New molecular targets in Hodgkin and Reed-Sternberg cells.

Recent discoveries shed light on molecular mechanisms responsible for classical Hodgkin lymphoma (HL) development and progression, along with features of Hodgkin - Reed and Sternberg cells (HRS). Here, we summarize current knowledge on characteristic molecular alterations in HL, as well as existing targeted therapies and potential novel treatments for this disease. We discuss the importance of cluster of differentiation molecule 30 (CD30) and the programmed cell death-1 protein (PD-1) and ligands (PD-L1/2), and other molecules involved in immune modulation in HL. We highlight emerging evidence indicating that the altered function of SWI/SNF-type chromatin remodeling complexes, PRC2, and other epigenetic modifiers, contribute to variations in chromatin status, which are typical for HL. We postulate that despite of the existence of plentiful molecular data, the understanding of HL development remains incomplete. We therefore propose research directions involving analysis of reverse signaling in the PD-1/PD-L1 mechanism, chromatin remodeling, and epigenetics-related alterations, in order to identify HL features at the molecular level. Such attempts may lead to the identification of new molecular targets, and thus will likely substantially contribute to the future development of more effective targeted therapies.

Retinoid X receptor modulates vitellogenin gene expression in black tiger shrimp, Penaeus monodon.

Effective inducing of ovarian maturation in female shrimp broodstock is important for successful breeding programs. Vitellogenesis is a biochemical process during which a yolk protein precursor vitellogenin (Vg) is synthesized and thus, can be used to indicate ovarian maturation stage. In this study, transcriptional regulation of Vg synthesis in the black tiger shrimp, Penaeus monodon was investigated. Genome walking on 5' upstream sequence of Vg gene revealed several putative binding sites of lipophilic retinoic acid response elements (RARE), and nuclear hormone responsive elements. Deletion of RARE significantly reduced the promoter activity to drive the expression of luciferase reporter gene in Sf-9 cells. To validate the trans-factor that potentially controls Vg expression through RARE, a cDNA encoding retinoid X receptor (PmRXR), one of the RARE-bound transcription factors was cloned from P. monodon's ovary. PmRXR expression was detected in various shrimp tissues, and was up-regulated during ovary development in a similar way to Vg expression. The DNA-binding domain of PmRXR protein showed specific binding to RARE-containing region on Vg 5' upstream sequence as determined by Electrophoretic Mobility Shift Assay (EMSA). Furthermore, dsRNA-mediated PmRXR silencing in previtellogenic and vitellogenic shrimp revealed that suppression of PmRXR could reduce Vg transcript in both stages. Taken together, the results presented in this study indicate that RXR is possibly an activator protein that modulates Vg expression in shrimp ovary through the binding to RARE.

Various forms of HIF-1α protein characterize the clear cell renal cell carcinoma cell lines.

Renal cell carcinoma (RCC) represents around 2-3% of all malignancies diagnosed in adult patients. Most frequent (around 70-80% cases) and the most aggressive subtype is clear cell RCC (ccRCC). Mutations in VHL (von Hippel Lindau) gene, characteristic for this cancer type, lead to altered activity of the trimeric VBC (pVHL-elongin B-C) complex and consequently to HIF-1α stabilization. In this study, we present results of exhaustive investigation of HIF-1α alternative transcript variants abundance in A498, CAKI-1, and 786-O ccRCC cell lines. We proved the existence of truncated HIF-1α protein form (HIF1A∆-6) in A498 and HIF1A gene rearrangements in 786-O cell lines. Subsequently, we found that HIF1A∆2-6 was more stable than the full-length HIF-1α. Moreover, the shorter HIF-1α was insensitive for hypoxia and was overaccumulated after proteasome inhibitor treatment indicative of potential diversified roles of full-length and truncated HIF-1α forms in the cell. We also showed that A498, CAKI-1, and 786-O exhibit differential expression of various regulatory genes involved in the control of metabolic processes, that is, glucose and lipid metabolism, and encoding subunits of such machineries like SWI/SNF chromatin remodeling complex. Furthermore, these cell lines exhibited differential responses to axitinib, everolimus, and sunitinib-anticancer drugs-in normoxia and hypoxia as well as various alterations in metabolism-related regulatory processes. Finally, we have shown that overexpression of truncated HIF1A∆2-6 form may affect the protein level of endogenous full-length HIF-1α protein. Thus, our study proves an important role of HIF-1α in the ccRCC development.

Regulation of vitellogenin gene expression under the negative modulator, gonad-inhibiting hormone in Penaeus monodon.

Vitellogenesis is a principal process during ovarian maturation in crustaceans. This process is negatively regulated by gonad-inhibiting hormone (GIH), a neuronal peptide hormone from eyestalks. However, the detailed mechanism through which GIH regulates Vg expression is still ambiguous. In this study, suppression subtractive hybridization (SSH) under specific GIH-knockdown condition was utilized to determine the expression of genes in the ovary that may act downstream of GIH to control vitellogenin synthesis in Penaeus monodon. The total of 102 and 82 positive clones of up-regulated and down-regulated genes in GIH- knockdown shrimp were identified from the forward and reverse SSH libraries, respectively. Determination of the expression profiles of these reproduction-related genes during ovarian development revealed that the expression of calreticulin (CALR) was significantly reduced in vitellogenic ovary suggesting its role in vitellogenesis. Suppression of CALR by specific dsRNA showed elevated vitellogenin (Vg) transcript level in the ovary at day 7 post-dsRNA injection. Since CALR can bind to steroid hormone receptors and prevents the binding of the receptor to its responsive element to regulate gene expression, it is possible that CALR is an inhibitory mediator of vitellogenin synthesis via steroidal pathway. Our results posted a possible novel pathway of GIH signaling that might interfere the steroid signaling cascade to mediate Vg synthesis in the shrimp.