LncPSCA in the 8q24.3 risk locus drives gastric cancer through destabilizing DDX5.

Genome-wide association studies (GWAS) have identified multiple gastric cancer risk loci and several protein-coding susceptibility genes. However, the role of long-noncoding RNAs (lncRNAs) transcribed from these risk loci in gastric cancer development and progression remains to be explored. Here, we functionally characterize a lncRNA, lncPSCA, as a novel tumor suppressor whose expression is fine-regulated by a gastric cancer risk-associated genetic variant. The rs2978980 T > G change in an intronic enhancer of lncPSCA interrupts binding of transcription factor RORA, which down-regulates lncPSCA expression in an allele-specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation through ubiquitination. Increased expression of lncPSCA results in low levels of DDX5, less RNA polymerase II (Pol II) binding with DDX5 in the nucleus, thus activating transcription of multiple p53 signaling genes by Pol II. These findings highlight the importance of functionally annotating lncRNAs in GWAS risk loci and the great potential of modulating lncRNAs as innovative cancer therapy.

miR-1262 Transcriptionally Modulated by an Enhancer Genetic Variant Improves Efficiency of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Advanced Lung Adenocarcinoma.

Advanced nonsmall-cell lung cancer (NSCLC) patients with mutated epidermal growth factor receptor (EGFR) can remarkably benefit from target therapy of EGFR-tyrosine kinase inhibitors (TKIs). However, increasing drug sensitivity and improving outcomes of NSCLC patients to EGFR-TKI therapy remains a challenge. Several studies have shown a link between microRNAs and drug resistance in cancer. In this study, we hypothesized that the rs12740674 single nucleotide polymorphism in the enhancer of miR-1262 may affect its expression, which may impact the outcome of NSCLC patients treated with EGFR-TKIs. The rs12740674 polymorphism was genotyped in two independent cohorts, including 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The allele-specific regulation on miR-1262 transcription by rs12740674 and impacts of miR-1262 on gefitinib sensitivity were evaluated in vitro and in vivo. Cox regression analyses indicated that the rs12740674 T allele was significantly associated with short survival time in both cohorts (p < 0.05). Luciferase assays demonstrated that the rs12740674 T allelic enhancer showed weaker capability to promote miR-1262 transcription compared with the C allelic enhancer, which may be due to reduced transcription factor binding according to electrophoretic mobility shift assays. Furthermore, significantly decreased miR-1262 expression in NSCLC and nontumor lung tissues of T allele carriers was observed compared with levels in C allele carriers. Moreover, miR-1262 expression enhanced the anticancer effects of gefitinib on NSCLC cells. Our data indicate that miR-1262 may be a potential therapeutic target for NSCLC.

DACT2 modulated by TFAP2A-mediated allelic transcription promotes EGFR-TKIs efficiency in advanced lung adenocarcinoma.

Patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer (NSCLC) benefits from EGFR-tyrosine kinase inhibitor (TKI) treatment. However, drug resistance to EGFR-TKIs remains a great challenge. Single nucleotide polymorphisms (SNPs) may significantly influence prognosis of EGFR-TKI therapy. Herein, we hypothesized that the functional SNP in DACT2, coding a pivotal inhibitor of the Wnt/ß-catenin signaling, may affect gene expression, which in turn, impact prognosis of NSCLC treated with EGFR-TKIs. Genotypes of the DACT2 promoter rs9364433 SNP were determined in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The allele-specific regulation on DACT2 expression by rs9364433 and impacts of DACT2 on gefitinib sensitivity was evaluated in vitro and in vivo. Cox regression analyses demonstrated that rs9364433 was significantly associated with patient survival in both cohorts (all P < 0.05). Reporter gene assays and Electrophoretic Mobility Shift Assays demonstrated that rs9364433 has an allele-specific effect on gene expression modulated by transcription factor TFAP2A. The G allele associated with diminished TFAP2A binding leads to significantly decreased DACT2 expression in NSCLC cell lines and tissues. Consistently, DACT2 could evidently increase the anti-proliferation effect of gefitinib on NSCLC cells. Our findings elucidated potential clinical implications of DACT2, which may result in better understanding and outcome assessment of EGFR-TKI treatments.

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumor-specific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

Leukocyte Telomere Length and Risk of Papillary Thyroid Carcinoma.

CONTEXT: Telomere length may contribute to predisposition to papillary thyroid cancer (PTC). OBJECTIVE: To test this hypothesis, we examined the association between leukocyte telomere length and PTC risk. DESIGN/SETTING: Case-control study in a Chinese Han population. PARTICIPANTS/INTERVENTION: A total of 1200 PTC cases and 1201 age- and sex-matched healthy controls were included in the study. ORs and 95% CIs were calculated by logistic regression. RESULTS: Short relative telomere length (RTL) was significantly associated with elevated risk of PTC (OR = 1.61, 95% CI = 1.35 to 1.92; P = 1.30 × 10-7). Interestingly, when individuals were categorized into four groups on the basis of quartile distribution of relative telomere length (RTL) in controls, we observed a reverse U-shaped association between telomere length and PTC risk. Compared with those in the first (the longest) quartile as the reference group, ORs (95% CIs) were 5.61 (4.04 to 7.78) (P = 6.10 × 10-25), 9.33 (6.78 to 12.83) (P = 6.99 × 10-43), and 1.23 (0.83 to 1.81) (P = 0.300) for individuals in the second, third, and fourth (the shortest) quartiles, respectively. This reverse U-shaped relationship was more apparent in younger individuals. CONCLUSIONS: Our findings suggest that RTL is significantly associated with susceptibility to PTC. There is an obvious reverse U-shaped association between telomere length and PTC risk. Telomere length may be a potential pronouncing biomarker to identify individuals with a high risk of developing PTC.

Functional BCL-2 rs2279115 Promoter Noncoding Variant Contributes to Glioma Predisposition, Especially in Males.

As a crucial oncogene, B cell lymphoma-2 (BCL-2) could promote cancer cell survival by inhibiting apoptosis via suppressing activation of proapoptotic proteins, such as BAX and BAK. There is a functional rs2279115 genetic polymorphism locating in BCL-2 promoter and deregulating BCL-2 expression. However, it is still largely undefined how BCL-2 rs2279115 promoter noncoding genetic variant is involved in glioma development. We examined the association between BCL-2 rs2279115 and glioma risk using a case-control approach. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression adjusted by age and sex. Our results demonstrated that BCL-2 rs2279115 was significantly associated with glioma risk. The odd of individuals harboring A allele (CA + AA genotype) was 0.50 (95% CI = 0.39-0.64, p = 1.0 × 10-7) compared with CC genotype carriers. Stratification analyses by sex elucidated that BCL-2 rs2279115 was significantly associated with glioma risk in males (OR = 0.41, 95% CI = 0.30-0.58, p = 1.0 × 10-7), but not in females (p > 0.05). In summary, our results indicate that the functional BCL-2 rs2279115 genetic variant contributes to glioma predisposition and suggest prevalent involvement of regulatory genetic variations in glioma development.

Leukocyte telomere length and risk of gastric cardia adenocarcinoma.

As a chromosome stabilizer, telomeres play an essential part in maintaining the stability and integrity of human genome. Shortened telomeres have been associated with the development of cancers but it is still largely unclear whether leukocyte telomere length contributes to predisposition of gastric cardia adenocarcinoma (GCA). We conducted a case-control study consisting of 524 GCA cases and 510 controls to assess the association between telomere length in peripheral blood leukocytes and GCA risk in a Chinese Han population. The GCA patients had significantly overall shorter relative leukocyte telomere length (RTL) (median ± SD: 1.10 ± 0.54) when compared with the controls (1.24 ± 0.58). Individuals with the shortest quartile of RTL performed a doubled GCA risk (OR = 2.18; 95% CI = 1.47-3.22, P = 9.90 × 10-5) when compared with those with the highest quartile. We also found that telomere shortening and smoking have a significantly synergistic effect in intensifying risk of GCA (OR = 7.03, 95% CI = 4.55-10.86, P = 1.43 × 10-18). These findings indicate that short RTL contributes to increased susceptibility of gastric cardia adenocarcinoma and might be a promising marker to identify high-risk individuals combined with lifestyle risk factors.