Annotation and functional characterization of long noncoding RNAs deregulated in pancreatic adenocarcinoma.

PURPOSE: Transcriptome analysis of pancreatic ductal adenocarcinoma (PDAC) has been useful to identify gene expression changes that sustain malignant phenotypes. Yet, most studies examined only tumor tissues and focused on protein-coding genes, leaving long non-coding RNAs (lncRNAs) largely underexplored. METHODS: We generated total RNA-Seq data from patient-matched tumor and nonmalignant pancreatic tissues and implemented a computational pipeline to survey known and novel lncRNAs. siRNA-mediated knockdown in tumor cell lines was performed to assess the contribution of PDAC-associated lncRNAs to malignant phenotypes. Gene co-expression network and functional enrichment analyses were used to assign deregulated lncRNAs to biological processes and molecular pathways. RESULTS: We detected 9,032 GENCODE lncRNAs as well as 523 unannotated lncRNAs, including transcripts significantly associated with patient outcome. Aberrant expression of a subset of novel and known lncRNAs was confirmed in patient samples and cell lines. siRNA-mediated knockdown of a subset of these lncRNAs (LINC01559, LINC01133, CCAT1, LINC00920 and UCA1) reduced cell proliferation, migration and invasion. Gene co-expression network analysis associated PDAC-deregulated lncRNAs with diverse biological processes, such as cell adhesion, protein glycosylation and DNA repair. Furthermore, UCA1 knockdown was shown to specifically deregulate co-expressed genes involved in DNA repair and to negatively impact DNA repair following damage induced by ionizing radiation. CONCLUSIONS: Our study expands the repertoire of lncRNAs deregulated in PDAC, thereby revealing novel candidate biomarkers for patient risk stratification. It also provides a roadmap for functional assays aimed to characterize novel mechanisms of action of lncRNAs in pancreatic cancer, which could be explored for therapeutic development.

Effect of the bone marrow cell transplantation on elevated plus-maze performance in hippocampal-injured mice.

Several reports have shown that the hippocampus plays an important role in different aspects of the emotional control. There is evidence that lesions in this structure cause behavioral disinhibition, with reduction of reactions expressing fear and anxiety. Thus, to portray the aptitude of cell therapy to abrogate injuries of hippocampal tissue, we examined the behavioral effects of bone marrow mononuclear cells (BMMCs) transplantation on C57BL/6 mice that had the hippocampus damaged by electrolytic lesion. For this purpose, mice received, seven days after bilateral electrolytic lesion in the dorsal hippocampus, culture medium or BMMCs expressing the enhanced green fluorescent protein (EGFP) transgene. One week after transplantation, animals were tested in the elevated plus-maze (EPM). On the whole, three assessment sessions in the EPM were carried out, with seven days separating each trial. Thirty-five days after the induction of injury, mice were sacrificed and their brains removed for immunohistochemistry. The behavioral evaluation showed that the hippocampal lesion caused disinhibition, an effect which was slightly lessened, from the second EPM test, in transplanted subjects. On the other hand, immunohistochemical data revealed an insignificant presence of EGFP(+) cells inside the brains of injured mice. In view of such scenario, we hypothesized that the subtle rehabilitation of the altered behavior might be a result from a paracrine effect from the transplanted cells. This might have been caused by the release of bioactive factors capable of boosting endogenous recuperative mechanisms for a partial regaining of the hippocampal functions.