CLDN18.2-specific CAR T cells could be a promising treatment strategy for gastric cancer and potentially other CLDN18.2-positive tumors.

Osteoarthritis is a common cause of functional deterioration in older adults and is an immense burden on the aging population. Altered chondrogenesis is the most important pathophysiological process involved in the development of osteoarthritis. However, the molecular mechanism underlying the regulation of chondrogenesis in patients with osteoarthritis requires further elucidation, particularly with respect to the role of microRNAs. MiR-21 expression in cartilage specimens was examined in 10 patients with knee osteoarthritis and 10 traumatic amputees. The effect of miR-21 on chondrogenesis was also investigated in a chondrocyte cell line. The effect of miR-21 on the expression of growth differentiation factor 5 (GDF-5) was further assessed by luciferase reporter assay and western blot. We found that endogenous miR-21 is upregulated in osteoarthritis patients, and overexpression of miR-21 could attenuate the process of chondrogenesis. Furthermore, we identified GDF-5 as the direct target of miR-21 during the regulation of chondrogenesis. Our data suggest that miR-21 has an important role in the pathogenesis of osteoarthritis and is a potential therapeutic target.

MicroRNAs (miRNAs) have recently been recognized to have a role in human orthopedic disorders. The objective of our study was to explore the expression profile and biological function of miRNA-17-5p (miR-17-5p), which is well known to be related to cancer cell proliferation and invasion, in osteoblastic differentiation and in cell proliferation. The expression levels of miR-17-5p in the femoral head mesenchymal stem cells of 20 patients with non-traumatic osteonecrosis (ON) and 10 patients with osteoarthritis (OA) were examined by quantitative reverse transcription-PCR (qRT–PCR). Furthermore, the interaction between miR-17-5p and SMAD7 was observed. We found that in non-traumatic ON samples the level of mature miR-17-5p was significantly lower than that of OA samples (P=0.0002). By targeting SMAD7, miR-17-5p promoted nuclear translocation of β-catenin, enhanced expression of COL1A1 and finally facilitated the proliferation and differentiation of HMSC-bm cells. We also demonstrated that restoring expression of SMAD7 in HMSC-bm cells partially reversed the function of miR-17-5p. Together, our data suggested a theory that dysfunction of a network containing miR-17-5p, SMAD7 and β-catenin could contribute to ON pathogenesis. The present study prompts the potential clinical value of miR-17-5p in non-traumatic ON.

Drug resistance remains a major clinical obstacle to successful treatment in ovarian cancer patients, and the evidence of microRNAs involvement in drug resistance has been emerging recently. In this report, we investigated the role of let-7e in the development of cisplatin-resistant ovarian cancer. On the cellular level, let-7e expression was significantly reduced in cisplatin-resistant human epithelial ovarian cancer (EOC) cell line A2780/CP compared with parental A2780 cell and decreased in a concentration-dependent manner in A2780, SKOV3 and ES2 cells treated with cisplatin. Overexpression of let-7e by transfection of agomir could resensitize A2780/CP and reduce the expression of cisplatin-resistant-related proteins enhancer of zeste 2 (EZH2) and cyclin D1 (CCND1), whereas let-7e inhibitors increased resistance to cisplatin in parental A2780 cells. Quantitative methylation-specific PCR analysis showed hypermethylation of the CpG island adjacent to let-7e in A2780/CP cells, and demethylation treatment with 5-aza-CdR or transfection of pYr-let-7e-shRNA plasmid containing unmethylated let-7e DNA sequence could restore let-7e expression and partly reduce the chemoresistance. In addition, cisplatin combined with let-7e agomirs inhibited the growth of A2780/CP xenograft more effectively than cisplatin alone. Diminished expression of EZH2 and CCND1 and higher cisplatin concentrations in tumor tissue of mice subjected to administration of let-7e agomirs in addition to cisplatin were revealed by immunohistochemistry and atomic absorption spectroscopy, respectively. Taken together, our findings suggest that let-7e may act as a promising therapeutic target for improvement of the sensibility to cisplatin in EOC.

Edited by Tamas DalmayKeywords: MiR-199a-5p DRAM1 Beclin1 Autophagy Irradiation a b s t r a c t Autophagy is a self-degrading process that is triggered by diverse stimuli including ionizing radiation. In this study we show novel phenomena in which transfection of miR-199a-5p mimic significantly suppresses IR-induced autophagy in MCF7 cells, and up-regulates basal and IR-induced autophagy in MDA-MB-231 breast cancer cells. We also identify DRAM1 and Beclin1 as novel target genes for miR-199a-5p. Overexpression of miR-199a-5p inhibits DRAM1 and Beclin1 expression in MCF7 cells, while it enhances expression of these genes in MDA-MB-231 cells. Furthermore, we show that miR-199a-5p sensitizes MDA-MB-231 cells to irradiation. Therefore, our data identify miR-199a-5p as a novel and unique regulator of autophagy, which plays an important role in cancer biology and cancer therapy.

a b s t r a c tOsteogenesis depends on a coordinated network of transcription factors including Sp7. Emerging evidence indicates that microRNAs (miRNAs) act as pivotal regulators in various biological processes including osteoblast proliferation and differentiation. Here, we investigated the effect of miR-145 on osteogenic differentiation. miR-145 was decreased during osteogenic differentiation, which could suppress the osteogenic differentiation of C 2 C 12 and MC3T3-E1 cells confirmed by gain-and loss-of-function experiments. Moreover, bioinformatic analysis combined with luciferase reporter assay, and Western blot validated that miR-145 negatively regulated Sp7 expression. Inhibition of Sp7 showed similar effect with miR-145 on osteogenic differentiation, whereas overexpression of Sp7 attenuated this effect. Collectively, these data indicate that miR-145 is a novel regulator of Sp7, and it suppresses the osteogenic differentiation of C 2 C 12 and MC3T3-E1 cells.

No abstract

Resveratrol is a non-flavonoid polyphenol compound with a stilbene structure. As a type of phytoalexin produced under stress in plants, it improves the plant's resistance against pathogens and environment deterioration, and performs important functions beneficial to human health, such as anti-cancer, anti-oxidation, regulating blood lipid levels and prolonging life span. The effects of resveratrol were examined in a rat model of osteoarthritis (OA) and observed to ameliorate inflammatory damage and protect against OA. In the present study, resveratrol significantly inhibited the induction of clinical scores in rats with OA. Resveratrol inhibited tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-18 expression levels, and decreased caspase-3/9 activity in rats with OA. Inducible nitric oxide synthase, nuclear factor (NF)-κB, phosphorylated-(p)-AMP-activated protein kinase and sirtuin 1 protein expression were significantly suppressed and heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) protein expression was stimulated in rats with OA treated with resveratrol. The current results indicate that resveratrol ameliorates inflammatory damage and protects against OA in a rat model of OA via NF-κB and HO-1/Nrf-2 signaling.