Mantang Qiu

Long noncoding RNA: an emerging paradigm of cancer research

Recent studies have demonstrated the importance of non-protein coding part of human genome in carcinogenesis and metastasis. Among numerous kinds of non-protein coding RNAs, long noncoding RNAs (lncRNAs) play a key regulatory role in cancer biology. LncRNAs are dysregulated in different kinds of cancer and the expression levels of certain lncRNAs are associated with recurrence, metastasis, and prognosis of cancer. It is also proved that overexpression of certain lncRNAs, behaving like oncogenes, can promote matrix invasion of cancer cells and tumor growth. In this review, we focus our attention on lncRNAs those have been validated in human cancer tissues to suggest reasonable strategies for future research. We introduce an update view of lncRNA, extract cancer-related lncRNAs from literature, and describe the known functions and possible underlying molecular mechanisms of some well investigated lncRNAs (MALAT1, HOX antisense intergenic RNA, and highly upregulated in hepatocellular cancer), as well as their current and potential future application in cancer diagnosis (PCA3) and treatment (H19).

Upregulation of the long noncoding RNA TUG1 promotes proliferation and migration of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the prevalent and deadly cancers worldwide, especially in Eastern Asia. The prognosis of ESCC remains poor; thus, it is still necessary to further dissect the underlying mechanisms and explore therapeutic targets of ESCC. Recent studies show that long noncoding RNAs (lncRNAs) have critical roles in diverse biological processes, including tumorigenesis. Some lncRNAs, such as HOTAIR and POU3F3, were reported to play important roles in ESCC. Here, we characterized the expression profile of taurine-upregulated gene 1 (TUG1), a lncRNA recruiting and binding to polycomb repressive complex 2 (PRC2), in ESCC. In a cohort of 62 patients, TUG1 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues, and high expression level of TUG1 was associated with family history and upper segment of esophageal cancer (p < 0.05). Further, in vitro silencing TUG1 via siRNA inhibited the proliferation and migration of ESCC cells and blocked the progression of cell cycle. Therefore, our study indicates that TUG1 promotes proliferation and migration of ESCC cells and is a potential oncogene of ESCC.

Circulating tumor DNA is effective for the detection of EGFR mutation in non-small cell lung cancer: a meta-analysis.

Background: Circulating tumor DNA (ctDNA) has offered a minimally invasive and feasible approach for detection of EGFR mutation for non–small cell lung cancer (NSCLC). This meta-analysis was designed to investigate the diagnostic value of ctDNA, compared with current “gold standard,” tumor tissues. Methods: We searched PubMed, EMBASE, Cochrane Library, and Web of Science to identify eligible studies that reported the sensitivity and specificity of ctDNA for detection of EGFR mutation status in NSCLC. Eligible studies were pooled to calculate the pooled sensitivity, specificity, and diagnostic odds ratio (DOR). The summary ROC curve (SROC) and area under SROC (AUSROC) were used to evaluate the overall diagnostic performance. Results: Twenty-seven eligible studies involving 3,110 participants were included and analyzed in our meta-analysis, and most studies were conducted among Asian population. The pooled sensitivity, specificity, and DOR were 0.620 [95% confidence intervals (CI), 0.513–0.716), 0.959 (95% CI, 0.929–0.977), and 38.270 (95% CI, 21.090–69.444), respectively. The AUSROC was 0.91 (95% CI, 0.89–0.94), indicating the high diagnostic performance of ctDNA. Conclusion: ctDNA is a highly specific and effective biomarker for the detection of EGFR mutation status. Impact: ctDNA analysis will be a key part of personalized cancer therapy of NSCLC. Cancer Epidemiol Biomarkers Prev; 24(1); 206–12. ©2014 AACR.

Circular RNA has_circ_0067934 is upregulated in esophageal squamous cell carcinoma and promoted proliferation

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and deadly types of cancer worldwide especially in Eastern Asia and the prognosis of ESCC remain poor. Recent evidence suggests that circular RNAs (circRNAs) play important roles in multiple diseases, including cancer. In this study, we characterized a novel circRNA termed hsa_circ_0067934 in ESCC tumor tissues and cell lines. We analyzed a cohort of 51 patients and found that hsa_circ_0067934 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues. The high expression level of hsa_circ_0067934 was associated with poor differentiation (P = 0.025), I-II T stage (P = 0.04), and I-II TNM stage (P = 0.021). The in vitro silence of hsa_circ_0067934 by siRNA inhibited the proliferation and migration of ESCC cells and blocked cell cycle progression. Cell fraction analyses and fluorescence in situ hybridization detected that hsa_circ_0067934 was mostly located in the cytoplasm. Our findings suggest that hsa_circ_0067934 is upregulated in ESCC tumor tissue. Our data suggest that hsa_circ_0067934 represents a novel potential biomarker and therapeutic target of ESCC.

Hsa-miR-499 rs3746444 polymorphism contributes to cancer risk: a meta-analysis of 12 studies.

Background Single nucleotide polymorphisms (SNPs) occurred in pre-microRNAs or targets of microRNAs (miRs) may contribute to cancer risks. Since 2007, many studies have investigated the association between common SNPs located on hsa-miR-499 (rs3746444) and cancer risks; however, the results were inconclusive. Methodology/Principal Findings We conducted a meta-analysis of 12 studies that included 5765 cases and 7076 controls to identify the strength of association. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, individuals with the variant AG (OR = 1.215, 95% CI: 1.027, 1.437; Pheterogeneity<0.01) and AG/GG (OR = 1.227, 95% CI: 1.046, 1.439; Pheterogeneity<0.01) genotypes were associated with a significantly increased risk of cancer than those with wild AA genotype. Sub-group analysis revealed that the variant AG (OR = 1.411, 95% CI: 1.142, 1.745; Pheterogeneity = 0.01) and AG/GG (OR = 1.413, 95% CI: 1.163, 1.717, Pheterogeneity = 0.01) genotypes still showed an increased risk of cancer in Asians; however, a trend of reduced risk of cancer was observed in Caucasians (AG vs. AA: OR = 0.948, 955 CI: 0.851, 1.057, Pheterogeneity = 0.12; AG/GG vs. AA: OR = 0.959, 95% CI: 0.865, 1.064; Pheterogeneity = 0.19). Meta-regression showed that ethnicity (p = 0.048) and sample size (p = 0.02) but not cancer types (p = 0.89) or source of control (p = 0.97) were the sources of heterogeneity. Conclusions These meta-analysis results suggest that hsa-miR-499 polymorphism rs3746444 is associated with a significantly increased risk of cancer, especially in Asian populations.

MiR-145 regulates cancer stem-like properties and epithelial-to-mesenchymal transition in lung adenocarcinoma-initiating cells

MicroRNA-145 (MiR-145) is an important regulator of tumorigenesis. Our previous work indicated that miR-145 reduced the proliferation and invasion as well as the tumorosphere growth capacity in lung adenocarcinoma cells. However, the underlying molecular mechanisms remain elusive. Here, we reported that the expression level of miR-145 was downregulated in lung adenocarcinoma tissues and negatively correlated with the expression level of Oct4. MiR-145 inhibited the proliferation of lung cancer-initiating cells (LCICs), partially by regulating Oct4 expression. Furthermore, we found that miR-145 exerted repressive effect on cancer stem cell properties and inhibited epithelial-mesenchymal transition (EMT) in vitro, also partially by regulating Oct4. Finally, we confirmed the repressive effect of miR-145 on cancer stem cell properties and EMT in vivo. Taken together, these evidences suggest that miR-145 serves as a tumor suppressor which downregulates LCICs’ cancer stem cell properties and EMT process by targeting Oct4, leading to the inhibition of tumor growth and metastasis.

Enhanced cytotoxic activity of cetuximab in EGFR-positive lung cancer by conjugating with gold nanoparticles

Cetuximab (C225) is a unique agent, targeting epidermal growth factor receptor (EGFR)-positive cancer. However, the therapeutic effect of C225 in EGFR high-expressing non-small cell lung cancer (NSCLC) remains poor. Here, we report that conjugation of C225 with gold nanoparticles (AuNPs) enhances the cytotoxicity of C225 in NSCLC both in vitro and in vivo. The NSCLC cell lines A549 (EGFRhigh) and H1299 (EGFRlow) were employed to investigate different responses to C225, IgG-AuNPs and C225-AuNPs. The antitumor properties of C225-AuNPs were explored in vivo by establishing a tumor xenograft model in nude mice. Overall, the therapeutic effect of C225-AuNPs was more pronounced in EGFRhigh A549 cells compared with EGFRlow H1299 cells. The cytotoxic effect of C225-AuNPs in A549 cells increased in a dose-dependent manner. C225-AuNPs significantly suppressed A549 cell proliferation and migration capacity and accelerated apoptosis compared with C225, and this effect was probably due to enhanced EGFR endocytosis and the subsequent suppression of downstream signaling pathway. Finally in the tumor xenograft of nude mice, treatment with C225-AuNPs also led to a significant reduction in tumor weight and volume with low toxicity. Our findings suggest that C225-AuNPs conjugate has promising potential for targeted therapy of EGFR positive NSCLC patients.

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

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

Predictive value of XPD polymorphisms on platinum-based chemotherapy in non-small cell lung cancer: a systematic review and meta-analysis.

Background The correlation between xeroderma pigmentosum group D (XPD) polymorphisms (Lys751Gln and Asp312Asn) and clinical outcomes of non-small cell lung cancer (NSCLC) patients, who received platinum-based chemotherapy (Pt-chemotherapy), is still inconclusive. This meta-analysis was aimed to systematically review published evidence and ascertain the exact role of XPD polymorphisms. Methods Databases of MEDLINE and EMBASE were searched up to April 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according the Newcastle-Ottawa Quality Assessment Scales. The relationship between XPD polymorphisms and response to Pt-chemotherapy and survival was analyzed. Results A total of 22 eligible studies were included and analyzed in this meta-analysis. The overall analysis suggested that the XPD Lys751Gln polymorphism was not associated with response to Pt-chemotherapy or survival. However, the XPD 312Asn allele was significantly associated with poor response to Pt-chemotherapy compared with the Asp312 allele (Asn vs. Asp: OR = 0.435, 95% CI: 0.261–0.726). Additionally, the variant genotype of XPD Asp312Asn polymorphism was associated with favorable survival in Caucasian (AspAsn vs. AspAsp: HR = 0.781, 95% CI: 0.619–0.986) but unfavorable survival in Asian (AspAsn+AsnAsn vs. AspAsp: HR = 1.550, 95% CI: 1.038–2.315). Conclusions These results suggest that XPD Asp312Asn polymorphism may function as a predictive biomarker on platinum-based chemotherapy in NSCLC and further studies are warranted.

Association of Vitamin D Receptor BsmI Gene Polymorphism with Risk of Tuberculosis: A Meta-Analysis of 15 Studies

Background Genetic variations in vitamin D receptor (VDR) may contribute to tuberculosis (TB) risk. Many studies have investigated the association between VDR BsmI gene polymorphism and TB risk, but yielded inconclusive results. Methodology/Principal Findings We performed a comprehensive meta-analysis of 15 publications with a total of 2309 cases and 3568 controls. We assessed the strength of the association between VDR BsmI gene polymorphism and TB risk and performed sub-group analyses by ethnicity, sample size and Hardy–Weinberg equilibrium (HWE). We found a statistically significant correlation between VDR BsmI gene polymorphism and decreased TB risk in four comparison models: allele model (b vs. B: OR = 0.78, 95% CI = 0.67, 0.89; Pheterogeneity = 0.004), homozygote model (bb vs. BB: OR = 0.61, 95% CI = 0.43, 0.87; Pheterogeneity = 0.001), recessive model (bb vs. Bb+BB: OR = 0.70, 95% CI = 0.56, 0.88; Pheterogeneity = 0.005) and dominant model (bb+Bb vs. BB: OR = 0.77, 95% CI = 0.61, 0.97; Pheterogeneity = 0.010), especially in studies based on Asian population. Sub-group analyses also revealed that there was a statistically decreased TB risk in “small” studies (<500 participants) and studies with PHWE>0.5. Meta-regression and stratification analysis both showed that the ethnicity and sample size contributed to heterogeneity. Conclusions This meta-analysis suggests that VDR BsmI gene polymorphism is associated with a significant decreased TB risk, especially in Asian population.