Background
Chemoresistance poses a significant challenge in the treatment of osteosarcoma (OS). Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of cancer biology. Despite accumulating evidence linking dysregulation of lncRNAs to chemoresistance, the specific regulatory functions and complexities involved in lncRNA-mediated modulation of doxorubicin-based chemotherapy in OS remain understudied.
Conclusions
We conclude that Lnc-PHF3-3 contributes to doxorubicin resistance in OS by sequestering miR-142-3p and subsequently enhancing HMGB1 expression.
Methods
We examined expression levels of lncRNA Lnc-PHF3-3 and miR-142-3p in OS tissues and cell lines by lncRNA microarray profiling and qRT-PCR. Gain-of-function and loss-of-function assays were performed to examine the effect of lncRNA Lnc-PHF3-3 and miR-142-3p on chemoresistance of OS cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of Lnc-PHF3-3 in OS cells.
Results
This study aimed to investigate key lncRNAs associated with chemoresistance in OS and identify potential therapeutic targets for patients with chemoresistant OS. To identify chemoresistance-related lncRNAs, microarray analysis was conducted using drug-resistant/drug-sensitive OS cell lines and chemoresistant/chemosensitive OS tissues. Among the identified candidates, a novel lncRNA called Lnc-PHF3-3 was found to be upregulated in doxorubicin-resistant OS cell lines and chemoresistant OS patients. Functional characterization revealed that Lnc-PHF3-3 promoted doxorubicin resistance both in vitro and in vivo. Further investigation revealed that Lnc-PHF3-3 acted as a sponge for microRNA miR-142-3p, and overexpression of miR-142-3p resulted in reduced chemoresistance. Additionally, the high mobility group box 1 (HMGB1) gene was identified as a direct and functional target of miR-142-3p. Conclusions: We conclude that Lnc-PHF3-3 contributes to doxorubicin resistance in OS by sequestering miR-142-3p and subsequently enhancing HMGB1 expression.