HOXD‐AS2‐STAT3 feedback loop attenuates sensitivity to temozolomide in glioblastoma

AIMS: Glioblastoma multiforme (GBM) is the deadliest glioma and its resistance to temozolomide (TMZ) remains intractable. Long non‐coding RNAs (lncRNAs) play crucial roles in that and this study aimed to investigate underlying mechanism of HOXD‐AS2‐affected temozolomide sensitivity in glioblastoma. METHODS: We analyzed and validated the aberrant HOXD‐AS2 expression in glioma specimens. Then we explored the function of HOXD‐AS2 in vivo and in vitro and a clinical case was also reviewed to examine our findings. We further performed mechanistic experiments to investigate the mechanism of HOXD‐AS2 in regulating TMZ sensitivity. RESULTS: Elevated HOXD‐AS2 expression promoted progression and negatively correlated with prognosis of glioma; HOXD‐AS2 attenuated temozolomide sensitivity in vitro and in vivo; The clinical case also showed that lower HOXD‐AS2 sensitized glioblastoma to temozolomide; STAT3‐induced HOXD‐AS2 could interact with IGF2BP2 protein to form a complex and sequentially upregulate STAT3 signaling, thus forming a positive feedback loop regulating TMZ sensitivity in glioblastoma. CONCLUSION: Our study elucidated the crucial role of the HOXD‐AS2‐STAT3 positive feedback loop in regulating TMZ sensitivity, suggesting that this could be provided as a potential therapeutic candidate of glioblastoma.