Lnc-PHF3-3 aggravates the chemoresistance of osteosarcoma cells to doxorubicin via the miR-142-3p/HMGB1 axis

Background: Chemoresistance poses a significant challenge in the treatment of osteosarcoma (OS). Long noncoding 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. 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-1423p and subsequently enhancing HMGB1 expression.