Role of Wnt5b-Ror1 signaling in the proliferation of pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory cancers with the worst prognosis. Although several molecules are known to be associated with the progression of PDAC, the molecular mechanisms underlying the progression of PDAC remain largely elusive. The Ror-family receptors, Ror1 and Ror2, which act as a receptor(s) for Wnt-family ligands, particularly Wnt5a, are involved in the progression of various types of cancers. Here, we show that higher expression of Ror1 and Wnt5b, but not Ror2, are associated with poorer prognosis of PDAC patients, and that Ror1 and Wnt5b are expressed highly in a type of PDAC cell lines, PANC-1 cells. Knockdown of either Ror1 or Wnt5b in PANC-1 cells inhibited their proliferation significantly in vitro, and knockout of Ror1 in PANC-1 cells resulted in a significant inhibition of tumor growth in vivo. Furthermore, we show that Wnt5b-Ror1 signaling in PANC-1 cells promotes their proliferation in a cell-autonomous manner by modulating our experimental setting in vitro. Collectively, these findings indicate that Wnt5b-Ror1 signaling might play an important role in the progression of some if not all of PDAC by promoting proliferation.

Monoblastic leukemia (M5a) with chronic basophilic leukemia in a cat.

A cat was presented with depression and anorexia. The complete blood cell count (CBC) revealed non-regenerative anemia (PCV, 8.5%), marked thrombocytopenia (2,400/µl), and leukocytosis (32,090/µl). In the peripheral blood, proliferation of blast cells (85%; 27,276/µl) and basophils (7.7%; 2,460/µl) was observed. Bone marrow aspirate showed hyperplasia with 8.8% blasts and 90.2% basophils of all nucleated cells. The blast cells were negative for myeloperoxidase staining and positive for alpha-naphthol butyrate esterase staining, indicating the agranular blasts are monoblasts. Thus, acute monoblastic leukemia (M5a) with chronic basophilic leukemia was diagnosed. Basophils accounted for more than 40% of the bone marrow, and we diagnosed secondary basophilic leukemia. Secondary basophilic leukemia should be included in the differential list when abnormal basophil increases are observed in feline bone marrow.

E2F1-Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S phase transition in bFGF-stimulated NIH/3T3 fibroblasts.

Ror2 signaling has been shown to regulate the cell cycle progression in normal and cancer cells. However, the molecular mechanism of the cell cycle progression upon activation of Ror2 signaling still remains unknown. Here, we found that the expression levels of Ror2 in G1-arrested NIH/3T3 fibroblasts are low and are rapidly increased following the cell cycle progression induced by basic fibroblast growth factor (bFGF) stimulation. By expressing wild-type or a dominant negative mutant of E2F1, we show that E2F1 mediates bFGF-induced expression of Ror2, and that E2F1 binds to the promoter of the Ror2 gene to activate its expression. We also found that G1/S phase transition of bFGF-stimulated NIH/3T3 cells is delayed by the suppressed expression of Ror2. RNA-seq analysis revealed that the suppressed expression of Ror2 results in the decreased expression of various E2F target genes concomitantly with increased expression of Forkhead box O (FoxO) target genes, including p21Cip1 , and p27Kip1 . Moreover, the inhibitory effect of Ror2 knockdown on the cell cycle progression can be restored by suppressed expression of p21Cip1 , p27Kip1 ,or FoxO3a. Collectively, these findings indicate that E2F1-Ror2 signaling mediates the transcriptional activation and inhibition of E2F1-driven and FoxO3a-driven cell cycle-regulated genes, respectively, thereby promoting G1/S phase transition of bFGF-stimulated NIH/3T3 cells.