Biyun Qian

Up-regulation of microRNA-183-3p is a potent prognostic marker for lung adenocarcinoma of female non-smokers

BackgroundLung cancer in never smokers presents predominately as adenocarcinoma and in females. MicroRNA-183 (miR-183) has various expression patterns in types of human cancers. In the present study, we evaluated the expression of miR-183-3p in female lung adenocarcinoma and adjacent noncancerous tissues and explored its relationship with clinicopathological characteristics and prognosis.MethodsIn the present study, a hundred female nonsmoking patients who were newly diagnosed and histologically confirmed as lung adenocarcinoma at Tianjin Medical University Cancer Hospital were included. miR-183-3p expression of surgically removed NSCLC tissues and their corresponding normal lung tissues was measured by qRT-PCR assay. Associations of miR-183-3p expression with clinicopathological features were determined using the Student’s t test. Log-rank test, and Cox proportional hazards model were used for survival analysis.ResultsAt first, miR-183-3p was up-regulated in lung cancer tissues when compared with the corresponding noncancerous lung tissues. Moreover, the expression of miR-183-3p in tumor tissue was found to be associated with lymph node metastasis (Pxa0=xa00.043), clinical stage (Pxa0=xa00.015), and EGFR mutation (Pxa0=xa00.003). At last, high miR-183-3p expression was also associated with both poor overall survival and progression-free survival of women with lung adenocarcinoma (Pxa0=xa00.005 and Pxa0=xa00.010, respectively).ConclusionThis study suggested that miR-183-3p expression might be involved in lung cancer pathogenesis and progression, and could be used as a potential prognostic biomarker of female lung adenocarcinoma.

PM2.5 exposure-induced autophagy is mediated by lncRNA loc146880 which also promotes the migration and invasion of lung cancer cells

BACKGROUNDnEvidence shows that individuals who are under long-term exposure to environmental PM2.5 are at increased risk of lung cancer. Various laboratory experiments also suggest several mechanistic links between PM2.5 exposure and lung carcinogenesis. However, a long non-coding RNA (lncRNA) mediated pathogenic change after PM2.5 exposure and its potential roles in tumorigenesis and disease progression have not been reported.nnnMETHODSnCytotoxicity induced by PM2.5 was assessed by using scanning electron microscopy and transmission electron microscopy. ROS generation, autophagy, and metastasis induced by PM2.5 were detected by using comprehensive approaches. Expression of lncRNA-loc146880 and lc3b (autophagy marker) in A549 cells, lung tissue and serum were determined by RT-PCR and Western blotting.nnnRESULTSnPM2.5 could be internalized into lung cancer cells, resulting in marked increases in ROS levels and autophagy. ROS may be responsible for increased expression of loc146880 which further up-regulates autophagy. Both loc146880 and autophagy could promote lung tumor cell migration, invasion and EMT. In addition, a positive correlation was observed between loc146880 expression and lc3b levels in tumor tissues and serum of lung cancer patients.nnnCONCLUSIONnTaken together, our data suggest that PM2.5 exposure induces ROS, which activates loc146880 expression. The lncRNA, in turn, up-regulates autophagy and promotes the malignant behaviors of lung cancer cells.nnnGENERAL SIGNIFICANCEnThe results show the toxicological effects of PM2.5 in lung tumor progression and metastasis.

miRNAs in cancer prevention and treatment and as molecular targets for natural product anticancer agents.

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that regulate gene expression by binding to the 3´untranslated region of target mRNA, resulting in posttranscriptional gene silencing via mRNA degradation or translation inhibition. miRNAs are involved in many biological processes including carcinogenesis. They can act as oncogenes or tumor suppressors and their aberrant expressions are intimately linked with cancer development and progression. Therefore, miRNAs have been utilized as potential biomarkers for cancer diagnosis, prognosis, as well as cancer therapeutic targets. Recently, it has been demonstrated that dietary and natural chemopreventive agents exert their anticancer activities through the regulation of one or more miRNAs. In addition to expounding the latest findings of miRNAs in cancer, this review also discusses the recent efforts on the translational research of miRNAs, with an emphasis on natural products in the treatment of cancer.

RYBP predicts survival of patients with non-small cell lung cancer and regulates tumor cell growth and the response to chemotherapy.

Ring1 and YY1 binding protein (RYBP) is a member of the Polycomb group (PcG) proteins and regulates cell growth through both PcG-dependent and -independent mechanisms. Our initial study indicated that RYBP is down-regulated in human non-small cell lung cancer (NSCLC) tissues. The present study determined the molecular role of RYBP in the development of NSCLC. We systemically investigated the association between the RYBP expression and the survival of patients with NSCLC. We also carried out in vitro and in vivo studies to explore the molecular basis for the tumor suppressor role of RYBP in NSCLC. Our clinical results demonstrated that the RYBP mRNA and protein expressions were significantly down-regulated in NSCLC and significantly linked to the poor prognosis in NSCLC patients. The enforced expression of RYBP inhibited cell survival, induced apoptosis, and increased chemosensitivity in NSCLC cells; knockdown of RYBP showed the opposite effects. Moreover, adenoviral delivery of RYBP sensitized the NSCLC cells to chemotherapy in vivo. In addition, RYBP expression was induced by paclitaxel, the first-line chemotherapeutic agent for NSCLC. Our results reveal that RYBP inhibits the aggressiveness of NSCLC cells and downregulation of RYBP is associated with poor prognosis, suggesting that RYBP could be developed as a biomarker and a novel target for therapy in patients with lung cancer.

Analysis of microarray data on gene expression and methylation to identify long non-coding RNAs in non-small cell lung cancer

To identify what long non-coding RNAs (lncRNAs) are involved in non-small cell lung cancer (NSCLC), we analyzed microarray data on gene expression and methylation. Gene expression chip and HumanMethylation450BeadChip were used to interrogate genome-wide expression and methylation in tumor samples. Differential expression and methylation were analyzed through comparing tumors with adjacent non-tumor tissues. LncRNAs expressed differentially and correlated with coding genes and DNA methylation were validated in additional tumor samples using RT-qPCR and pyrosequencing. In vitro experiments were performed to evaluate lncRNA’s effects on tumor cells. We identified 8,500 lncRNAs expressed differentially between tumor and non-tumor tissues, of which 1,504 were correlated with mRNA expression. Two of the lncRNAs, LOC146880 and ENST00000439577, were positively correlated with expression of two cancer-related genes, KPNA2 and RCC2, respectively. High expression of LOC146880 and ENST00000439577 were also associated with poor survival. Analysis of lncRNA expression in relation to DNA methylation showed that LOC146880 expression was down-regulated by DNA methylation in its promoter. Lowering the expression of LOC146880 or ENST00000439577 in tumor cells could inhibit cell proliferation, invasion and migration. Analysis of microarray data on gene expression and methylation allows us to identify two lncRNAs, LOC146880 and ENST00000439577, which may promote the progression of NSCLC.

Genome-wide analysis of DNA methylation and their associations with long noncoding RNA/mRNA expression in non-small-cell lung cancer

AIMnThe goal of this study is to identify differentially methylated (DM) loci associated with long noncoding RNA (lncRNA)/mRNA expression in non-small-cell lung cancer (NSCLC).nnnMATERIALS & METHODSnMicroarrays were used to interrogate genome-wide methylation and expression of lncRNA/mRNA in NSCLC.nnnRESULTSnWe identified 113,644 DM loci between tumors and adjacent tissues. Among them, 26,310 DM loci were associated with 1685 differentially expressed genes, and 839 genes had significant correlations between methylation and expression, of which 26 hypermethylated loci in transcription start site 200 were correlated with low gene expression. We validated the correlations between methylation and expression in five genes (CDO1, C2orf40, SCARF1, ZFP106 and IFFO1) using pyrosequencing and quantitative polymerase chain reaction. We also found significant correlations between lncRNAs and mRNAs, and validated four of the correlations with quantitative polymerase chain reaction.nnnCONCLUSIONnIntegrated analysis of genome-wide DNA methylation and lncRNA/mRNA expression allows us to identify new DM loci-correlated with gene expression in NSCLC.

Promoter methylation of Wnt/β-Catenin signal inhibitor TMEM88 is associated with unfavorable prognosis of nonsmall cell lung cancer

Acute myeloid leukemia (AML) is a clonal disorder characterized by the accumulation of complex genomic alterations that define the disease pathophysiology and overall outcome. Recent advances in sequencing technologies have described the molecular landscape of AML and identified several somatic alterations that impact overall survival. Despite all these advancement, several challenges remain in translating this information into effective therapy. Herein we will review the molecular landscape of AML and discuss the impact of the most common somatic mutations on disease biology and outcome.

Suberoyl bis-hydroxamic acid activates Notch1 signaling and induces apoptosis in anaplastic thyroid carcinoma through p53

Anaplastic thyroid cancer (ATC), usually derived from well-differentiated thyroid cancers is one of the most lethal human endocrine malignancies. In the present study, we report that in human ATC tumor tissue samples exist undetectable Notch1 and the active Notch1 intracellular domain could not be detected in ATC-CAL-62 cells. Interesting, suberoyl bis-hydroxamic acid (SBHA) administration could induce Notch1 intracellular domain levels in a dose-dependent manner, coupled with the increase of p53 and p21. Furthermore, ectopic expression of Notch1 or deletion of p53 with small-interfering RNA was able to abolish the effects of SBHA to elevation of Notch1 and p53 in ATC cells. As a result, SBHA treatment efficiently induced ATC cell apoptosis. These results indicate that SBHA may play antitumor functions via regulating Notch1/p53 signals, and highlight that SBHA could have clinical potential to benefit the therapy of ATC patients.

Low expression of LINC00982 and PRDM16 is associated with altered gene expression, damaged pathways and poor survival in lung adenocarcinoma

Recently, long non‑coding RNAs (lncRNAs) have been shown to play critical roles in lung adenocarcinoma (LUAD). The present study aimed to explore the effect of LINC00982 and PRDM16 on clinical features and survival in LUAD. We found that LUAD patients demonstrated lower expression and copy number variation but higher methylation of long intergenic non‑protein coding RNA 982 (LINC00982) and PR domain containingxa016 (PRDM16) compared with controls. Thus, we divided the LUAD patients into two groups according to the median expression of LINC00982 and PRDM16. Through differential expression, KEGG pathway enrichment and Ingenuity® Pathway Analysis (IPA), we found that patients with low expression of both LINC00982 and PRDM16 presented with more deregulated genes, as well as more significant pathways, than patients with high expression of these two genes. In addition, Kaplan‑Meier curves and Cox proportional hazards models revealed that patients with low expression of LINC00982, PRDM16 or both, showed poorer survival than the groups with high expression of LINC00982, PRDM16. We further used multivariate survival models to verify these results. Furthermore, we confirmed that the expression of LINC00982 and PRDM16 was significantly decreased in LUAD cell lines compared to normal cell lines inxa0vitro. In conclusion, the present study revealed that LINC00982 and PRDM16 may serve as biomarkers or potential drug targets for the diagnosis and therapy of LUAD.

Abstract C93: RYBP predicts survival of patients with non-small cell lung cancer and sensitizes chemotherapy

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and associates with a poor prognosis. Despite several targeted therapies have been developed with promising results, the therapeutic options for NSCLC are limited and the 5-year survival rate remains poor (∼15%). Therefore, there is an urgent need for a better understanding of its pathogenesis and exploring novel therapeutic targets. Ring1 and YY1 binding protein (RYBP) is a member of polycomb group (PcG) proteins that typically act as transcriptional repressors via epigenetic modification of chromatin and participate in the establishment and maintenance of cell fates. Recent studies have shown that RYBP also possesses PcG-independent functions that promote apoptosis and cell cycle arrest in cancer cells. Our previous study has shown that RYBP stabilizes p53 through inhibiting MDM2 activity. Recent study indicates that RYBP is downregulated in human cancers, including NSCLC, but the underlying mechanisms are largely unknown. The present study was designed to demonstrate the molecular role of RYBP in NSCLC development and progression, chemotherapy, and patient survival. We systemically investigated the expression of RYBP in human NSCLC tissues and matched non-cancerous samples and evaluated the associations between the RYBP expression in NSCLCs and patient survial. We also generated a replication-deficient recombinant adenovirus driving the expression of RYBP (Adv-RYBP) and carried out in vitro and in vivo studies to explore the molecular basis for the tumor suppressing role of RYBP in NSCLC. We first demonstrated that the RYBP mRNA and protein expressions levels were significantly down-regulated in NSCLC tissues compared with matched noncancerous lung tissues. The low expression of RYBP was significantly associated with the poor prognosis in NSCLC patients. We then identified that enforced RYBP expression decreased cell viability, inhibited colony formation and induced apoptosis in NSCLC cells, while RYBP knockdown led to the opposite effects. RYBP affected the expression of several apoptosis-related proteins; and promoting apoptosis was one of the main mechanisms of RYBP-mediated cell growth inhibition in NSCLC. Moreover, AdRYBP led to a decreased NSCLC tumor xenograft growth. Additionally, clinically used chemotherapeutic agents induced the expression of RYBP, and RYBP sensitized NSCLC cells to chemotherapy in vitro and in vivo. In conclusion, our results reveal that RYBP is a potential biomarker for the diagnosis and prognosis of NSCLC and that reactivating RYBP in cancer cells may provide an effective and safe therapeutic approach to NSCLC therapy. (Supported by NIH/NCI grants R01 CA186662). Citation Format: wei wang, Sukesh Voruganti, Jiang-Jiang Qin, Biyun Qian, Ruiwen Zhang. RYBP predicts survival of patients with non-small cell lung cancer and sensitizes chemotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C93.