PCGEM1 stimulates proliferation of osteoarthritic synoviocytes by acting as a sponge for miR-770.

Long non-coding RNAs (lncRNAs) have been reported to play important roles in cellular metabolism and development. Various diseases have been associated with aberrant expression of lncRNAs and the related dysregulation of mRNAs. An lncRNA profiling assay was carried out to identify the key lncRNA in osteoarthritic human synoviocytes; the results revealed that prostate cancer gene expression marker 1 (PCGEM1) was significantly overexpressed in osteoarthritic synoviocytes. Exogenous overexpression of PCGEM1 inhibited apoptosis, induced autophagy, and stimulated the proliferation of human synoviocytes. The increased expression of PCGEM1 in human synoviocytes also suppressed the expression of miR-770. Transfection of the miR-770 precursor resulted in reduced proliferation, and induced apoptosis of human synoviocytes. This effect of miR-770 expression was reversed by co-introduction of PCGEM1. Target validation showed a direct binding between PCGEM1 and miR-770. We demonstrate that PCGEM1 act as sponge lncRNA for miR-770 that regulates proliferation/apoptosis and autophagy, and suggest PCGEM1 as possible target for OA therapy.

Down-regulation of Phospholipase D Stimulates Death of Lung Cancer Cells Involving Up-regulation of the Long ncRNA ANRIL.

Dysregulation of phospholipase D (PLD) has been found in several types of human cancer, but the underlying regulatory mechanism remains poorly-understood. Herein we found PLD inhibition in human H460 lung cancer cells has anti-tumorigenic effects such as stimulation of apoptosis and autophagy. In the present study, in order to identify the responsible key regulator of these anti-tumorigenic effects of PLD inhibition, we analyzed the expression levels of 90 long non-coding RNAs (lncRNAs). Among them, the expression level of antisense noncoding RNA in the INK4 locus (ANRIL) was increased up to 13.6-fold by PLD inhibition in H460 human lung cancer cells. Moreover, knockdown of ANRIL using its specific small-interfering RNA significantly suppressed PLD inhibition-induced apoptosis. Collectively, our findings showed that ANRIL is an lncRNA responsible in anti-tumorigenesis caused by PLD inhibition and combined incorporation of ANRIL into PLD inhibition-induced anti-tumorigenic signaling network could be a new effective therapeutic approach for controlling lung cancer.

Peroxisomal dysfunction is associated with up-regulation of apoptotic cell death via miR-223 induction in knee osteoarthritis patients with type 2 diabetes mellitus.

Recent increasing evidences showing the interconnection between mitochondria and peroxisome in performing metabolic functions imply that peroxisome dysfunction could lead to a wide variety of human diseases including cancer and osteoarthritis (OA) as mitochondria dysfunction. Even though there is a higher incidence and development of OA in diabetes mellitus (DM) patients, there is not much evidential mechanism study in this inter-regulation between OA and OA with DM in a new view of peroxisome. In this study, we analyzed the alteration of peroxisomal gene expression that could responsible for pathological difference between OA chondrocytes and OA/DM chondrocytes. To discriminate responsible genes in the OA/DM pathogenesis, the expressions of three hundred sixty-two genes reported to differentially relate to peroxisome were analyzed with OA chondrocytes in OA cartilage and OA/DM chondrocytes in the cartilage of OA with DM patient. Among them, PEX-16, a component of peroxisome, was significantly down-regulated in OA/DM chondrocytes and this down-regulation of PEX-16 increased the miR-223 induction. Knockdown studies using PEX-16 null cell line and PEX-16 specific siRNA showed the significant increase in apoptotic cell death. Moreover, over-expression of miR-223 stimulates apoptotic cell death in human articular chondrocytes and induced severe cartilage destruction in db/db mice. In conclusion, our study showed the differential peroxisomal gene expression profiles for OA/DM chondrocytes from OA chondrocytes and suggests the possibility that peroxisomal dysfunction in OA/DM could be responsible for early incidence and development of OA in DM patients.