LncRNA-SARCC sensitizes osteosarcoma to cisplatin through the miR-143-mediated glycolysis inhibition by targeting Hexokinase 2.

Chemotherapy is one of the primary treatments used against cancer. Cisplatin is a conventional chemotherapy drug used to treat osteosarcoma; however, due to the development of cisplatin resistance, advantageous therapeutic outcomes and prognosis of osteosarcoma remain low. Thus, investigation of the specific targeted therapies to circumvent the anti-chemoresistance of osteosarcoma depends on understanding the molecular mechanisms underlying cisplatin resistance. Tumor cells display an increased utilization of glycolysis rather than oxidative phosphorylation. This phenomenon is called the "Warburg effect," which presents a survival advantage for tumor cells, leading to chemoresistance. To date, the molecular mechanism underlying osteosarcoma cisplatin resistance remains to be fully elucidated. In this study, we reported the significant down-regulation of the long noncoding RNA-Suppressing Androgen Receptor in Renal Cell Carcinoma (lncRNA-SARCC) in the cells of osteosarcoma and in the specimens from osteosarcoma patients. Moreover, we observed a negative correlation between the lncRNA-SARCC and cisplatin resistance in the osteosarcoma tissues. Overexpression of the lncRNA-SARCC sensitizes osteosarcoma cells to cisplatin. From microarray analysis, we screened several miRNAs, which are significantly regulated by the lncRNA-SARCC in osteosarcoma cells, and revealed that lncRNA-SARCC promoted microRNA-43 (miR-143) expression in osteosarcoma. Interestingly, miR-143 showed the same expression pattern with the lncRNA-SARCC in osteosarcoma patient specimens. By establishing a cisplatin-resistant cell line from Sarcoma Osteogenic-2 (Saos-2), we found the cisplatin-resistant cells with down-regulated expressions of the lncRNA-SARCC and miR-143, but with a higher glycolysis rate compared to that in parental cells. We identified the glycolysis key enzyme, Hexokinase 2 (HK2), as a direct target for miR-143 in osteosarcoma. Restoration of the HK2 expression in the lncRNA-SARCC-overexpressing osteosarcoma cells reversed cisplatin resistance, suggesting that lncRNA-SARCC-mediated cisplatin sensitivity may be via glycolysis in the miR-143-inhibited osteosarcoma cells. Finally, results from both in vitro and in vivo xenograft models demonstrated that the lncRNA-SARCC was an effective therapeutic agent for overcoming cisplatin resistance in osteosarcoma. Our findings suggest an essential axis of the lncRNA-SARCC-miR-143-HK2 in regulation of osteosarcoma chemosensitivity, presenting the lncRNA-SARCC as a new therapeutic target against cisplatin-resistant osteosarcoma.

LncRNA-XIST promotes the oxidative stress-induced migration, invasion, and epithelial-to-mesenchymal transition of osteosarcoma cancer cells through miR-153-SNAI1 axis.

Osteosarcoma (OS) is the most common type of primary bone tumor that exhibits invasive growth and long-distance organ metastasis. Thus, investigating the specifically targeted therapeutic agents against metastatic osteosarcoma depends on understanding the molecular mechanisms. The long noncoding RNAs (lncRNA) XIST (X-inactive specific transcript) has been reported to have oncogenic roles in various malignant tumors including OS. However, its molecular mechanisms in OS migration and invasion are still under investigation. In the current study, we demonstrate that XIST is significantly upregulated in 30 pairs of OS tissues compared with their matched adjacent nontumor tissues by the quantitative reverse transcription polymerase chain reaction. Overexpression of XIST significantly induced the invasion, migration, and the epithelial-to-mesenchymal transition (EMT) phenotype. The epithelial marker, E-cadherin was effectively suppressed by XIST overexpression. On the other way, the mesenchymal marker, Fibronectin, Snail, and Vimentin were significantly activated by exogenous XIST overexpression. Furthermore, we observed XIST was upregulated by the oxidative stress-induced EMT. Bioinformatical analysis indicated that miR-153 has multiple biding sites for XIST and miR-153 was inversely suppressed by oxidative stress. XIST was verified to directly downregulate miR-153 via sponging. We identified the mesenchymal marker, SNAI1 was a direct messenger RNA target of miR-153. Importantly, inhibiting XIST successfully blocked the H2 O2 -induced EMT of OS cells. In conclusion, this work demonstrates that lncRNA-XIST promotes the oxidative stress-induced OS cell invasion, migration, and EMT through the miR-153/SNAI1 pathway, presenting lncRNA-XIST as a promising therapeutic target for treating metastatic OS.

[Progress on miRNA in mammal breast milk].

As an important regulator in eukaryote, miRNAs could be in the animal body fluids, including serum, blood plasma, saliva, urine and so on. More recently, it was reported that miRNAs were also in the breast milk of human or cow, which indicates that miRNAs could probably be transferred into the body of the next generation by lactation and play their key roles. This might be the prelude of studies on the regulation function of miRNAs in generations. Here, we introduced the process of finding miRNAs in mammal milk, the format of miRNAs in milk and the method for isolating miRNAs, and reviewed the main functions of several miRNAs in milk. We also discussed the research task and challenge associated with miRNAs in milk at the next.

Type-dependent differential expression of neuropeptide Y in chicken hypothalamus (Gallus domesticus).

Neuropeptide Y (NPY) is one of the most important orexigenic agents in central regulation of feeding behavior, body weight and energy homeostasis in domestic chickens. To examine differences in the hypothalamic NPY between layer-type and meat-type of chickens, which are two divergent kinds of the domestic chickens in feeding behavior and body weight, we detected mRNA levels of NPY in hypothalamic infundibular nucleus (IN), paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) of these two types of chickens using one-step real time RT-PCR. The meat-type chicken had more food daily (about 1.7 folds) and greater body weights (about 1.5 folds) and brain weights than the layer-type chicken at the age of 14 d. In the meat-type of chicken, NPY mRNA levels of the IN and PVN were significantly greater than those of the LHA, and were not significantly different between the IN and PVN. However, in the layer-type of chicken, NPY mRNA levels were significantly greater in the IN than those in the LHA and PVN, and were not significantly different between the PVN and LHA. In all these hypothalamic regions, the layer-type of chicken had significantly higher NPY mRNA levels than the meat-type chicken did. These results suggest the expression of NPY in the hypothalamus has a type-dependent pattern in domestic chickens.

Changes of cyclic AMP levels and phosphodiesterase activities in the rat ovary.

Cyclic AMP (cAMP) is a second messenger that plays a critical role in follicular recruitment, development and luteinization in the mammalian ovary. The cellular level of cAMP is largely dependent on the activity of phosphodiesterase (PDE), which degrades cAMP into 5'-AMP. The present study was conducted to investigate the level of cAMP and the activity of cAMP-PDE in postnatal rats; immature rats during gonadotropin-primed follicular development, ovulation and luteinization; adult rats during normal estrous cycling; and aged rats that spontaneously developed persistent estrous (PE) by radioimmunoassay (RIA). All four rat models were confirmed by histological examination of one ovary and assayed using the other ovary by RIA. In the postnatal rats, the ovarian cAMP level was high on day 10 after birth, while ovarian cAMP-PDE activity was highest at 21 days of age. In the immature female rats, both the ovarian cAMP level and cAMP-PDE activity increased remarkably after treatment with equine chorionic gonadotropin (eCG), increased continuously 24 h after injection of human chorionic gonadotropin (hCG) for induction of ovulation and luteinization, and then declined significantly. In the adult rats during the normal estrous cycle, the ovarian cAMP levels were low on the day of estrus, and there were no significant changes in ovarian cAMP-PDE activity throughout the estrous cycle. In the PE rats, the ovarian cAMP levels were similar to those of the adult rats on the day of estrus but were lower than those on the other days of the estrous cycle; ovarian cAMP-PDE activity was lower than that in the adult rats on any day of the estrous cycle. Together, these findings indicate that the ovarian cAMP level and cAMP-PDE activity were regulated in a stage-dependent manner during ovarian follicular development, atresia and luteinization and providing evidences that cAMP and cAMP-specific PDEs are involved in these physiological processes.