Hypoxia-induced lnc-IRP drives oxaliplatin resistance in colorectal cancer through IRP2 sequestration and iron metabolism reprogramming.

backgroundHypoxic microenvironment is an important characteristic of solid tumors. A series of adaptations associated with hypoxia occur in cancer cells, including reprogramming of multiple metabolic pathways. Gastrointestinal bleeding is a common clinical symptom of CRC, resulting in anemia and iron deficiency. CRC patients have unbalanced iron homeostasis due to blood loss, chronic inflammation, etc. However, the molecular mechanisms underlying the effect of hypoxia-induced reprogramming of iron metabolism on chemosensitivity in CRC remain unclear.

methodsRIP-seq combined with lncRNA-seq was conducted on hypoxia or normoxia CRC cells, to screen a profile of lncRNAs. Based on the characteristics of IRE elements, the sequence alignment and secondary structure analysis of the above screened lncRNAs were carried out by using open-access databases. Then lnc-IRP was obtained. RNA pull-down, RIP, RNA FISH and IF were used to confirm the binding and co-localization relationship between lnc-IRP and IRP2. Subsequently, the role of lnc-IRP in the chemosensitivity of CRC was verified both in vitro and in vivo.

resultslnc-IRP relied on its IRE-like element to competitively bind IRP2, which disrupted intracellular iron regulatory network, leading to a tendency of iron to be stored in a ferric form rather than converted to LIP, and ultimately inhibiting apoptosis and ferroptosis.

conclusionslnc-IRP is a potential therapeutic target to restore iron homeostasis under hypoxia, thereby increasing the sensitivity of CRC to oxaliplatin, which is expected to provide a new choice for clinical treatment, and thus improve the prognosis of patients.