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http://dx.doi.org/10.14348/molcells.2020.0133

Long Noncoding RNA HOXA11-AS Modulates the Resistance of Nasopharyngeal Carcinoma Cells to Cisplatin via miR-454-3p/c-Met  

Lin, Feng-Jie (Department of Head & Neck Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital)
Lin, Xian-Dong (Laboratory of Radiation Oncology and Radiobiology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital)
Xu, Lu-Ying (Department of Head & Neck Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital)
Zhu, Shi-Quan (Department of Pharmacy, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital)
Publication Information
Molecules and Cells / v.43, no.10, 2020 , pp. 856-869 More about this Journal
Abstract
To elucidate the mechanism of action of HOXA11-AS in modulating the cisplatin resistance of nasopharyngeal carcinoma (NPC) cells. HOXA11-AS and miR-454-3p expression in NPC tissue and cisplatin-resistant NPC cells were measured via quantitative reverse transcriptase polymerase chain reaction. NPC parental cells (C666-1 and HNE1) and cisplatin-resistant cells (C666-1/DDP and HNE1/DDP) were transfected and divided into different groups, after which the MTT method was used to determine the inhibitory concentration 50 (IC50) of cells treated with different concentrations of cisplatin. Additionally, a clone formation assay, flow cytometry and Western blotting were used to detect DDP-induced changes. Thereafter, xenograft mouse models were constructed to verify the in vitro results. Obviously elevated HOXA11-AS and reduced miR-454-3p were found in NPC tissue and cisplatin-resistant NPC cells. Compared to the control cells, cells in the si-HOXA11-AS group showed sharp decreases in cell viability and IC50, and these results were reversed in the miR-454-3p inhibitor group. Furthermore, HOXA11-AS targeted miR-454-3p, which further targeted c-Met. In comparison with cells in the control group, HNE1/DDP and C666-1/DDP cells in the si-HOXA11-AS group demonstrated fewer colonies, with an increase in the apoptotic rate, while the expression levels of c-Met, p-Akt/Akt and p-mTOR/mTOR decreased. Moreover, the si-HOXA11-AS-induced enhancement in sensitivity to cisplatin was abolished by miR-454-3p inhibitor transfection. The in vivo experiment showed that DDP in combination with si-HOXA11-AS treatment could inhibit the growth of xenograft tumors. Silencing HOXA11-AS can inhibit the c-Met/AKT/mTOR pathway by specifically upregulating miR-454-3p, thus promoting cell apoptosis and enhancing the sensitivity of cisplatin-resistant NPC cells to cisplatin.
Keywords
cisplatin; c-Met; drug resistance; HOXA11-AS; miR-454-3p; nasopharyngeal carcinoma;
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