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Midazolam increases cisplatin-sensitivity in non-small cell lung cancer (NSCLC) via the miR-194-5p/HOOK3 axis
Tingting Sun1, Jing Chen1, Xuechao Sun1
1Department of Anesthesiology, Harbin Medical University Cancer Hospital, Haping Road No. 150, Harbin, 150081, Heilongjiang, China.
Backgrounds:
As previously reported, midazolam anesthesia exerts tumor-suppressing effects in non-small cell lung cancer (NSCLC), but the regulating effects of this drug on cisplatin-resistance in NSCLC have not been studied. Thus, we designed this study to investigate this issue and preliminarily delineate the potential molecular mechanisms.
Methods:
We performed MTT assay and trypan blue staining assay to measure cell proliferation and viability. Cell apoptosis was examined by FCM. qRT-PCR and immunoblotting were performed to determine the expression levels of genes. The targeting sites between genes were predicted by bioinformatics analysis and were validated by dual-luciferase reporter gene system assay. Mice tumor-bearing models were established and the tumorigenesis was evaluated by measuring tumor weight and volume. Immunohistochemistry (IHC) was used to examine the pro-proliferative Ki67 protein expressions in mice tumor tissues.
Results:
The cisplatin-resistant NSCLC (CR-NSCLC) cells were treated with high-dose cisplatin (50 μg/ml) and low-dose midazolam (10 μg/ml), and the results showed that midazolam suppressed cell proliferation and viability, and promoted cell apoptosis in cisplatin-treated CR-NSCLC cells. In addition, midazolam enhanced cisplatin-sensitivity in CR-NSCLC cell via modulating the miR-194-5p/hook microtubule-tethering protein 3 (HOOK3) axis. Specifically, midazolam upregulated miR-194-5p, but downregulated HOOK3 in the CR-NSCLC cells, and further results validated that miR-194-5p bound to the 3' untranslated region (3'UTR) of HOOK3 mRNA for its inhibition. Also, midazolam downregulated HOOK3 in CR-NSCLC cells by upregulating miR-194-5p. Functional experiments validated that both miR-194-5p downregulation and HOOK3 upregulation abrogated the promoting effects of midazolam on cisplatin-sensitivity in CR-NSCLC cells.
Conclusions:
Taken together, this study found that midazolam anesthesia reduced cisplatin-resistance in CR-NSCLC cells by regulating the miR-194-5p/HOOK3 axis, implying that midazolam could be used as adjuvant drug for NSCLC treatment in clinical practices.
Insights
Midazolam anesthesia reduces cisplatin-resistance in non-small cell lung cancer (NSCLC) by upregulating miR-194-5p and downregulating HOOK3. This suggests midazolam as a potential adjuvant therapy for NSCLC treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Midazolam anesthesia shows tumor-suppressing effects in non-small cell lung cancer (NSCLC).
- The impact of midazolam on cisplatin-resistance in NSCLC remains uninvestigated.
- This study aims to explore midazolam's effects on cisplatin-resistance and its underlying molecular mechanisms in NSCLC.
Purpose of the Study:
- To investigate the effect of midazolam on cisplatin-resistant NSCLC (CR-NSCLC) cells.
- To elucidate the molecular mechanisms by which midazolam influences cisplatin-resistance.
- To evaluate midazolam's potential as an adjuvant therapy for NSCLC.
Main Methods:
- Cell viability and apoptosis assays (MTT, trypan blue, FCM).
- Gene expression analysis (qRT-PCR, immunoblotting).
- Bioinformatic prediction and dual-luciferase reporter assay for gene interactions.
- In vivo studies using tumor-bearing mice models and immunohistochemistry (IHC).
Main Results:
- Midazolam suppressed proliferation and viability, and promoted apoptosis in CR-NSCLC cells.
- Midazolam enhanced cisplatin sensitivity by upregulating miR-194-5p and downregulating HOOK3.
- miR-194-5p directly targets and inhibits HOOK3, a mechanism validated in CR-NSCLC cells.
Conclusions:
- Midazolam reduces cisplatin-resistance in CR-NSCLC by modulating the miR-194-5p/HOOK3 axis.
- Midazolam's ability to overcome cisplatin-resistance suggests its potential as an adjuvant drug in clinical NSCLC treatment.
