Investigation of Toll-like Receptor-2, -3 and -4 Gene Expressions in Larynx Squamous Cell Carcinoma.

Objective: Despite all the recent advancements, larynx cancer has shown no improvement in survival rates. The aim of this study was to investigate the expressions of toll-like receptor (TLR)-2, -3, and -4 genes, and determine any relationships with the histopathologic characteristics of the disease. Methods: This retrospective study included 50 subjects who underwent total or partial laryngectomy with an open surgical method for larynx squamous cell carcinoma. Measurements of TLRs-2, -3, and -4 expression values were taken with quantitative real time-polymerase chain reaction in normal tissue and tumor tissue samples of the patients. Results: Evaluations were made of TLR-2, -3, and -4 mRNA expressions according to 2-ΔΔCT calculations in 50 subjects with larynx cancer. When the tumor tissue was compared with the healthy tissue from the same subjects, reductions were determined in TLR expression in 86%, 84%, and 82%, respectively. This reduction in each gene expression was statistically significant (p<0.001). No statistically significant correlation was determined between the change in TLR-2, -3, and -4 expression and the histopathologic characteristics of the disease. Conclusion: The data obtained in this study demonstrated that TLR-2, -3, and -4 expressions were reduced in larynx squamous cell cancer. The results of further studies targeting these genes would be useful in the diagnosis and treatment of the disease.

Glycopolymer and Poly(ß-amino ester)-Based Amphiphilic Block Copolymer as a Drug Carrier.

Glycopolymers are synthetic macromolecules having pendant sugar moieties and widely utilized to target cancer cells. They are usually considered as a hydrophilic segment of amphiphilic block copolymers to fabricate micelles as drug carriers. A novel amphiphilic block copolymer, namely, poly(2-deoxy-2-methacrylamido-d-glucose-co-2-hydroxyethyl methacrylate)-b-poly(ß-amino ester) [P(MAG-co-HEMA)-b-PBAE], with active cancer cell targeting potential and pH responsivity was prepared. Tetrazine end functional P(MAG-co-HEMA) and norbornene end functional PBAE blocks were separately synthesized through reversible addition fragmentation chain transfer polymerization and Michael addition-based poly-condensation, respectively, and followed by end-group transformation. Then, inverse electron demand Diels Alder reaction between the tetrazine and the norbornene groups was performed by simply mixing to obtain the amphiphilic block copolymer. After characterization of the block copolymer in terms of chemical structure, pH responsivity, and drug loading/releasing, pH-responsive micelles were obtained with or without doxorubicin (DOX), a model anticancer drug. The micelles exhibited a sharp protonated/deprotonated transition on tertiary amine groups around pH 6.75 and the pH-specific release of DOX below this value. Eventually, the drug delivery potential was evaluated by cytotoxicity assays on both the noncancerous human umbilical vein endothelial cell (HUVEC) cell line and glioblastoma cell line, U87-MG. While the DOX-loaded polymeric micelles were not toxic in noncancerous HUVEC cells, being toxic only to the cancer cells indicates that it is a potential specific cell targeting strategy in the treatment of cancer.

A novel BH3 mimetic Bcl-2 inhibitor promotes autophagic cell death and reduces in vivo Glioblastoma tumor growth.

Anti-apoptotic members of the Bcl-2 family proteins play central roles in the regulation of cell death in glioblastoma (GBM), the most malignant type of brain tumor. Despite the advances in GBM treatment, there is still an urgent need for new therapeutic approaches. Here, we report a novel 4-thiazolidinone derivative BH3 mimetic, BAU-243 that binds to Bcl-2 with a high affinity. BAU-243 effectively reduced overall GBM cell proliferation including a subpopulation of cancer-initiating cells in contrast to the selective Bcl-2 inhibitor ABT-199. While ABT-199 successfully induces apoptosis in high BCL2-expressing neuroblastoma SHSY-5Y cells, BAU-243 triggered autophagic cell death rather than apoptosis in GBM A172 cells, indicated by the upregulation of BECN1, ATG5, and MAP1LC3B expression. Lc3b-II, a potent autophagy marker, was significantly upregulated following BAU-243 treatment. Moreover, BAU-243 significantly reduced tumor growth in vivo in orthotopic brain tumor models when compared to the vehicle group, and ABT-199 treated animals. To elucidate the molecular mechanisms of action of BAU-243, we performed computational modeling simulations that were consistent with in vitro results. Our results indicate that BAU-243 activates autophagic cell death by disrupting the Beclin 1:Bcl-2 complex and may serve as a potential small molecule for treating GBM.

No Tumor Suppressor Role for LKB1 in Prostate Cancer.

To elucidate the pathogenesis of prostate diseases, following in silico analysis, the LKB1 gene was selected for further investigation. The LKB1 gene has been associated with poor prognosis and is frequently mutated in different types of cancers. In this study, 50 benign prostatic hyperplasia (BPH) and 57 prostate cancer (PCa) tissues, including matched normal tissue for the patients, were analyzed by qRT-PCR and DNA sequencing for LKB1 expression and the mutation profile, respectively. Expression of LKB1 was increased in 60.7% of the PCa tissues compared with noncancerous tissue samples (p ≤ 0.001). However, LKB1 expression was lower when compared with normal tissues in BPH (p = 0.920). Four coding sequence alterations were detected in BPH. Three silent mutations were located in codons 9, 32, and 275 and a missense mutation was observed in codon 384. Six alterations were identified in the intronic regions of the LKB1 gene in both PCa and BPH. Five mutations were observed in both patient groups. A new alteration in intron 6 was observed in a patient with PCa. The LKB1 gene may be associated with benign transformations rather than the tumors in prostate pathogenesis when its expression and mutation status are considered. However, the mechanism of LKB1 in PCa needs further studies.

Silencing of Wwox Increases Nuclear Import of Dvl proteins in Head and Neck Cancer.

Background: Wnt signaling pathway is associated with a variety of human cancers, including HNSCC. Wnt proteins control cellular events such as proliferation, fate specification, polarity, and migration by transducing signals to the nucleus through several cytoplasmic relay proteins. Although activation of the Wnt/ß-catenin pathway is a frequent event in various cancers, there is limited knowledge on the contribution of this signaling mechanism in HNSCC. The Wwox tumor suppressor protein participates in the regulation of Wnt signaling by interacting with Dvl proteins. Methods: In this study, we used qRT-PCR and western blotting to examine the mRNA and protein levels of the Dvls in association with WWOX in HNSCC cell lines and tumor tissues. Results: We found that silencing of WWOX leads to increased nuclear localization of the Dvl proteins in cell lines. However, we detected an increase only in the nuclear localization of Dvl-1 in tumor tissues. Conclusions: Our results suggest that aberrant WWOX expression contributes to HNSCC through the Wnt signaling pathway. Decreased expression of WWOX may function in HNSCC progression by allowing the nuclear localization of Dvl proteins.

The investigation of hyaluronic acid and hyaluronidase-1 levels as tumour marker in larynx cancer.

OBJECTIVE: The purpose of this study was to investigate the hyaluronic acid (HA) and hyaluronidase-1 (HYAL-1) levels in laryngeal cancer patients. STUDY DESIGN: Prospective, controlled clinical trial. SETTING: University Medical Center. PARTICIPANTS: Fifty laryngeal squamous cell carcinoma patients and 50 volunteers who gave saliva samples investigated prospectively between 2016 and 2017. METHODS: Hyaluronidase-1 expression was measured by RT-PCR in normal and tumour tissue samples; hyaluronic acid values of saliva and tumour tissues were measured by ELISA method. RESULTS: HYAL-1 expression increased 2.5-fold in tumour tissues compared to normal tissues, and the difference was statistically significant (P < 0.001).Mean saliva HA levels were 103.93 ± 69.04 ng/mL and 177.29 ± 98.44 ng/mL in the patients and controls' saliva specimens, respectively. The difference was not statistically significant (P = 0.657). HA levels were higher in tumour tissue samples than saliva samples, but there was not statistically significant difference between saliva and tumour tissue HA levels. CONCLUSION: HYAL-1 expression in laryngeal squamous cell carcinomas is elevated compared to normal tissues of same patients. Targeting this gene and HA catabolism products may use treatment of larynx cancer in the future.