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Molecular Cancer
Published in: Molecular Cancer 1/2020

01-12-2020 | Breast Cancer | Research

The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer

Authors: Xiaying Zheng, Mengge Huang, Lei Xing, Rui Yang, Xiaosong Wang, Rong Jiang, Luyu Zhang, Junxia Chen

Published in: Molecular Cancer | Issue 1/2020

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Abstract

Background

Increasing studies have shown that circRNA is closely related to the carcinogenesis and development of many cancers. However, biological functions and the underlying molecular mechanism of circRNAs in triple-negative breast cancer (TNBC) remain largely unclear so far.

Methods

Here, we investigated the expression pattern of circRNAs in four pairs of TNBC tissues and paracancerous normal tissues using RNA-sequencing. The expression and prognostic significance of circSEPT9 were evaluated with qRT-PCR and in situ hybridization in two TNBC cohorts. The survival curves were drawn by the Kaplan-Meier method, and statistical significance was estimated with the log-rank test. A series of in vitro and in vivo functional experiments were executed to investigate the role of circSEPT9 in the carcinogenesis and development of TNBC. Mechanistically, we explored the potential regulatory effects of E2F1 and EIF4A3 on biogenesis of circSEPT9 with chromatin immunoprecipitation (ChIP), luciferase reporter and RNA immunoprecipitation (RIP) assays. Furthermore, fluorescent in situ hybridization (FISH), luciferase reporter and biotin-coupled RNA pull-down assays were implemented to verify the relationship between the circSEPT9 and miR-637 in TNBC.

Results

Increased expression of circSEPT9 was found in TNBC tissues, which was positively correlated with advanced clinical stage and poor prognosis. Knockdown of circSEPT9 significantly suppressed the proliferation, migration and invasion of TNBC cells, induced apoptosis and autophagy in TNBC cells as well as inhibited tumor growth and metastasis in vivo. Whereas up-regulation of circSEPT9 exerted opposite effects. Further mechanism research demonstrated that circSEPT9 could regulate the expression of Leukemia Inhibitory Factor (LIF) via sponging miR-637 and activate LIF/Stat3 signaling pathway involved in progression of TNBC. More importantly, we discovered that E2F1 and EIF4A3 might promote the biogenesis of circSEPT9.

Conclusions

Our data reveal that the circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer through circSEPT9/miR-637/LIF axis. Therefore, circSEPT9 could be used as a potential prognostic marker and therapeutical target for TNBC.
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Literature
1.
Gupta I, Sareyeldin RM, Al-Hashimi I, Al-Thawadi HA, Al Farsi H, Vranic S, Al Moustafa AE. Triple negative breast cancer profile, from gene to microRNA, in relation to ethnicity. Cancers (Basel). 2019;11:363.
2.
Guestini F, McNamara KM, Ishida T, Sasano H. Triple negative breast cancer chemosensitivity and chemoresistance: current advances in biomarkers indentification. Expert Opin Ther Targets. 2016;20:705–20.CrossRef
3.
Hwang SY, Park S, Kwon Y. Recent therapeutic trends and promising targets in triple negative breast cancer. Pharmacol Ther. 2019;199:30–57.
4.
Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, Wu YM, Dhanasekaran SM, Engelke CG, Cao X, Robinson DR, Nesvizhskii AI, Chinnaiyan AM. The landscape of circular RNA in cancer. Cell. 2019;176:869–81.CrossRef
5.
Bach DH, Lee SK, Sood AK. Circular RNAs in cancer. Mol Ther Nucleic Acids. 2019;16:118–29.CrossRef
6.
Li XN, Wang ZJ, Ye CX, Zhao BC, Li ZL, Yang Y. RNA sequencing reveals the expression profiles of circRNA and indicates that circDDX17 acts as a tumor suppressor in colorectal cancer. J Exp Clin Cancer Res. 2018;37:325.CrossRef
7.
Zhen N, Gu S, Ma J, Zhu J, Yin M, Xu M, Wang J, Huang N, Cui Z, Bian Z, Sun F, Pan Q. CircHMGCS1 promotes hepatoblastoma cell proliferation by regulating the IGF signaling pathway and glutaminolysis. Theranostics. 2019;9:900–19.CrossRef
8.
Zeng K, He B, Yang BB, Xu T, Chen X, Xu M, Liu X, Sun H, Pan Y, Wang S. The pro-metastasis effect of circANKS1B in breast cancer. Mol Cancer. 2018;17:160.CrossRef
9.
Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, Chen D, Gu J, He X, Huang S. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25:981–4.CrossRef
10.
Yang Z, Qu CB, Zhang Y, Zhang WF, Wang DD, Gao CC, Ma L, Chen JS, Liu KL, Zheng B, Zhang XH, Zhang ML, Wang XL, Wen JK, Li W. Dysregulation of p53-RBM25-mediated circAMOTL1L biogenesis contributes to prostate cancer progression through the circAMOTL1L-miR-193a-5p-Pcdha pathway. Oncogene. 2019;38:2516–32.CrossRef
11.
Zhang C, Wang GX, Fu B, Zhou XC, Li Y, Li YY. LncRNA CASC15 promotes migration and invasion in prostate cancer via targeting miR-200a-3p. Eur Rev Med Pharmacol Sci. 2019;23(19):8303–9.PubMed
12.
Lv C, Li F, Li X, Tian Y, Zhang Y, Sheng X, Song Y, Meng Q, Yuan S, Luan L, Andl T, Feng X, Jiao B, Xu M, Plikus MV, Dai X, Lengner C, Cui W, Ren F, Shuai J, Millar SE, Yu Z. MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists. Nat Commun. 2017;8:1036.CrossRef
13.
Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the rosetta stone of a hidden RNA language? Cell. 2011;146:353–8.CrossRef
14.
Bolha L, Ravnik-Glavač M, Glavač D. Circular RNAs: biogenesis, function, and a role as possible cancer biomarkers. Int J Genomics. 2017;2017:6218353.CrossRef
15.
Kristensen LS, Hansen TB, Venø MT, Kjems J. Circular RNAs in cancer: pportunities and challenges in the field. Oncogene. 2018;37:555–65.CrossRef
16.
Liu H, Chen D, Bi J, Han J, Yang M, Dong W, Lin T, Huang J. Circular RNA circUBXN7 represses cell growth and invasion by sponging miR-1247-3p to enhance B4GALT3 expression in bladder cancer. Aging (Albany NY). 2018;10:2606–23.CrossRef
17.
Xu JZ, Shao CC, Wang XJ, Zhao X, Chen JQ, Ouyang YX, Feng J, Zhang F, Huang WH, Ying Q, Chen CF, Wei XL, Dong HY, Zhang GJ, Chen M. CircTADA2As suppress breast cancer progression and metastasis via targeting miR-203a-3p/SOCS3 axis. Cell Death Dis. 2019;10:175.CrossRef
18.
Xu L, Feng X, Hao X, Wang P, Zhang Y, Zheng X, Li L, Ren S, Zhang M, Xu M. CircSETD3 (Hsa_circ_0000567) acts as a sponge for microRNA-421 inhibiting hepatocellular carcinoma growth. J Exp Clin Cancer Res. 2019;38:98.CrossRef
19.
Yang R, Xing L, Zheng X, Sun Y, Wang X, Chen J. The circRNA circAGFG1 acts as a sponge of miR-195-5p to promote triple-negative breast cancer progression through regulating CCNE1 expression. Mol Cancer. 2019;18:4.CrossRef
20.
Wang Y, Li J, Du C, Zhang L, Zhang Y, Zhang J, Wang L. Upregulated circular RNA circ-UBE2D2 predicts poor prognosis and promotes breast Cancer progression by sponging miR-1236 and miR-1287. Transl Oncol. 2019;12:1305–13.CrossRef
21.
Cong Z, Diao Y, Xu Y, Li X, Jiang Z, Shao C, Ji S, Shen Y, De W, Qiang Y. Long non-coding RNA linc00665 promotes lung adenocarcinoma progression and functions as ceRNA to regulate AKR1B10-ERK signaling by sponging miR-98. Cell Death Dis. 2019;10:84.CrossRef
22.
Dong Y, He D, Peng Z, Peng W, Shi W, Wang J, Li B, Zhang C, Duan C. Circular RNAs in cancer: an emerging key player. J Hematol Oncol. 2017;10:2.CrossRef
23.
Ng WL, Mohd Mohidin TB, Shukla K. Functional role of circular RNAs in cancer development and progression. RNA Biol. 2018;15:995–1005.PubMedPubMedCentral
24.
Feng Y, Zhang L, Wu J, Khadka B, Fang Z, Gu J, Tang B, Xiao R, Pan G, Liu J. CircRNA circ_0000190 inhibits the progression of multiple myeloma through modulating miR-767-5p/MAPK4 pathway. J Exp Clin Cancer Res. 2019;38:54.CrossRef
25.
Chen X, Chen RX, Wei WS, Li YH, Feng ZH, Tan L, Chen JW, Yuan GJ, Chen SL, Guo SJ, Xiao KH, Liu ZW, Luo JH, Zhou FJ, Xie D. PRMT5 circular RNA promotes metastasis of urothelial carcinoma of the bladder through sponging miR-30c to induce epithelial-mesenchymal transition. Clin Cancer Res. 2018;24:6319–30.CrossRef
26.
Han D, Li J, Wang H, Su X, Hou J, Gu Y, Qian C, Lin Y, Liu X, Huang M, Li N, Zhou W, Yu Y, Cao X. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology. 2017;66:1151–64.CrossRef
27.
Leivonen SK, Sahlberg KK, Mäkelä R, Due EU, Kallioniemi O, Børresen-Dale AL, Perälä M. High-throughput screens identify microRNAs essential for HER2 positive breast cancer cell growth. Mol Oncol. 2014;8:93–104.CrossRef
28.
Que T, Song Y, Liu Z, Zheng S, Long H, Li Z, Liu Y, Wang G, Liu Y, Zhou J, Zhang X, Fang W, Qi S. Decreased miRNA-637 is an unfavorable prognosis marker and promotes glioma cell growth, migration and invasion via direct targeting Akt1. Oncogene. 2015;34:4952–63.CrossRef
29.
Zhang JF, He ML, Fu WM, Wang H, Chen LZ, Zhu X, Chen Y, Xie D, Lai P, Chen G, Lu G, Lin MC, Kung HF. Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling. Hepatology. 2011;54:2137–48.CrossRef
30.
Bressy C, Lac S, Nigri J, Leca J, Roques J, Lavaut MN, Secq V, Guillaumond F, Bui TT, Pietrasz D, Granjeaud S, Bachet JB, Ouaissi M, Iovanna J, Vasseur S, Tomasini R. LIF drives neural remodeling in pancreatic cancer and offers a new candidate biomarker. Cancer Res. 2018;78:909–21.CrossRef
31.
Yue X, Zhao Y, Zhang C, Li J, Liu Z, Liu J, Hu W. Leukemia inhibitory factor promotes EMT through STAT3-dependent miR-21 induction. Oncotarget. 2016;7:3777–90.PubMed
32.
Yu H, Yue X, Zhao Y, Li X, Wu L, Zhang C, Liu Z, Lin K, Xu-Monette ZY, Young KH, Liu J, Shen Z, Feng Z, Hu W. LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers. Nat Commun. 2014;5:5218.CrossRef
33.
Lin Y, Zhang J, Cai J, Liang R, Chen G, Qin G, Han X, Yuan C, Liu Z, Li Y, Zou D, Mao Y. Systematic analysis of gene expression alteration and co-expression network of eukaryotic initiation factor 4A-3 in cancer. J Cancer. 2018;9:4568–77.CrossRef
34.
Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, Roslan S, Schreiber AW, Gregory PA, Goodall GJ. The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015;160:1125–34.CrossRef
35.
Wang R, Zhang S, Chen X, Li N, Li J, Jia R, Pan Y, Liang H. EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis. Mol Cancer. 2018;17:166.CrossRef
36.
Fischer M, Grossmann P, Padi M, DeCaprio JA. Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks. Nucleic Acids Res. 2016;44:6070–86.CrossRef
37.
Meng J, Chen S, Han JX, Qian B, Wang XR, Zhong WL, Qin Y, Zhang H, Gao WF, Lei YY, Yang W, Yang L, Zhang C, Liu HJ, Liu YR, Zhou HG, Sun T, Yang C. Twist1 regulates vimentin through Cul2 circular RNA to promote EMT in hepatocellular carcinoma. Cancer Res. 2018;78:4150–62.CrossRef
Metadata
Title
The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer
Authors
Xiaying Zheng
Mengge Huang
Lei Xing
Rui Yang
Xiaosong Wang
Rong Jiang
Luyu Zhang
Junxia Chen
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2020
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-020-01183-9

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