PAICS, a De Novo Purine Biosynthetic Enzyme, Is Overexpressed in Pancreatic Cancer and Is Involved in Its Progression.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with an extremely poor prognosis. There is an urgent need to identify new therapeutic targets and also understand the mechanism of PDAC progression that leads to aggressiveness of the disease. To find therapeutic targets, we analyzed data related to PDAC transcriptome sequencing and found overexpression of the de novo purine metabolic enzyme phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS). Immunohistochemical analysis of PDAC tissues showed high expression of the PAICS protein. To assess the biological roles of PAICS, we used RNA interference and knock down of its expression in PDAC cell lines that caused a reduction in PDAC cell proliferation and invasion. Furthermore, results of chorioallantoic membrane assays and pancreatic cancer xenografts demonstrated that PAICS regulated pancreatic tumor growth. Our data also showed that, in PDAC cells, microRNA-128 regulates and targets PAICS. PAICS depletion in PDAC cells caused upregulation in E-cadherin, a marker of the epithelial-mesenchymal transition. In PDAC cells, a BET inhibitor, JQ1, reduced PAICS expression. Thus, our investigations show that PAICS is a therapeutic target for PDAC and, as an enzyme, is amenable to targeting by small molecules.

Inclusiveness and ethical considerations for observational, translational, and clinical cancer health disparity research.

BACKGROUND: Although general trends in cancer outcomes are improving, racial/ethnic disparities in patient outcomes continue to widen, suggesting disparity-related shortcomings in cancer research designs. METHODS: Using convenience sampling, a total of 24 data sources, representing several research designs and 5 high-burden tumor types, were included for analyses. The percentages of races/ethnicities across each design/tumor type were compared with those of the 2017 US Census data. The authors used a framework based on the Belmont principles to evaluate the ethical strengths and/or weaknesses of each design. RESULTS: In all designs, white individuals were found to be overrepresented. African American and Asian individuals were underrepresented, and Native Americans had consistently poor or no representation. In general, ethical concerns varied according to the study design. Clinical trials were high with regard to respect for persons and beneficence but low for equitable subject selection related to the inclusion of race/ethnicity. Observational study designs were more inclusive for race/ethnicity compared with clinical and translational studies, but their clinical usefulness was less. CONCLUSIONS: The authors proposed that ethical concerns should vary according to the study design. Because observational designs have strengths in inclusiveness for race/ethnicity, their clinical usefulness can be improved by extending the Learning Health System in hospital catchment populations, the use of health records linked to biospecimens, and minority oversampling. Likewise, minority enrollment into clinical trials can be improved through Learning Health System linking and by using National Cancer Institute-mandated Community Outreach and Engagement Cores. This will allow precision medicine for otherwise overlooked minority subgroups.

MTHFD1L, A Folate Cycle Enzyme, Is Involved in Progression of Colorectal Cancer.

Identification of new molecular targets is needed for the treatment of colorectal cancer (CRC). Methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L), an enzyme in the folate cycle, is involved in formate generation and therefore in one-carbon metabolism. Here, we examined the expression and the role of MTHFD1L in CRC progression. Bioinformatics analysis of several public databases showed overexpression of MTHFD1L in CRC tissues as compared to normal tissues. Quantitative real-time PCR and Western blotting revealed that expressions of MTHFD1L RNA and protein were higher in CRC tissues compared to their corresponding normal tissues of CRC patients. Immunohistochemical staining demonstrated higher cytoplasmic MTHFD1L reactivity in tumor tissues compared to paired normal tissues. Further, to determine the functional relevance of MTHFD1L, it was knocked down by an siRNA in CRC cells. Silencing of MTHFD1L inhibited CRC cell proliferation, colony formation, invasion, and migration. Thus, to our knowledge for the first time in the literature, we show that MTHFD1L is involved in CRC progression and that blocking of MTHFD1L decreases the growth of colon cancer cells, thus providing an avenue to target this enzyme with small molecule inhibitors.