miR‑21 modulates paclitaxel sensitivity and hypoxia‑inducible factor‑1α expression in human ovarian cancer cells

Xie,Zhongbin; Cao,Liping; Zhang,Jun

doi:10.3892/ol.2013.1432

miR‑21 modulates paclitaxel sensitivity and hypoxia‑inducible factor‑1α expression in human ovarian cancer cells

Authors:
- Zhongbin Xie
- Liping Cao
- Jun Zhang
View Affiliations

Affiliations: Department of Clinical Laboratory Medicine, Yulin Number Two Hospital, Yulin 719000, P.R. China, Department of Obstetrics and Gynecology, Yulin Traditional Chinese Medical Hospital, Yulin 719000, P.R. China, Department of Clinical Laboratory Medicine, 3201 Hospital, Hanzhong, Shanxi 723000, P.R. China
Published online on: June 28, 2013 https://doi.org/10.3892/ol.2013.1432
Pages: 795-800

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Drug resistance is a major problem encountered in the treatment of ovarian cancer. Previous studies have demonstrated that in several types of cancer the overexpression of the multidrug resistance 1 (MDR1) gene is mainly associated with drug resistance. The present study aimed to investigate the role of miR‑21 in the development of drug resistance in ovarian cancer cells. The expression levels of miR‑21 in the ovarian cancer A2780 and A2780/taxol cell lines were detected by stem‑loop real‑time PCR. A2780 and A2780/taxol cells were transfected with mimics or inhibitors of miR‑21 or negative control RNA. The expression levels of P‑glycoprotein (P‑gp) and hypoxia‑inducible factor‑1α (HIF‑1α) proteins were assessed by western blot analysis. Drug sensitivity was analyzed by the 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) assay. The expression levels of miR‑21 and P‑gp were upregulated to a greater extent in the paclitaxel‑resistant ovarian cancer A2780/taxol cell line compared with the parental A2780 cell line. Transfection of A2780/taxol cells with inhibitors of miR‑21 decreased the expression levels of the P‑gp and HIF‑1α proteins, and increased the sensitivity of the A2780/taxol cells to paclitaxel. The expression levels of P‑gp were additionally increased; however, the sensitivity of the miR‑21 mimic‑treated A2780 cells to paclitaxel was decreased. miR‑21 may be involved in the development of drug resistance and the regulation of MDR1/P‑gp expression, at least in part, by targeting HIF‑1α in ovarian cancer cells.

View Figures

View References

1	Hassan MK, Watari H, Christenson L, Bettuzzi S and Sakuragi N: Intracellular clusterin negatively regulates ovarian chemoresistance: compromised expression sensitizes ovarian cancer cells to paclitaxel. Tumour Biol. 32:1031–1047. 2011. View Article : Google Scholar
2	McGuire WP 3rd and Markman M: Primary ovarian cancer chemotherapy: current standards of care. Br J Cancer. 89(Suppl 3): S3–S8. 2003. View Article : Google Scholar : PubMed/NCBI
3	Ozols RF and Young RC: Chemotherapy of ovarian cancer. Semin Oncol. 11:251–263. 1984.
4	Dai Z, Huang Y and Sadée W: Growth factor signaling and resistance to cancer chemotherapy. Curr Top Med Chem. 4:1347–1356. 2004.PubMed/NCBI
5	Fuchs J, Habild G, Leuschner I, Schweinitz DV, Haindl J and Knop E: Paclitaxel: an effective antineoplastic agent in the treatment of xenotransplanted hepatoblastoma. Med Pediatr Oncol. 32:209–215. 1999. View Article : Google Scholar : PubMed/NCBI
6	Heney M, Alipour M, Vergidis D, et al: Effectiveness of liposomal paclitaxel against MCF-7 breast cancer cells. Can J Physiol Pharmacol. 88:1172–1180. 2010. View Article : Google Scholar : PubMed/NCBI
7	Pisters KM, Vallières E, Crowley JJ, et al: Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol. 28:1843–1849. 2010. View Article : Google Scholar
8	Selimovic D, Hassan M, Haikel Y and Hengge UR: Taxol-induced mitochondrial stress in melanoma cells is mediated by activation of c-Jun N-terminal kinase (JNK) and p38 pathways via uncoupling protein 2. Cell Signal. 20:311–322. 2008. View Article : Google Scholar : PubMed/NCBI
9	Fojo T and Menefee M: Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents. Ann Oncol. 18(Suppl 5): v3–v8. 2007. View Article : Google Scholar : PubMed/NCBI
10	Roberti A, La Sala D and Cinti C: Multiple genetic and epigenetic interacting mechanisms contribute to clonally selection of drug-resistant tumors: current views and new therapeutic prospective. J Cell Physiol. 207:571–581. 2006. View Article : Google Scholar
11	Leonard GD, Fojo T and Bates SE: The role of ABC transporters in clinical practice. Oncologist. 8:411–424. 2003. View Article : Google Scholar : PubMed/NCBI
12	Gottesman MM and Ling V: The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett. 580:998–1009. 2006.PubMed/NCBI
13	Li Z, Hu S, Wang J, et al: MiR-27a modulates MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells. Gynecol Oncol. 119:125–130. 2010. View Article : Google Scholar : PubMed/NCBI
14	Chen C, Ridzon DA, Broomer AJ, et al: Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33:e1792005. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Hu MD, Xu JC, Fan Y, Xie QC, Li Q, Zhou CX, Mao M and Yang Y: Hypoxia-inducible factor 1 promoter-induced JAB1 overexpression enhances chemotherapeutic sensitivity of lung cancer cell line A549 in an anoxic environment. Asian Pac J Cancer Prev. 13:2115–2120. 2012. View Article : Google Scholar : PubMed/NCBI
17	Bourguignon LY, Spevak CC, Wong G, Xia W and Gilad E: Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the Production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem. 284:26533–26546. 2009.
18	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar
19	Hilpert F, Krause G, Venhoff L, Kuhnle E, Schem C and Maass N: Epithelial ovarian cancer. Ther Umsch. 64:375–380. 2007.(In German).
20	Li H, Hui L, Xu W, et al: Triptolide modulates the sensitivity of K562/A02 cells to adriamycin by regulating miR-21 expression. Pharm Biol. 50:1233–1240. 2012. View Article : Google Scholar : PubMed/NCBI
21	Li Y, Zhu X, Gu J, et al: Anti-miR-21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis. Cancer Sci. 101:948–954. 2010. View Article : Google Scholar : PubMed/NCBI
22	Li Y, Zhu X, Gu J, et al: Anti-miR-21 oligonucleotide enhances chemosensitivity of leukemic HL60 cells to arabinosylcytosine by inducing apoptosis. Hematology. 15:215–221. 2010. View Article : Google Scholar : PubMed/NCBI
23	Nardinocchi L, Puca R and D’Orazi G: HIF-1α antagonizes p53-mediated apoptosis by triggering HIPK2 degradation. Aging (Albany NY). 3:33–43. 2011.