Overexpression of SMARCA2 or CAMK2D is associated with cisplatin resistance in human epithelial ovarian cancer

Xu,Xiaoli; Zheng,Zhiguo; Jia,Lanlan; Suo,Shasha; Liu,Bowen; Shao,Tianning; Tu,Qinqing; Hua,Yuejin; Xu,Hong

doi:10.3892/ol.2018.9109

Overexpression of SMARCA2 or CAMK2D is associated with cisplatin resistance in human epithelial ovarian cancer

Authors:
- Xiaoli Xu
- Zhiguo Zheng
- Lanlan Jia
- Shasha Suo
- Bowen Liu
- Tianning Shao
- Qinqing Tu
- Yuejin Hua
- Hong Xu
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Affiliations: Institute of Nuclear‑Agricultural Sciences, Zhejiang University, Hangzhou, Zhejiang 310029, P.R. China, Institute of Zhejiang Cancer Research, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
Published online on: July 10, 2018 https://doi.org/10.3892/ol.2018.9109
Pages: 3796-3804
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ovarian cancer is one of the most lethal types of gynecological cancer. Drug resistance is a major underlying cause of treatment failure, which has lead to continued poor mortality and morbidity rates in patients. In the present study, highly sensitive transcriptome sequencing was performed to systematically identify differentially expressed mRNAs in cisplatin‑sensitive (A2780) and ‑resistant (A2780‑DR) cells. Calcium/calmodulin dependent protein kinase IIδ (CAMK2D) and SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily A member 2 (SMARCA2) were identified as exhibiting increased expression in cisplatin‑resistant cells. Overexpression of either SMARCA2 or CAMK2D led to a significant increase in the survival rates of A2780 and SKVO3 cells following cisplatin treatment. To further verify the contribution of these two genes in the development of drug resistance, the RNA levels in tissues with different recurrence‑free survival (RFS) rates were compared. An increased mRNA level of CAMK2D was detected in samples with shorter RFS rates. An apoptosis assay revealed that overexpression of SMARCA2 or CAMK2D increased the resistance of ovarian cancer cells to cisplatin, as indicated by the decreased apoptotic cell populations. The levels of these two genes also affected the cell cycle and apoptosis‑associated protein expression. Quantitative proteomic analyses revealed that overexpression of SMARCA2 or CAMK2D influences multiple metabolism and cancer‑associated signaling pathways, which are critical for responses to cisplatin treatment and drug resistance development.

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1	Wu H, Wang K, Liu W and Hao Q: Recombinant adenovirus-mediated overexpression of PTEN and KRT10 improves cisplatin resistance of ovarian cancer in vitro and in vivo. Genet Mol Res. 14:6591–6597. 2015. View Article : Google Scholar : PubMed/NCBI
2	Schumann C, Chan S, Khalimonchuk O, et al: Mechanistic nanotherapeutic approach based on siRNA-mediated DJ-1 protein suppression for platinum-resistant ovarian cancer. Mol Pharm. 13:2070–2083. 2016. View Article : Google Scholar : PubMed/NCBI
3	Duan Z BK and Seiden MV: Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Mol Cancer Ther. 3:833–838. 2004.PubMed/NCBI
4	Ren L, Xiao L and Hu J: MDR1 and MDR3 genes and drug resistance to cisplatin of ovarian cancer cells. J Huazhong Univ Sci Technolog Med Sci. 27:721–724. 2007. View Article : Google Scholar : PubMed/NCBI
5	Zheng ZG, Xu H, Suo SS, Xu XL, Ni MW, Gu LH, Chen W, Wang LY, Zhao Y, Tian B and Hua YJ: The essential role of H19 contributing to cisplatin resistance by regulating glutathione metabolism in high-grade serous ovarian cancer. Sci Rep. 6:260932016. View Article : Google Scholar : PubMed/NCBI
6	Jin AH and Wei ZL: Molecular mechanism of increased sensitivity of cisplatin to ovarian cancer by inhibition of microRNA-23a expression. Int J Clin Exp Med. 8:13329–13334. 2015.PubMed/NCBI
7	Kim DK, Seo EJ, Choi EJ, Lee SI, Kwon YW, Jang IH, Kim SC, Kim KH, Suh DS, Seong-Jang K, et al: Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells. Exp Mol Med. 48:e2552016. View Article : Google Scholar : PubMed/NCBI
8	Liu FT, Pan H, Xia GF, Qiu C and Zhu ZM: Prognostic and clinicopathological significance of long noncoding RNA H19 overexpression in human solid tumors: Evidence from a meta-analysis. Oncotarget. 7:83177–83166. 2016. View Article : Google Scholar : PubMed/NCBI
9	Sun KX, Jiao JW, Chen S, Liu BL and Zhao Y: MicroRNA-186 induces sensitivity of ovarian cancer cells to paclitaxel and cisplatin by targeting ABCB1. J Ovarian Res. 8:802015. View Article : Google Scholar : PubMed/NCBI
10	Zeng Q, Tao X, Huang F, Wu T, Wang J, Jiang X, Kuang Z and Cheng B: Overexpression of miR-155 promotes the proliferation and invasion of oral squamous carcinoma cells by regulating BCL6/cyclin D2. Int J Mol Med. 37:1274–1280. 2016. View Article : Google Scholar : PubMed/NCBI
11	Xie C, Han Y, Fu L, Li Q, Qiu X and Wang E: Overexpression of CARMA3 is associated with advanced tumor stage, cell cycle progression and cisplatin resistance in human epithelial ovarian cancer. Tumour Biol. 35:7957–7964. 2014. View Article : Google Scholar : PubMed/NCBI
12	Gao M, Miao L, Liu M, Li C, Yu C, Yan H, Yin Y, Wang Y, Qi X and Ren J: miR-145 sensitizes breast cancer to doxorubicin by targeting multidrug resistance-associated protein-1. Oncotarget. 13:59714–59726. 2016.
13	Permuth-Wey J, Chen YA, Tsai YY, Chen Z, Qu X, Lancaster JM, Stockwell H, Dagne G, Iversen E, Risch H, et al: Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk. Cancer Epidemiol Biomarkers Prev. 20:1131–1145. 2011. View Article : Google Scholar : PubMed/NCBI
14	Wu Q, Madany P, Akech J, Dobson JR, Douthwright S, Browne G, Colby JL, Winter GE, Bradner JE, Pratap J, et al: The SWI/SNF ATPases are required for triple negative breast cancer cell proliferation. J Cell Physiol. 230:2683–2694. 2015. View Article : Google Scholar : PubMed/NCBI
15	Saddouk FZ, Sun LY, Liu YF, Jiang M, Singer DV, Backs J, Van Riper D, Ginnan R, Schwarz JJ and Singer HA: Ca2+/calmodulin-dependent protein kinase II-γ (CaMKIIγ) negatively regulates vascular smooth muscle cell proliferation and vascular remodeling. FASEB J. 30:1051–1064. 2016. View Article : Google Scholar : PubMed/NCBI
16	Tang S, Pan Y, Wang Y, Hu L, Cao S, Chu M, Dai J, Shu Y, Xu L, Chen J, et al: Genome-wide association study of survival in early-stage non-small cell lung cancer. Ann Surg Oncol. 22:630–635. 2015. View Article : Google Scholar : PubMed/NCBI
17	Wilson BG, Helming KC, Wang X, Kim Y, Vazquez F, Jagani Z, Hahn WC and Roberts CW: Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol Cell Biol. 34:1136–1144. 2014. View Article : Google Scholar : PubMed/NCBI
18	Hoffman GR RR, Buxton F, Xiang K, McAllister G and Frias E: Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc Natl Acad Sci USA. 111:3128–3133. 2014. View Article : Google Scholar : PubMed/NCBI
19	Puvanenthiran S, Essapen S, Seddon AM and Modjtahedi H: Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs. Int J Oncol. 49:1825–1838. 2016. View Article : Google Scholar : PubMed/NCBI
20	Ho AS, Kannan K, Roy DM, Morris LG, Ganly I, Katabi N, Ramaswami D, Walsh LA, Eng S, Huse JT, et al: The mutational landscape of adenoid cystic carcinoma. Nat Genet. 45:791–798. 2013. View Article : Google Scholar : PubMed/NCBI
21	Chang H, Sheng JJ, Zhang L, Yue ZJ, Jiao B, Li JS, et al: ROS-induced nuclear translocation of calpain-2 facilitates cardiomyocyte apoptosis in tail-suspended rats. J Cell Biochem. 116:2258–2269. 2015. View Article : Google Scholar : PubMed/NCBI