MicroRNA-214 targets PTK6 to inhibit tumorigenic potential and increase drug sensitivity of prostate cancer cells.

Prostate cancer is the most commonly diagnosed cancer in men with African American men disproportionally suffering from the burden of this disease. Biomarkers that could discriminate indolent from aggressive and drug resistance disease are lacking. MicroRNAs are small non-coding RNAs that affect numerous physiological and pathological processes, including cancer development and have been suggested as biomarkers and therapeutic targets. In the present study, we investigated the role of miR-214 on prostate cancer cell survival/migration/invasion, cell cycle regulation, and apoptosis. miR-214 was differentially expressed between Caucasian and African American prostate cancer cells. Importantly, miR-214 overexpression in prostate cancer cells induced apoptosis, inhibiting cell proliferation and colony forming ability. miR-214 expression in prostate cancer cells also inhibited cell migration and 3D spheroid invasion. Mechanistically, miR-214 inhibited prostate cancer cell proliferation by targeting protein tyrosine kinase 6 (PTK6). Restoration of PTK6 expression attenuated the inhibitory effect of miR-214 on cell proliferation. Moreover, simultaneous inhibition of PTK6 by ibrutinib and miR-214 significantly reduced cell proliferation/survival. Our data indicates that miR-214 could act as a tumor suppressor in prostate cancer and could potentially be utilized as a biomarker and therapeutic target

Gallbladder Cancer Predisposition: A Multigenic Approach to DNA-Repair, Apoptotic and Inflammatory Pathway Genes

Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4-15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 –196 to –174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 -1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population

Comprehensive review of genetic association studies and meta-analyses on miRNA polymorphisms and cancer risk.

MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs). Variations in the level of expression of distinct miRNAs have been observed in the genesis, progression and prognosis of multiple human malignancies. The present study was aimed to investigate the association between four highly studied miRNA polymorphisms (mir-146a rs2910164, mir-196a2 rs11614913, mir-149 rs2292832 and mir-499 rs3746444) and cancer risk by using a two-sided meta-analytic approach.An updated meta-analysis based on 53 independent case-control studies consisting of 27573 cancer cases and 34791 controls was performed. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association.Overall, the pooled analysis showed that mir-196a2 rs11614913 was associated with a decreased cancer risk (OR = 0.846, P = 0.004, TT vs. CC) while other miRNA SNPs showed no association with overall cancer risk. Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that there was a strong association between miR-146a rs2910164 and overall cancer risk in Caucasian population under recessive model (OR = 1.274, 95%CI = 1.096-1.481, P = 0.002). Stratified analysis by cancer type also associated mir-196a2 rs11614913 with lung and colorectal cancer at allelic and genotypic level.The present meta-analysis suggests an important role of mir-196a2 rs11614913 polymorphism with overall cancer risk especially in Asian population. Further studies with large sample size are needed to evaluate and confirm this association

Meta-analysis of mir-149 rs2292832 polymorphism.

<p>Random effects model was used when <i>P</i> value of Q-test for heterogeneity test (<i>P_Het</i>)<0.05; otherwise, fixed effect model was used.</p>a<p>Number of studies involved.</p><p>OR: odds ratio; CI: confidence interval.</p

Characteristics of eligible studies in meta-analysis.

<p>HCC: hepatocellular cancer; BC: breast cancer; GBC: gallbladder cancer; GC: gastric cancer; NSCLC: non-small cell lung carcinoma; CC: cervical cancer; LC: lung cancer; EC: esophageal cancer; PC: prostate cancer; HNSCC: head and neck squamous cell carcinoma; NHL: Non-Hodgkin lymphoma; OC: ovarian cancer; PTC: papillary thyroid carcinoma; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; UBC: urinary bladder cancer; CRC: colorectal cancer; ESCC: esophageal squamous cell carcinoma; NPC: Nasopharyngeal Carcinoma; OSCC: oral squamous cell carcinoma; HWE: Hardy-Weinberg equilibrium; PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism; PCR–LDR: polymerase chain reaction–ligation detection reaction; PCR-FRET: polymerase chain reaction–fluorescent resonance energy transfer; HRMA: high-resolution melting analysis; PCR-CTPP: polymerase chain reaction with confronting two-pair primers; Tm-shift: Melting-temperature–shift allele-specific genotyping; HB: hospital based; PB: population based; NR: not reported;</p>*<p>Let7f-2 rs17276588 deviated from HWE in controls.</p>$<p>mir-492 rs2289030 and mir-149 rs2292832 deviated from HWE in controls.</p>#<p>Cirrhosis patients without HCC served as controls.</p>@<p>miR-499 rs3746444 deviated from HWE in controls.</p>!<p>mir196a2 rs11614913 and mir146a rs2910164 deviated from HWE in controls.</p>&<p>miRNA149 rs2292832 deviated from HWE in controls.</p

Meta-analysis of mir-146a rs2910164 polymorphism.

<p>Random effects model was used when <i>P</i> value of Q for heterogeneity test (<i>P_Het</i>)<0.05; otherwise, fixed effect model was used.</p>a<p>Number of studies involved.</p>*<p>The study by Lung et al., <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050966#pone.0050966-Lung1" target="_blank">[85]</a> has both hospital based and population based controls.</p><p>OR: odds ratio; CI: confidence interval.</p

Meta-analysis of mir-499 rs3746444 polymorphism.

<p>Random effects model was used when <i>P</i> value of Q-test for heterogeneity test (<i>P_Het</i>)<0.05; otherwise, fixed effect model was used.</p>a<p>Number of studies involved.</p><p>OR: odds ratio; CI: confidence interval.</p

Description of meta-analyses included in the systematic review.

<p>BC: breast cancer; GBC: gallbladder cancer; GC: gastric cancer; LC: lung cancer; PC: prostate cancer; HNSCC: head and neck squamous cell carcinoma; PTC: papillary thyroid carcinoma; ESCC: esophageal squamous cell carcinoma; HCC: hepatocellular cancer; CRC: colorectal cancer; OSCC: oral squamous cell carcinoma; PSCC: pharynx squamous cancer; OC: ovarian cancer; CC: cervical cancer; RCC: renal cell cancer.</p>*<p>Considered T allele as variant allele as in the present study.</p><p>P_het, <i>p</i>-value for heterogeneity.</p><p>OR, odds ratio.</p><p>CI, confidence interval.</p>*<p>Homozygous wild vs. homozygous variant genotype.</p

Effect of Genetic Variant (rs11887534) in ABCG8 Gene in Coronary Artery Disease and Response to Atorvastatin Therapy

Background: ATP-binding cassette transporter ABCG8 plays an important role in excretion of cholesterol from liver. Common genetic polymorphisms in ABCG8 gene may genetically predispose an individual to coronary artery disease (CAD) along with response to atorvastatin therapy. Thus, we aimed to examine the role of ABCG8 D19H polymorphism (rs11887534) in susceptibility to CAD and its influence on atorvastatin response