Overcoming cisplatin resistance in osteosarcoma through the miR-199a-modulated inhibition of HIF-1α

Abstract

Dysregulation of microRNAs has been shown to contribute to multiple tumorigenic processes, as well as to correlate with tumor progression and prognosis. MiR-199a has been shown to be dysregulated in multiple tumor types. However, the association between miR-199a and the chemoresistance features of osteosarcoma is not well understood, and the target genes for miR-199a and the regulatory mechanisms are also unknown. In this study, we demonstrated that miR-199a is expressed at low levels in osteosarcoma cells and patient samples. By the selection and establishment of cisplatin resistant osteosarcoma cell line, we observed a correlation between miR-199a and cisplatin resistance in osteosarcoma cells: resistant cells exhibit attenuated miR-199a expressions and exogenous overexpression of miR-199a sensitizes osteosarcoma cells to cisplatin. Moreover, we identified HIF-1α as a direct target of miR-199a. Intriguingly, cisplatin resistant osteosarcoma cells display significantly elevated HIF-1α expression under hypoxia. We report here overexpression of miR-199a re-sensitizes cisplatin resistant cells to cisplatin through inhibition of HIF-1α and Finally, by analyzing the clinical osteosarcoma patient samples, we demonstrate a reverse correlation between miR-199a and HIF-1α mRNAs. Our study will provide mechanisms for the microRNAs-mediated anti-cancer therapy and miR-199a may be considered a promising therapeutic agent for osteosarcoma patients who fail to respond to conventional chemotherapy.

Feasibility of Cell Lines for In Vitro Co-Cultures Models for Bone Metabolism

“…Cal-72 cells basically disqualified due to the lack in RANKL expression. Notwithstanding, it has to be addressed that many osteosarcoma cell lines highly express hypoxia-inducible factor 1-alpha (HIF-1α) due to their cancerous origin [201,202]. HIF-1α is a well-known inducer of vascular endothelial growth factor (VEGF), which has been reported to be a substitute for M-CSF in RANKL-induced osteoclastogenesis [164,203].…”

Overexpression of miR-26b decreases the cisplatin-resistance in laryngeal cancer by targeting ATF2

“…It has been demonstrated that dysregulation of miRNAs is required in tumorigenesis and tumor development [ 15 - 17 ]. Furthermore, Aberrant expression of miRNAs is found to induce chemoresistance in various cancers including laryngeal cancer [ 18 - 20 ]. The present study demonstrates that reduction of miR-26b is associated with chemoresistance in cisplatin-resistant laryngeal cancer cell model, and recovery of miR-26b is able to decrease this cisplatin resistance by targeting ATF2.…”

HIF in Nephrotoxicity during Cisplatin Chemotherapy: Regulation, Function and Therapeutic Potential

“…Generally, intratumoral hypoxia, together with functional alterations of tumor suppressor genes (most importantly, VHL) and oncogenes, upregulates HIF activity, which regulate multiple pathological processes and eventually result in the resistance to chemotherapy, radiation therapy, and targeted therapy [ 195 , 196 ]. Studies have revealed HIF overexpression in multiple tumors [ 20 , 197 ] and found that HIF is closely related to tumor resistance to cisplatin [ 198 , 199 , 200 , 201 , 202 ]. Zhang et al [ 200 ] reported that HIF-1α may act as a mediator of the interaction between p53 and RAS signaling to participate in the cisplatin resistance in ovarian cancer and that silencing HIF-1α significantly decreased the cellular sensitivity to cisplatin.…”

“…Zhang et al [ 200 ] reported that HIF-1α may act as a mediator of the interaction between p53 and RAS signaling to participate in the cisplatin resistance in ovarian cancer and that silencing HIF-1α significantly decreased the cellular sensitivity to cisplatin. Keremu et al [ 201 ] found dramatically elevated HIF-1α expression in cisplatin-resistant osteosarcoma cells under hypoxia. The inhibition of HIF-1α by miR-199a overexpression can sensitize the response of cisplatin-resistant cells.…”