MicroRNA-7 sensitizes non-small cell lung cancer cells to paclitaxel

Liu,Ronghua; Liu,Xiaoming; Zheng,Yijie; Gu,Jie; Xiong,Shudao; Jiang,Pei; Jiang,Xuechao; Huang,Enyu; Yang,Yixian; Ge,Di; Chu,Yiwei

doi:10.3892/ol.2014.2500

MicroRNA-7 sensitizes non-small cell lung cancer cells to paclitaxel

Authors:
- Ronghua Liu
- Xiaoming Liu
- Yijie Zheng
- Jie Gu
- Shudao Xiong
- Pei Jiang
- Xuechao Jiang
- Enyu Huang
- Yixian Yang
- Di Ge
- Yiwei Chu
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Affiliations: Department of Immunology, Shanghai Medical College, Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, Shanghai 200032, P.R. China, Department of Thoracic Surgery, The Affiliated Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
Published online on: September 4, 2014 https://doi.org/10.3892/ol.2014.2500
Pages: 2193-2200

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Abstract

Paclitaxel (PTX) is the front‑line chemotherapeutic agent against human non‑small cell lung cancer (NSCLC). However, its therapeutic efficacy is restricted by the increasing frequency of chemotherapeutic resistance in NSCLC. Accumulating evidence has shown the potential role of microRNAs (miRNAs) in the chemotherapeutic sensitivity of cancer cells. Previously it was reported that microRNA‑7 (miR‑7) acts as an important tumor suppressor in NSCLC. Therefore, the present study was conducted to determine the regulatory role of miR‑7 in PTX chemotherapy for NSCLC. Four NSCLC cell lines were used to analyze the correlation of the PTX‑sensitivity and endogenoaus miR‑7 expression. miR‑7 expression was up‑ and downregulated using miR‑7 mimics and inhibitors respectively, and the role of miR‑7 in sensitizing NSCLC cells to PTX was assessed by cell viability and apoptosis assays. The molecular mechanism of PTX sensitivity was determined by quantitative polymerase chain reaction and western blotting. It was found that the sensitivity of NSCLC cells to PTX was dependent on endogenous miR‑7. Upregulation of miR‑7 enhanced the PTX‑sensitivity of NSCLC cells by suppressing cell proliferation and promoting cell apoptosis, while the inhibition of miR‑7 abrogated the antiproliferative proapoptotic effects of PTX. Pretreatment of miR‑7 mimics enhanced the PTX‑mediated downregulation of epidermal growth factor receptor (EGFR) in NSCLC cells. These results have identified miR‑7 as a potential EGFR‑targeting sensitizer in PTX therapy. These data may facilitate the development of novel chemotherapeutic approaches for NSCLC.

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1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010.
2	Gu J, Ding JY, Lu CL, et al: Overexpression of CD88 predicts poor prognosis in non-small-cell lung cancer. Lung Cancer. 81:259–265. 2013.
3	Edelman MJ: Novel taxane formulations and microtubule-binding agents in non-small-cell lung cancer. Clin Lung Cancer. 10:S30–S34. 2009.
4	Morales-Cano D, Calviño E, Rubio V, et al: Apoptosis induced by paclitaxel via Bcl-2, Bax and caspases 3 and 9 activation in NB4 human leukaemia cells is not modulated by ERK inhibition. Exp Toxicol Pathol. 65:1101–1108. 2013.
5	Kavallaris M: Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer. 10:194–204. 2010.
6	Wan YF, Guo XQ, Wang ZH, Ying K and Yao MH: Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 25:378–384. 2004.
7	Xu R, Sato N, Yanai K, et al: Enhancement of paclitaxel-induced apoptosis by inhibition of mitogen-activated protein kinase pathway in colon cancer cells. Anticancer Res. 29:261–270. 2009.
8	Kastl L, Brown I and Schofield AC: Altered DNA methylation is associated with docetaxel resistance in human breast cancer cells. Int J Oncol. 36:1235–1241. 2010.
9	Le XF and Bast RC Jr: Src family kinases and paclitaxel sensitivity. Cancer Biol Ther. 12:260–269. 2011.
10	Modok S, Mellor HR and Callaghan R: Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer. Curr Opin Pharmacol. 6:350–354. 2006.
11	Lujambio A and Lowe SW: The microcosmos of cancer. Nature. 482:347–355. 2012.
12	Volinia S, Calin GA, Liu CG, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006.
13	Jiang P, Liu R, Zheng Y, et al: MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages. Exp Cell Res. 318:1175–1184. 2012.
14	Zheng Y, Xiong S, Jiang P, et al: Glucocorticoids inhibit lipopolysaccharide-mediated inflammatory response by downregulating microRNA-155: a novel anti-inflammation mechanism. Free Radic Biol Med. 52:1307–1317. 2012.
15	Haenisch S and Cascorbi I: miRNAs as mediators of drug resistance. Epigenomics. 4:369–381. 2012.
16	Schoof CR, Botelho EL, Izzotti A and Vasques Ldos R: MicroRNAs in cancer treatment and prognosis. Am J Cancer Res. 2:414–433. 2012.
17	Miller TE, Ghoshal K, Ramaswamy B, et al: MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem. 283:29897–29903. 2008.
18	Takwi AA, Wang YM, Wu J, et al: miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells. Oncogene. 2013.
19	Yang SM, Huang C, Li XF, Yu MZ, He Y and Li J: miR-21 confers cisplatin resistance in gastric cancer cells by regulating PTEN. Toxicology. 306:162–168. 2013.
20	Pan YZ, Morris ME and Yu AM: MicroRNA-328 negatively regulates the expression of breast cancer resistance protein (BCRP/ABCG2) in human cancer cells. Mol Pharmacol. 75:1374–1379. 2009.
21	Liang Z, Wu H, Xia J, et al: Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochem Pharmacol. 79:817–824. 2010.
22	Kastl L, Brown I and Schofield AC: miRNA-34a is associated with docetaxel resistance in human breast cancer cells. Breast Cancer Res Treat. 131:445–454. 2012.
23	Xiong S, Zheng Y, Jiang P, Liu R, Liu X and Chu Y: MicroRNA-7 inhibits the growth of human non-small cell lung cancer A549 cells through targeting BCL-2. Int J Biol Sci. 7:805–814. 2011.
24	Xiong S, Zheng Y, Jiang P, Liu R, Liu X, Qian J, Gu J, Chang L, Ge D and Chu Y: PA28gamma emerges as a novel functional target of tumor suppressor microRNA-7 in non-small-cell lung cancer. Br J Cancer. 110:353–362. 2014.
25	Nordentoft I, Birkenkamp-Demtroder K, Agerbæk M, et al: miRNAs associated with chemo-sensitivity in cell lines and in advanced bladder cancer. BMC Med Genomics. 5:402012.
26	Tian W, Chen J, He H and Deng Y: MicroRNAs and drug resistance of breast cancer: basic evidence and clinical applications. Clin Transl Oncol. 15:335–342. 2013.
27	Zhang Y, Hu H, Song L, Cai L, Wei R and Jin W: Epirubicin-mediated expression of miR-302b is involved in osteosarcoma apoptosis and cell cycle regulation. Toxicol Lett. 222:1–9. 2013.
28	Costa PM, Cardoso AL, Nóbrega C, et al: MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma. Hum Mol Genet. 22:904–918. 2013.
29	Duncavage E, Goodgame B, Sezhiyan A, Govindan R and Pfeifer J: Use of microRNA expression levels to predict outcomes in resected stage I non-small cell lung cancer. J Thorac Oncol. 5:1755–1763. 2010.
30	Rai K, Takigawa N, Ito S, et al: Liposomal delivery of MicroRNA-7-expressing plasmid overcomes epidermal growth factor receptor tyrosine kinase inhibitor-resistance in lung cancer cells. Mol Cancer Ther. 10:1720–1727. 2011.
31	Kefas B, Godlewski J, Comeau L, et al: microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res. 68:3566–3572. 2008.
32	Webster RJ, Giles KM, Price KJ, et al: Regulation of epidermal growth factor receptor signaling in human cancer cells by microRNA-7. J Biol Chem. 284:5731–5741. 2009.
33	Chou YT, Lin HH, Lien YC, et al: EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF. Cancer Res. 70:8822–8831. 2010.
34	Merlo V, Longo M, Novello S and Scagliotti GV: EGFR pathway in advanced non-small cell lung cancer. Front Biosci (Schol Ed). 3:501–517. 2011.
35	Petitprez A and Larsen AK: Irinotecan resistance is accompanied by upregulation of EGFR and Src signaling in human cancer models. Curr Pharm Des. 19:958–964. 2013.
36	Rekhtman N, Paik PK, Arcila ME, et al: Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res. 18:1167–1176. 2012.
37	Tanaka K, Babic I, Nathanson D, et al: Oncogenic EGFR signaling activates an mTORC2-NF-kappaB pathway that promotes chemotherapy resistance. Cancer Discov. 1:524–538. 2011.
38	Lee KM, Choi EJ and Kim IA: microRNA-7 increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Radiother Oncol. 101:171–176. 2011.