Prostate cancer is a major health problem worldwide. MiR-183 is an oncomiR and a candidate biomarker in prostate cancer, affecting various pathways responsible for disease initiation and progression. We sought to discover the most relevant processes controlled by miR-183 through an unbiased transcriptomic approach using prostate cell lines and patient tissues to identify miR-183 responsive genes and pathways. Gain of function experiments, reporter gene assays, and transcript and protein measurements were conducted to validate predicted functional effects and protein mediators. A total of 135 candidate miR-183 target genes overrepresenting cell adhesion terms were inferred from the integrated transcriptomic analysis. Cell attachment, spreading assays and focal adhesion quantification of miR-183-overexpressing cells confirmed the predicted reduction in cell adhesion. ITGB1 was validated as a major target of repression by miR-183 as well as a mediator of cell adhesion in response to miR-183. The reporter gene assay and PAR-CLIP read mapping suggest that ITGB1 may be a direct target of miR-183. The negative correlation between miR-183 and ITGB1 expression in prostate cancer cohorts supports their interaction in the clinical set. Overall, cell adhesion was uncovered as a major pathway controlled by miR-183 in prostate cancer, and ITGB1 was identified as a relevant mediator of this effect.

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Nature Inspired Design NEW HIT Graphical AbstractProstate cancer (PC) is the most common cancer in men around the world. It is a complex and heterogeneous disease in which androgens and their receptor play a crucial role in the progression and development. The current treatment for PC is a combination of surgery, radiation and chemotherapy. Therapeutic agents commonly used in the clinic include steroidal and non-steroidal anti-androgens, such as cyproterone acetate. These few agents have multiple adverse effects and are not 100% effective. Several plant compounds and mixtures, have been shown to be effective against PC cell growth. Some insolated compounds were reported with in vivo activity on PC murine model like capsaicin and curcumin. We prepared a library of plant extracts from traditional Mayan medicine. These plants were selected for their use in the contemporaneous Maya communities with application in different types of diseases and treatments. These extracts were used in a phenotypic screening in LNCaP (androgen sensitive) prostate cancer cells in a fixed dose (25 μg / mL). Ten plants out of 11 were identified with cytotoxic activity in these cells. With the active extracts, a bioguided fractionation method was performed until the elucidation of the mayor components. We identified 3 compounds with activity and design one hybrid molecule with the natural product structure and steroid analog to enhance the antiproliferative activity.

Introduction: We previously identified by a genome-wide approach, differentially methylated genes in head and neck squamous cell carcinoma (HNSCC), including genes uniquely methylated in each HNSCC anatomic subsite. To define their potential prognostic value the validation of uniquely methylated genes in a cohort of HNSCC patients, according to the anatomic subsite, is warranted. Thus, here we present validation data of three potential DNA methylation biomarkers in a cohort comprising primary tumors of 54 HNSCC patients. Methods: Tumor DNA was extracted from HNSCC patients, stratified by the primary tumor anatomic subsite, which included 21 laryngeal cancers, 21 oral cavity cancer, and 12 pharyngeal cancers. The DNA methylation status of three candidate biomarkers, CDH1 for laryngeal cancer, PITX2 for oral cavity cancer, and SFRP1 for pharyngeal cancer were assessed. DNA methylation analysis was performed using qMSP MethyLight assay and quantitative methylation value for each gene was expressed as the Percentage of Methylation Reference (PMR). A PMR value cut-off was established to classify samples as positively or negatively methylated. PMR values <10 were classified as negatively methylated and PMR values of ≥10 were classified as positively methylated for each gene. Results: Positive methylation (PMR ≥10) was detected in 71% of laryngeal samples for CDH1 and, in pharyngeal cancer, 66% showed positive methylation for SFRP1. 90% of oral cavity samples showed positive methylation for PITX2. No association with clinicopathologic characteristics (stage, differentiation, recurrence) was found. However, high PMR values (PMR ≥20) were observed in early stage tumors (I and II) as for late stage tumors (III and IV) for all candidate genes tested. Conclusion: HNSCC subsites (larynx, oral cavity and pharynx) show differential DNA methylation patterns for selected genes. Aberrant methylation of CDH1, PITX2 and SFRP1 was established in a high percentage of tumors, suggesting these candidate genes might be useful as molecular classifiers for HNSCC subsite. In addition, aberrant methylation of CDH1, PITX2, and SFRP1 was detected in early stage tumors; which might be indicators of hypermethylation as an early event in HNSCC carcinogenesis, and in association to the anatomic subsite. Analysis of these unique DNA methylation biomarkers for HNSCC may be valuable for an accurate disease prognosis and for design of novel treatments. Citation Format: Bianca L. Rivera, Jaime Aponte, Sol Nadal, Sebastian Oliva, Sebastian Bravo, Rafael Guerrero, Juan Trinidad, Adriana Baez. Validation of potential predictive DNA methylation biomarkers for head and neck squamous cell carcinoma anatomic subsite [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 46.