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.