Blocking lncRNA HCG18 re-sensitizes Taxol resistant lung cancer cells to Taxol through modulating the miR-34a-5p/HDAC1 axis

Abstract

Lung cancer is one of the most frequently diagnosed cancers worldwide, associated with a poor survival rate. Taxol (Paclitaxel) is commonly used as a chemotherapeutic treatment for advanced lung cancers. While Taxol has improved clinical outcomes for lung cancer patients, a significant number of them develop resistance to Taxol, resulting in treatment failure. The role of the long noncoding RNA HCG18 in lung cancer and Taxol resistance has not yet been fully understood. To investigate this, we examined the expression of HCG18 and miR-34a-5p in lung tumors and normal lung tissues using qRT-PCR. We also assessed Taxol resistance through cell viability and apoptosis assays. Through the starBase online service, we analyzed the interactions between lncRNA and mRNA as well as miRNA and mRNA. We further validated the association between lncRNA and miRNA through luciferase and RNA pull-down assays. Our findings demonstrated that HCG18 was significantly upregulated in lung cancer tissues compared to normal lung tissues. Silencing HCG18 increased the sensitivity of lung cancer cells to Taxol. Additionally, our study established a Taxol-resistant cell line and observed a substantial upregulation of HCG18 in Taxol-resistant lung cancer cells. Bioinformatic analysis predicted that HCG18 could bind to miR-34a-5p, forming a competing endogenous RNA network, which was confirmed through luciferase assay. We found that miR-34a-5p was downregulated in lung cancer tissues and negatively correlated with Taxol resistance, as it directly bound to the 3’UTR region of HDAC1. Further results showed that inhibition of HCG18 significantly increased miR-34a-5p expression and sensitized lung cancer cells to Taxol. This sensitization could be reversed by inhibiting miR-34a-5p. Finally, we demonstrated in a xenograft mouse model that inhibition of HCG18 sensitized Taxol-resistant lung cancer cells to Taxol treatment by modulating the miR-34a-5p-HDAC1 axis. In conclusion, our in vitro and in vivo results uncover a novel molecular mechanism by which HCG18 promotes Taxol resistance through modulation of the miR-34a-5p/HDAC1 axis. These findings contribute to the diagnosis and treatment of chemo-resistant lung cancer.

Keywords:

• Lung cancer
• lncRNA HCG18
• miR-34a-5p
• HDAC1
• Taxol resistance

Ethics approval and consent to participate

All procedures performed in this study were in accordance with the ethical standards of the research committee of the First Affiliated Hospital of Kunming Medical University and the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all participants enrolled in the study.

Data and materials availability

The datasets generated and/or analyzed during this study are available from the corresponding author on reasonable request.

Authors’ contributions

F.J.ZH. and R.G. designed the research. All authors carried out the experiments, analyzed and interpreted the results. R.G. wrote the manuscript. All authors have read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by the Kunming Medical University Joint Special Fund (#007234726065).