Upregulation of Heme oxygenase-1 (HO-1) strengthens drug-resistance to apoptotic death in the several kinds of cancer cells. Our recent study shows the higher levels of HO-1 expression in the thyrosine kinase inhibitors (TKI) resistance K562 cell line and cells from Imatinb-insensitive CML patients. The cause of HO-1 upregulating, though, is still unclear yet.

MicroRNAs (miRNAs) play a significant role in the pathogenesis of cancer. They also are known as potential biomarkers and therapeutic targets. In the hematological neoplasm, miRNAs take part in not only cancer development, but also drug resistance. However, the problem has not been solved yet is how the microRNA involved in.

This study found that the expression level of microRNAs were much different depended on if it is Imatinb-insensitive or not. The phenomenon was observed both in the K562 and CML patients. The mir217 was one of these microRNAs that significantly deceased when the K562 had been induced to resist the Imatinb. Meanwhile,TKI-resistance K562 cells can be in association with an increase in levels of HO-1 and a decrease in levels of miR-217. In the TKI-resistant K562 cells, the decreased of miR-217 upregulated the expression of HO-1 through a 3'-untranslated region(UTR) of HO-1 and induced the resistance against TKI. Interestingly, TKI-resistant K562 cells exposed to miR-217 mimic can partially make the cells be sensitized to TKI again in association with upregulation of miR-217 and downregulation of HO-1 in vitro. The IC50 of the TKI-resistant K562 cells exposed in 7.5uM Imatinb for 48 hours also decreased after transfecting miR-217 mimic for 48 hours.

In our on-going experiment, the express level and interaction of HO-1 and miR-217 will be tested in K562 tumors growing in immune-deficient mice that were treated with the combination of mir-217 inhibitor, expression HO-1 virus and TKI. The express of HO-1 and miR-217 also will be examined in the TKI-insensitive CML patients and the mir217 and HO-1 regulated mechanism will be investigated in vivo.

According to our results, the reversibility of the mir-217 downregulating Heme oxygenase-1 in the K562 cells with TKI drug tolerance likely provides a potentially exciting miRNA therapeutic strategy.

MiRNAs therapy could be utilized as a powerful therapy which would focus to the drug-resistance patients. Drug-resistance cancer cells may be sensitized to former conventional or targeted chemotherapy.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.

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