1A-AS2, by MTT and colony formation assay in vitro, and tumor formation assay in a nude mouse model in vivo., Results: The expression of HIF1A-AS2 was upregulated in GC tumorous tissues compared with the adjacent normal tissues (P < 0.001). Its overexpression was correlated with TNM stages (P = 0.008), tumor invasion (P = 0.016), lymph node metastasis (P = 0.042), and poor prognosis (P = 0.001). In addition, ROC(AUC) of HIF1A-AS2 was up to 0.673 (95 % CI 0.596-0.744, P < 0.001). Moreover, knockdown of HIF1A-AS2 expression by siRNA could inhibit cell proliferation in vitro and tumorigenesis in vivo., Conclusions: HIF1A-AS2 is overexpressed in GC and may play a pivotal role in tumor cell proliferation. It can be used as a potential diagnostic and prognostic biomarker for GC.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, especially in China. And the mechanism of its progression remains poorly understood. Growing evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in many cancers, including HCC. CDKN2B antisense RNA1 (ANRIL), a lncRNA, coclustered mainly with p14/ARF has been reported to be dysregulated in gastric cancer, esophageal squamous cell carcinoma, and lung cancer. However, its clinical significance and potential role in HCC is still not documented., Methods and Results: In this study, expression of ANRIL was analyzed in 77 HCC tissues and matched normal tissues by using quantitative real-time polymerase chain reaction (qRT-PCR). ANRIL expression was up-regulated in HCC tissues, and the higher expression of ANRIL was significantly correlated with tumor size and Barcelona Clinic Liver Cancer (BCLC) stage. Moreover, taking advantage of loss of function experiments in HCC cells, we found that knockdown of ANRIL expression could impair cell proliferation and invasion and induce cell apoptosis both in vitro and in vivo. We also found that ANRIL could epigenetically repress KLF2 transcription in HCC cells by binding with PRC2 and recruiting it to KLF2 promoter region. We also found that Sp1 could regulate the expression of ANRIL., Conclusion: Our results suggest that lncRNA ANRIL, as a growth regulator, may serve as a new biomarker and target for therapy in HCC.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, especially in China. And the mechanism of its progression remains poorly understood. Growing evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in many cancers, including HCC. ANRIL, a lncRNA co-clustered mainly with p14/ARF has been reported to be dysregulated in gastric cancer, esophageal squamous cell carcinoma, and lung cancer. However, its clinical significance and potential role in HCC are still not documented., Methods and Results: In this study, expression of ANRIL was analyzed in 77 HCC tissues and matched normal tissues by using quantitative polymerase chain reaction (qRT-PCR). ANRIL expression was upregulated in HCC tissues, and the higher expression of ANRIL was significantly correlated with tumor size and Barcelona Clinic Liver Cancer (BCLC) stage. Moreover, taking advantage of loss-of-function experiments in HCC cells, we found that knockdown of ANRIL expression could impair cell proliferation and invasion and induce cell apoptosis both in vitro and in vivo. We also found that ANRIL could epigenetically repress Kruppel-like factor 2 (KLF2) transcription in HCC cells by binding with PRC2 and recruiting it to the KLF2 promoter region. We also found that SP1 could regulate the expression of ANRIL., Conclusion: Our results suggest that lncRNA ANRIL, as a growth regulator, may serve as a new biomarker and target for therapy in HCC.

Background: Mounting evidence indicates that long noncoding RNAs (lncRNAs) could play a pivotal role in cancer biology. However, the overall biological role and clinical significance of PVT1 in gastric carcinogenesis remains largely unknown., Methods: Expression of PVT1 was analyzed in 80 GC tissues and cell lines by qRT-PCR. The effect of PVT1 on proliferation was evaluated by MTT and colony formation assays, and cell apoptosis was evaluated by Flow-cytometric analysis. GC cells transfected with shPVT1 were injected into nude mice to study the effect of PVT1 on tumorigenesis in vivo. RIP was performed to confirm the interaction between PVT1 and EZH2. ChIP was used to study the promoter region of related genes., Results: The higher expression of PVT1 was significantly correlated with deeper invasion depth and advanced TNM stage. Multivariate analyses revealed that PVT1 expression served as an independent predictor for overall survival (p = 0.031). Further experiments demonstrated that PVT1 knockdown significantly inhibited the proliferation both in vitro and in vivo. Importantly, we also showed that PVT1 played a key role in G1 arrest. Moreover, we further confirmed that PVT1 was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of p15 and p16. To our knowledge, this is the first report showed that the role and the mechanism of PVT1 in the progression of gastric cancer., Conclusions: Together, these results suggest that lncRNA PVT1 may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer.

Kruppel-like factor 2 (KLF2) expression is diminished in many malignancies. However, its expression and role in nonsmall-cell lung cancer (NSCLC) remain unknown. In this study, we found that KLF2 levels were decreased in NSCLC tissues compared with adjacent normal tissues. Its expression level was significantly correlated with TNM stages, tumor size, and lymph node metastasis. Moreover, patients with low levels of KLF2 expression had a relatively poor prognosis. Furthermore, knockdown of KLF2 expression by siRNA could promote cell proliferation, while ectopic expression of KLF2 inhibited cell proliferation and promoted apoptosis in NSCLC cells partly via regulating CDKN1A/p21 and CDKN2B/p15 protein expression. Our findings present that decreased KLF2 could be identified as a poor prognostic biomarker in NSCLC and regulate cell proliferation and apoptosis.

Recently, a novel class of transcripts, long noncoding RNAs (lncRNAs), is involved in diseases including cancer. Here, we investigated the the role of lncRNA PANDAR in the progression of non-small cell lung carcinoma (NSCLC). PANDAR, interacting with NF-YA, was generally downregulated in NSCLC tissues. In a cohort of 140 NSCLC patients, decreased PANDAR expression was negatively correlated with greater tumor size (P<0.001) and advanced TNM stage (P=0.002). Moreover, PANDAR could serve as an independent predictor for overall survival in NSCLC (P=0.015). Further experiments demonstrated that PANDAR expression was induced by p53, and chromatin immunoprecipitation (ChIP) assays confirmed that PANDAR was a direct transcriptional target of p53 in NSCLC cells. PANDAR overexpression significantly repressed the proliferation in vitro and in vivo. We also showed that PANDAR-mediated growth regulation is in part due to the transcriptional modulation of Bcl-2 by interacting with NF-YA, thus affecting NSCLC cell apoptosis. To our knowledge, this is the first report which showed the role of PANDAR in the progression of NSCLC. The p53/PANDAR/NF-YA/Bcl-2 interaction might serve as targets for NSCLC diagnosis and therapy.

Recent evidence highlights long noncoding RNAs (lncRNA) as crucial regulators of cancer biology that contribute to essential cancer cell functions such as cell proliferation, apoptosis, and metastasis. In non-small cell lung cancer (NSCLC), several lncRNAs' expressions are misregulated and have been nominated as critical actors in NSCLC tumorigenesis. LncRNA ANRIL was first found to be required for the PRC2 recruitment to and silencing of p15(INK4B), the expression of which is induced by the ATM-E2F1 signaling pathway. Our previous study showed that ANRIL was significantly upregulated in gastric cancer, and it could promote cell proliferation and inhibit cell apoptosis by silencing of miR99a and miR449a transcription. However, its clinical significance and potential role in NSCLC is still not documented. In this study, we reported that ANRIL expression was increased in NSCLC tissues, and its expression level was significantly correlated with tumor-node-metastasis stages and tumor size. Moreover, patients with high levels of ANRIL expression had a relatively poor prognosis. In addition, taking advantage of loss-of-function experiments in NSCLC cells, we found that knockdown of ANRIL expression could impair cell proliferation and induce cell apoptosis both in vitro and vivo. Furthermore, we uncover that ANRIL could not repress p15 expression in PC9 cells, but through silencing of KLF2 and P21 transcription. Thus, we conclusively demonstrate that lncRNA ANRIL plays a key role in NSCLC development by associating its expression with survival in patients with NSCLC, providing novel insights on the function of lncRNA-driven tumorigenesis., (©2014 American Association for Cancer Research.)

Background: FENDRR is a long non-coding RNAs (lncRNA) that binds to polycomb repressive complexe 2 (PRC2) to epigenetically regulate the expression of its target gene. The clinical role of FENDRR in carcinomas remains yet to be found., Method: Real-time polymerase chain reaction (PCR) was used to examine FENDRR expression in gastric cancer cell lines/tissues compared with normal epithelial cells/adjacent non-tumorous tissues. Cell proliferation assays, Wound healing assays, and in vitro and in vivo invasion and migration assays were performed to detect the biological effects of FENDRR in gastric cancer cells. Real-time PCR, western-blot and immunohistochemistry were used to evaluate the mRNA and protein expression of fibronectin1 (FN1). Secreted matrix metalloproteinase (MMP) activities were detected and characterized using gelatin zymography assay., Results: FENDRR was downregulated in gastric cancer cell lines and cancerous tissues, as compared with normal gastric epithelial cells and adjacent noncancerous tissue samples. Low FENDRR expression was correlated with deeper tumor invasion (p < 0.001), higher tumor stage (p = 0.001), and lymphatic metastasis (p = 0.007). Univariate and multivariate analyses indicated that low FENDRR expression predicted poor prognosis. Histone deacetylation was involved in the downregulation of FENDRR in gastric cancer cells. FENDER overexpression suppressed invasion and migration by gastric cancer cells in vitro, by downregulating FN1 and MMP2/MMP9 expression., Conclusion: Low expression of the lncRNA FENDRR occurs in gastric cancer and is associated with poor prognosis. Thus, FENDRR plays an important role in the progression and metastasis of gastric cancer.

Long non-coding RNAs (lncRNAs) have emerged as major players in governing fundamental biological processes, and many of which are misregulated in multiple cancers and likely to play a functional role in tumorigenesis. Therefore, identification of cancer-associated lncRNAs and investigation of their biological functions and molecular mechanisms are important for understanding the development and progression of cancer. lncRNA associated with microvascular invasion in HCC (lncRNA MVIH) was found to be generally upregulated in HCC. Moreover, MVIH overexpression could serve as an independent risk factor to predict poor RFS and promote tumor growth and metastasis via activating angiogenesis. However, its biological role and clinical significance in non-small cell lung cancer (NSCLC) development and progression is unknown. In this study, we found that lncRNA MVIH levels were increased in NSCLC tissues compared with adjacent normal tissues. Its expression level was significantly correlated with TNM stages, tumor size, and lymph node metastasis. Moreover, patients with high levels of MVIH expression had a relatively poor prognosis. Furthermore, knockdown of MVIH expression by siRNA could inhibit cell proliferation and invasion, while ectopic expression of MVIH promoted cell proliferation and invasion in NSCLC cells partly via regulating MMP2 and MMP9 protein expression. Our findings present that increased lncRNA MVIH could be identified as a poor prognostic biomarker in NSCLC and regulate cell proliferation and invasion.

Recent evidence indicates that long noncoding RNAs (lncRNAs) have a critical role in the regulation of cellular processes such as differentiation, proliferation, and metastasis. These lncRNAs are dysregulated in a variety of cancers and many function as tumor suppressors; however, the regulatory factors involved in silencing lncRNA transcription are poorly understood. In this study, we showed that epigenetic silencing of lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) occurs in non-small-cell lung cancer (NSCLC) cells through direct transcriptional repression mediated by the Polycomb group protein enhancer of zeste homolog 2 (EZH2). SPRY4-IT1 is derived from an intron within SPRY4, and is upregulated in melanoma cells; knockdown of its expression leads to cell growth arrest, invasion inhibition, and elevated rates of apoptosis. Upon depletion of EZH2 by RNA interference, SPRY4-IT1 expression was restored, and transfection of SPRY4-IT1 into NSCLC cells resulted in a significant antitumoral effect, both in culture and in xenografted nude mice. Moreover, overexpression of SPRY4-IT1 was found to have a key role in the epithelial-mesenchymal transition through the regulation of E-cadherin and vimentin expression. In EZH2-knockdown cells, which characteristically showed impaired cell proliferation and metastasis, the induction of SPRY4-IT1 depletion partially rescued the oncogenic phenotype, suggesting that SPRY4-IT1 repression has an important role in EZH2 oncogenesis. Of most relevance, translation of these findings into human NSCLC tissue samples demonstrated that patients with low levels of SPRY4-IT1 expression had a shorter overall survival time, suggesting that SPRY4-IT1 could be a biomarker for poor prognosis of NSCLC.

Background: Gastric cancer is the second leading cause of cancer death and remains a major clinical challenge due to poor prognosis and limited treatment options. Long noncoding RNAs (lncRNAs) have emerged recently as major players in tumor biology and may be used for cancer diagnosis, prognosis, and potential therapeutic targets. Although downregulation of lncRNA GAS5 (Growth Arrest-Specific Transcript) in several cancers has been studied, its role in gastric cancer remains unknown. Our studies were designed to investigate the expression, biological role and clinical significance of GAS5 in gastric cancer., Methods: Expression of GAS5 was analyzed in 89 gastric cancer tissues and five gastric cancer cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Over-expression and RNA interference (RNAi) approaches were used to investigate the biological functions of GAS5. The effect of GAS5 on proliferation was evaluated by MTT and colony formation assays, and cell apoptosis was evaluated by hochest stainning. Gastric cancer cells transfected with pCDNA3.1 -GAS5 were injected into nude mice to study the effect of GAS5 on tumorigenesis in vivo. Protein levels of GAS5 targets were determined by western blot analysis. Differences between groups were tested for significance using Student's t-test (two-tailed)., Results: We found that GAS5 expression was markedly downregulated in gastric cancer tissues, and associated with larger tumor size and advanced pathologic stage. Patients with low GAS5 expression level had poorer disease-free survival (DFS; P = 0.001) and overall survival (OS; P < 0.001) than those with high GAS5 expression. Further multivariable Cox regression analysis suggested that decreased GAS5 was an independent prognostic indicator for this disease (P = 0.006, HR = 0.412; 95%CI = 2.218-0.766). Moreover, ectopic expression of GAS5 was demonstrated to decrease gastric cancer cell proliferation and induce apoptosis in vitro and in vivo, while downregulation of endogenous GAS5 could promote cell proliferation. Finally, we found that GAS5 could influence gastric cancer cells proliferation, partly via regulating E2F1 and P21 expression., Conclusion: Our study presents that GAS5 is significantly downregulated in gastric cancer tissues and may represent a new marker of poor prognosis and a potential therapeutic target for gastric cancer intervention.

Long noncoding RNAs are involved in diseases including cancer. Here, we reported that ANRIL (CDKN2B-AS1), a 3.8-kb long noncoding RNA, recruiting and binding to PRC2, was generally upregulated in human gastric cancer (GC) tissues. In a cohort of 120 GC patients, the higher expression of ANRIL was significantly correlated with a higher TNM stage (P=0.041) and tumor size (P=0.001). Multivariate analyses revealed that ANRIL expression served as an independent predictor for overall survival (P=0.036). Further experiments revealed that ANRIL knockdown significantly repressed the proliferation both in vitro and in vivo. We also showed that E2F1 could induce ANRIL and ANRIL-mediated growth promotion is in part due to epigenetic repression of miR-99a/miR-449a in Trans (controlling the targets--mTOR and CDK6/E2F1 pathway) by binding to PRC2, thus forming a positive feedback loop, continuing to promote GC cell proliferation. To our knowledge, this is the first report showed that the role of ANRIL in the progression of GC and ANRIL could crosstalk with microRNAs in epigenetic level. Our results suggest that ANRIL, as a growth regulator, may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer.

Background: Recent evidence indicates that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cellular processes, such as differentiation, proliferation and metastasis. These lncRNAs are found to be dysregulated in a variety of cancers. BRAF activated non-coding RNA (BANCR) is a 693-bp transcript on chromosome 9 with a potential functional role in melanoma cell migration. The clinical significance of BANCR, and its' molecular mechanisms controlling cancer cell migration and metastasis are unclear., Methods: Expression of BANCR was analyzed in 113 non-small cell lung cancer (NSCLC) tissues and seven NSCLC cell lines using quantitative polymerase chain reaction (qPCR) assays. Gain and loss of function approaches were used to investigate the biological role of BANCR in NSCLC cells. The effects of BANCR on cell viability were evaluated by MTT and colony formation assays. Apoptosis was evaluated by Hoechst staining and flow cytometry. Nude mice were used to examine the effects of BANCR on tumor cell metastasis in vivo. Protein levels of BANCR targets were determined by western blotting and fluorescent immunohistochemistry., Results: BANCR expression was significantly decreased in 113 NSCLC tumor tissues compared with normal tissues. Additionally, reduced BANCR expression was associated with larger tumor size, advanced pathological stage, metastasis distance, and shorter overall survival of NSCLC patients. Reduced BANCR expression was found to be an independent prognostic factor for NSCLC. Histone deacetylation was involved in the downregulation of BANCR in NSCLC cells. Ectopic expression of BANCR impaired cell viability and invasion, leading to the inhibition of metastasis in vitro and in vivo. However, knockdown of BANCR expression promoted cell migration and invasion in vitro. Overexpression of BANCR was found to play a key role in epithelial-mesenchymal transition (EMT) through the regulation of E-cadherin, N-cadherin and Vimentin expression., Conclusion: We determined that BANCR actively functions as a regulator of EMT during NSCLC metastasis, suggesting that BANCR could be a biomarker for poor prognosis of NSCLC.

Lung cancer is the most frequent cancer in China and all over the world. Recent studies have shown that long noncoding RNAs play critical roles in multiple biological processes including oncogenesis. In this study, we reported a new lncRNA GAS6-AS1 (GAS6 antisense RNA 1), whose expression was downregulated in tumor tissues in 50 patients with non-small cell lung cancer (NSCLC) compared with those in the adjacent normal tissues (P < 0.001). Furthermore, decreased GAS6-AS1 expression was negatively correlated with lymph node metastasis (P = 0.032) and advanced tumor node metastasis stage (P = 0.003). Univariate and multivariate analyses showed that GAS6-AS1 expression served as an independent predictor for overall survival (P = 0.036). Also, GAS6-AS1 level was inversely correlated with GAS6 (growth-arrest-specific gene6) mRNA level (Pearson's correlation -0.620). In conclusion, our study demonstrated that altered lncRNA GAS6-AS1 expression might be involved in the development and progression of NSCLC by influencing its host gene and promised to be a potential diagnostic target in patients with NSCLC.

Background: C-X-C chemokine receptor type 4 (CXCR4) has been implicated in the invasiveness and metastasis of diverse cancers. However, the published data remain controversial on the correlation between CXCR4 expression level, as well as its subcellular distribution in tumor cells, and the clinical outcome of patients with breast cancer., Methods: To identify the precise role of CXCR4 in the clinical outcome of breast cancer, we performed a meta-analysis including 15 published studies. Original data included the hazard ratios (HRs) of overall survival (OS) and disease-free survival (DFS) in breast cancer with high CXCR4 expression versus low expression. We pooled hazard ratios (HRs) with 95% confidence intervals (CIs) to estimate the hazard., Results: A total of 15 published studies (including 3104 patients) were eligible. Overall survival (OS) and disease-free survival (DFS) of breast cancer were found to be significantly related to CXCR4 expression level, with the HR being 1.65 (95%CI: 1.34-2.03; P<0.00001) and 1.94 (95%CI: 1.42-2.65; P<0.00001) respectively. Stratified analysis according to subcellular distribution of CXCR4 showed that high expression in whole cells, cytoplasm and nucleus could predict unfavorable OS, with the HR of 2.02 (95%CI: 1.43-2.85; P<0.0001), 1.57 (95%CI: 1.13-2.18; P=0.007), and 1.47 (95%CI: 1.19-1.81; P=0.0004) respectively. As for DFS, elevated expression level of CXCR4 both in whole cells and cytoplasm predicted a poor outcome, with the HR being 2.23 (95%CI: 1.48-3.37; P=0.0001) and 1.76 (95%CI: 1.11-2.80; P=0.02), while high expression in the nucleus had no statistical significance, with HR 1.15 (95%CI: 0.52-2.55; P=0.73)., Conclusions: Increased CXCR4 expression, especially in whole cells and cytoplasm, may serve as a poor prognostic indicator in patients with breast cancer. Future studies are warranted to investigate the relationship between CXCR4 expression and survival of patients with breast carcinoma, which could help predict the clinical outcome and guide clinical decision-making for therapy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The published data on the predictive role of ERCC1 polymorphisms in lung cancer risk and survival of patients with advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy remains inconsistent. The aim of this meta-analysis was to determine the role of ERCC1 gene polymorphisms (C118T and C8092A) in this clinical situation. Eligible studies were included and assessed for quality using multiple search strategies. Thirty-nine published papers involving 9615 cases (4606 with Stage III/IV disease) and 5542 controls were included in the analysis. Pooled odds ratios (OR) or hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate risk. ERCC1-C118T was associated with lung cancer risk. The OR was 0.90 (95% CI: 0.81-0.99, p=0.043) in an additive genetic model (C allele vs. T allele) and 0.77 (95% CI: 0.63-0.95, p=0.013) in a recessive genetic model (CC/CT vs. TT). The corresponding risk was 0.74 (95% CI: 0.58-0.94, p=0.013) based on a homozygous comparison (CC vs. TT). No significant correlation was found for ERCC1 C8092A and there was no obvious relationship between ERCC1 C118T/C8092A polymorphisms and objective response to platinum-based chemotherapy. Overall survival (OS) of patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy was significantly related to ERCC1 C118T (HR: 1.29, 95% CI: 1.07-1.56, p=0.007, CT/TT vs. CC). There was no relationship between ERCC1 C8092A and survival (HR: 1.32, 95% CI: 0.84-2.10, p=0.23, CA/AA vs. CC). These findings suggest that ERCC1 C118T polymorphisms may serve as a biomarker for lung cancer risk and have prognostic value in patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based treatment. Further studies with larger numbers of subjects from a worldwide arena are needed to validate the associations., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To detect effects of plumbagin on proliferation and apoptosis in non-small cell lung cancer cell lines, and investigate the underlying mechanisms., Materials and Methods: Human non-small cell lung cancer cell lines A549, H292 and H460 were treated with various concentrations of plumbagin. Cell proliferation rates was determined using both cell counting kit-8 (CCK-8) and clonogenic assays. Apoptosis was detected by annexin V/propidium iodide double-labeled flow cytometry and TUNEL assay. The levels of reactive oxygen species (ROS) were detected by flow cytometry. Activity of NF-κB was examined by electrophoretic mobility shift assay (EMSA) and luciferase reporter assay. Western blotting was used to assess the expression of both NF-κB regulated apoptotic-related gene and activation of p65 and IκBκ., Results: Plumbagin dose-dependently inhibited proliferation of the lung cancer cells. The IC50 values of plumbagin in A549, H292, and H460 cells were 10.3 μmol/L, 7.3 μmol/L, and 6.1 μmol/L for 12 hours, respectively. The compound concentration-dependently induced apoptosis of the three cell lines. Treatment with plumbagin increased the intracellular level of ROS, and inhibited the activation of NK-κB. In addition to inhibition of NF-κB/p65 nuclear translocation, the compound also suppressed the degradation of IκBκ. ROS scavenger NAC highly reversed the effect of plumbagin on apoptosis and inactivation of NK-κB in H460 cell line. Treatment with plumbagin also increased the activity of caspase-9 and caspase-3, downregulated the expression of Bcl-2, upregulated the expression of Bax, Bak, and CytC., Conclusions: Plumbagin inhibits cell growth and induces apoptosis in human lung cancer cells through an NF-κB-regulated mitochondrial-mediated pathway, involving activation of ROS.

Objective: Published data have shown that microRNAs (miRNAs) could play a potential role as diagnostic and prognostic indicators in cancers. Data for the predictive value of microRNA-155 are inconclusive. The aim of the present analysis was therefore to evaluate the role of miR-155 in prognosis for patients with a variety of carcinomas., Methods: Relevant studies were identified by searching PubMed and EMBASE. Data were extracted from studies comparing overall survival (OS), recurrence-free survival (RFS) or cancer-specific survival (CSS) in patients with carcinoma with higher miR-155 expression and those with lower levels. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) of miR-155 for clinical outcome were calculated., Results: A total of 15 studies were included. The pooled hazard ratio (HR) for OS of higher miR-155 expression in cancerous tissue was 1.89 (95% CI: 1.20-2.99, P =0.006), which could markedly predict poorer survival in general cancer. For RFS/CSS, elevated miR-155 was also associated with poor prognosis of cancer (HR= 1.50, 95% CI: 1.10-2.05, P = 0.01). On subgroup analysis, the pooled HR for OS in non-small cell lung cancer (NSCLC) was 2.09 (95% CI: 0.68-6.41, P > 0.05), but for RFS/CSS was 1.28 (95% CI: 1.05-1.55, P = 0.015), with statistical significance; the pooled HRs for OS and RFS/CSS in digestive system neoplasms were 3.04 (95% CI: 1.48-6.24, P =0.003) and 2.61 (95% CI: 1.98-3.42, P<0.05), respectively., Conclusions: The results indicated that the miR-155 expression level plays a prognostic role in patients with cancer, especially NSCLCs and digestive system carcinomas.