Long non‑coding RNA BLACAT2/miR‑378a‑3p/YY1 feedback loop promotes the proliferation, migration and invasion of uterine corpus endometrial carcinoma

Zhang,Chen; Wang,Ruicong; Li,Mengyuan; Yang,Qing

doi:10.3892/or.2023.8544

Long non‑coding RNA BLACAT2/miR‑378a‑3p/YY1 feedback loop promotes the proliferation, migration and invasion of uterine corpus endometrial carcinoma

Authors:
- Chen Zhang
- Ruicong Wang
- Mengyuan Li
- Qing Yang
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Affiliations: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Published online on: April 13, 2023 https://doi.org/10.3892/or.2023.8544
Article Number: 108
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Uterine corpus endometrial carcinoma (UCEC) is a common gynecological malignancy with high rates of mortality and morbidity. The expression of long non‑coding RNA bladder cancer‑associated transcript 2 (BLACAT2) has been previously found to be aberrantly upregulated in UCEC. However, the regulatory consequences of this in UCEC progression remain poorly understood. In the present study, human UCEC cell lines AN3CA and HEC‑1‑A were infected with lentiviruses to overexpress BLACAT2 (Lv‑BLACAT2) or knock down BLACAT2 using short hairpin RNA (Lv‑shBLACAT2). BLACAT2 overexpression was found to promote the G1/S transition of cell cycle progression and UCEC cell proliferation. In addition, BLACAT2 overexpression was observed to facilitate UCEC cell migration and invasion. By contrast, BLACAT2 knockdown resulted in inhibitory effects in UCEC cell physiology. BLACAT2 overexpression also contributed to the activation of the MEK/ERK pathway. Subsequently, BLACAT2 was demonstrated to bind to microRNA (miR)‑378a‑3p according to dual‑luciferase assays, where it appeared to function as a sponge of miR‑378a‑3p in 293T cells. miR‑378a‑3p overexpression was found to suppress UCEC cell proliferation, invasion, and ERK activation. Lentivirus‑mediated knockdown of its target, the transcription factor Yin Yang‑1 (YY1), was observed to reverse the oncogenic effects of BLACAT2 overexpression. Furthermore, YY1 was found to bind to the promoter of BLACAT2, suggesting that YY1 can regulate BLACAT2 expression. To conclude, results from the present study suggest that BLACAT2, miR‑378a‑3p and YY1 can form a feedback loop instead of an unidirectional axis, which can in turn regulate UCEC tumorigenesis through the MEK/ERK pathway. The present study furthered the understanding of UCEC tumorigenesis and may provide novel therapeutic targets for UCEC treatment.

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1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Morice P, Leary A, Creutzberg C, Abu-Rustum N and Darai E: Endometrial cancer. Lancet. 387:1094–1108. 2016. View Article : Google Scholar : PubMed/NCBI
3	Aoki Y, Kanao H, Wang X, Yunokawa M, Omatsu K, Fusegi A and Takeshima N: Adjuvant treatment of endometrial cancer today. Jpn J Clin Oncol. 50:753–765. 2020. View Article : Google Scholar : PubMed/NCBI
4	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
5	Slavoff SA, Mitchell AJ, Schwaid AG, Cabili MN, Ma J, Levin JZ, Karger AD, Budnik BA, Rinn JL and Saghatelian A: Peptidomic discovery of short open reading frame-encoded peptides in human cells. Nat Chem Biol. 9:59–64. 2013. View Article : Google Scholar : PubMed/NCBI
6	Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A and Bozzoni I: A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 147:358–369. 2011. View Article : Google Scholar : PubMed/NCBI
7	Bhan A and Mandal SS: Long noncoding RNAs: Emerging stars in gene regulation, epigenetics and human disease. ChemMedChem. 9:1932–1956. 2014. View Article : Google Scholar : PubMed/NCBI
8	Bhan A, Soleimani M and Mandal SS: Long noncoding RNA and cancer: A new paradigm. Cancer Res. 77:3965–3981. 2017. View Article : Google Scholar : PubMed/NCBI
9	Seitz AK, Christensen LL, Christensen E, Faarkrog K, Ostenfeld MS, Hedegaard J, Nordentoft I, Nielsen MM, Palmfeldt J, Thomson M, et al: Profiling of long non-coding RNAs identifies LINC00958 and LINC01296 as candidate oncogenes in bladder cancer. Sci Rep. 7:3952017. View Article : Google Scholar : PubMed/NCBI
10	He W, Zhong G, Jiang N, Wang B, Fan X, Chen C, Chen X, Huang J and Lin T: Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. J Clin Invest. 128:861–875. 2018. View Article : Google Scholar : PubMed/NCBI
11	Zuo X, Chen Z, Gao W, Zhang Y, Wang J, Wang J, Cao M, Cai J, Wu J and Wang X: M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma. J Hematol Oncol. 13:52020. View Article : Google Scholar : PubMed/NCBI
12	Zhao H, Zheng GH, Li GC, Xin L, Wang YS, Chen Y and Zheng XM: Long noncoding RNA LINC00958 regulates cell sensitivity to radiotherapy through RRM2 by binding to microRNA-5095 in cervical cancer. J Cell Physiol. 234:23349–23359. 2019. View Article : Google Scholar : PubMed/NCBI
13	Chen M, Xu Z, Zhang Y and Zhang X: LINC00958 promotes the malignancy of nasopharyngeal carcinoma by sponging microRNA-625 and thus upregulating NUAK1. Onco Targets Ther. 12:9277–9290. 2019. View Article : Google Scholar : PubMed/NCBI
14	Chen S, Chen JZ, Zhang JQ, Chen HX, Qiu FN, Yan ML, Tian YF, Peng CH, Shen BY, Chen YL and Wang YD: Silencing of long noncoding RNA LINC00958 prevents tumor initiation of pancreatic cancer by acting as a sponge of microRNA-330-5p to down-regulate PAX8. Cancer Lett. 446:49–61. 2019. View Article : Google Scholar : PubMed/NCBI
15	Luo Z, Han Z, Shou F, Li Y and Chen Y: LINC00958 accelerates cell proliferation and migration in non-small cell lung cancer through JNK/c-JUN signaling. Hum Gene Ther Methods. 30:226–234. 2019. View Article : Google Scholar : PubMed/NCBI
16	Hu H, Kong Q, Huang XX, Zhang HR, Hu KF, Jing Y, Jiang YF, Peng Y, Wu LC, Fu QS, et al: Longnon-coding RNA BLACAT2 promotes gastric cancer progression via the miR-193b-5p/METTL3 pathway. J Cancer. 12:3209–3221. 2021. View Article : Google Scholar : PubMed/NCBI
17	Ren Y, Zhao C, He Y, Xu H and Min X: Long non-coding RNA bladder cancer-associated transcript 2 contributes to disease progression, chemoresistance and poor survival of patients with colorectal cancer. Oncol Lett. 18:2050–2058. 2019.PubMed/NCBI
18	Zhu J, Zhu Z, Cai P, Gu Z and Wang J: Bladder cancer-associated transcript 2 contributes to nephroblastoma progression. J Gene Med. 24:e32922022. View Article : Google Scholar : PubMed/NCBI
19	Binang HB, Wang YS, Tewara MA, Du L, Shi S, Li N, Nsenga AGA and Wang C: Expression levels and associations of five long non-coding RNAs in gastric cancer and their clinical significance. Oncol Lett. 19:2431–2445. 2020.PubMed/NCBI
20	Chen BJ, Byrne FL, Takenaka K, Modesitt SC, Olzomer EM, Mills JD, Farrell R, Hoehn KL and Janitz M: Transcriptome landscape of long intergenic non-coding RNAs in endometrial cancer. Gynecol Oncol. 147:654–662. 2017. View Article : Google Scholar : PubMed/NCBI
21	Jiang Y, Qiao Z, Jiang J and Zhang J: LINC00958 promotes endometrial cancer cell proliferation and metastasis by regulating the miR-145-3p/TCF4 axis. J Gene Med. 23:e33452021. View Article : Google Scholar : PubMed/NCBI
22	Khachigian LM: The Yin and Yang of YY1 in tumor growth and suppression. Int J Cancer. 143:460–465. 2018. View Article : Google Scholar : PubMed/NCBI
23	Sarvagalla S, Kolapalli SP and Vallabhapurapu S: The two sides of YY1 in cancer: A friend and a foe. Front Oncol. 9:12302019. View Article : Google Scholar : PubMed/NCBI
24	Thomas MJ and Seto E: Unlocking the mechanisms of transcription factor YY1: Are chromatin modifying enzymes the key? Gene. 236:197–208. 1999. View Article : Google Scholar : PubMed/NCBI
25	Qiao K, Ning S, Wan L, Wu H, Wang Q, Zhang X, Xu S and Pang D: LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway. J Exp Clin Cancer Res. 38:4182019. View Article : Google Scholar : PubMed/NCBI
26	Berchuck A, Iversen ES, Lancaster JM, Pittman J, Luo J, Lee P, Murphy S, Dressman HK, Febbo PG, West M, et al: Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers. Clin Cancer Res. 11:3686–3696. 2005. View Article : Google Scholar : PubMed/NCBI
27	Seligson D, Horvath S, Huerta-Yepez S, Hanna S, Garban H, Roberts A, Shi T, Liu X, Chia D, Goodglick L and Bonavida B: Expression of transcription factor Yin Yang 1 in prostate cancer. Int J Oncol. 27:131–141. 2005.PubMed/NCBI
28	Luo J, Zhou X, Ge X, Liu P, Cao J, Lu X, Ling Y and Zhang S: Upregulation of Ying Yang 1 (YY1) suppresses esophageal squamous cell carcinoma development through heme oxygenase-1. Cancer Sci. 104:1544–1551. 2013. View Article : Google Scholar : PubMed/NCBI
29	Zhao G, Li Q, Wang A and Jiao J: YY1 regulates melanoma tumorigenesis through a miR-9~RYBP axis. J Exp Clin Cancer Res. 34:662015. View Article : Google Scholar : PubMed/NCBI
30	Yang Y, Zhou L, Lu L, Wang L, Li X, Jiang P, Chan LK, Zhang T, Yu J, Kwong J, et al: A novel miR-193a-5p-YY1-APC regulatory axis in human endometrioid endometrial adenocarcinoma. Oncogene. 32:3432–3442. 2013. View Article : Google Scholar : PubMed/NCBI
31	Masood N, Basharat Z, Khan T and Yasmin A: Entangling relation of micro RNA-let7, miRNA-200 and miRNA-125 with various cancers. Pathol Oncol Res. 23:707–715. 2017. View Article : Google Scholar : PubMed/NCBI
32	Xiao M, Iglinski-Benjamin KC, Sharpe O, Robinson WH and Abrams GD: Exogenous micro-RNA and antagomir modulate osteogenic gene expression in tenocytes. Exp Cell Res. 378:119–123. 2019. View Article : Google Scholar : PubMed/NCBI
33	Jiang T, Sui D, You D, Yao S, Zhang L, Wang Y, Zhao J and Zhang Y: MiR-29a-5p inhibits proliferation and invasion and induces apoptosis in endometrial carcinoma via targeting TPX2. Cell Cycle. 17:1268–1278. 2018. View Article : Google Scholar : PubMed/NCBI
34	Wang P, Zeng Z, Shen X, Tian X and Ye Q: Identification of a multi-RNA-type-based signature for recurrence-free survival prediction in patients with uterine corpus endometrial carcinoma. DNA Cell Biol. 39:615–630. 2020. View Article : Google Scholar : PubMed/NCBI
35	Cui Y, Xie M and Zhang Z: LINC00958 involves in bladder cancer through sponging miR-378a-3p to elevate IGF1R. Cancer Biother Radiopharm. 35:776–788. 2020.PubMed/NCBI
36	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
37	Thomas GJ, Lewis MP, Hart IR, Marshall JF and Speight PM: AlphaVbeta6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9. Int J Cancer. 92:641–650. 2001. View Article : Google Scholar : PubMed/NCBI
38	Wang L, Zhong Y, Yang B, Zhu Y, Zhu X, Xia Z, Xu J and Xu L: LINC00958 facilitates cervical cancer cell proliferation and metastasis by sponging miR-625-5p to upregulate LRRC8E expression. J Cell Biochem. 121:2500–2509. 2020. View Article : Google Scholar : PubMed/NCBI
39	Xie M, Fu Q, Wang PP and Cui YL: STAT1-induced upregulation lncRNA LINC00958 accelerates the epithelial ovarian cancer tumorigenesis by regulating Wnt/β-catenin signaling. Dis Markers. 2021:14050452021. View Article : Google Scholar : PubMed/NCBI
40	Zhang D, Ma Q, Wang Z, Zhang M, Guo K, Wang F and Wu E: β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway. Mol Cancer. 10:1462011. View Article : Google Scholar : PubMed/NCBI
41	Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E and Seiki M: A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 370:61–65. 1994. View Article : Google Scholar : PubMed/NCBI
42	Roberts PJ and Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 26:3291–3310. 2007. View Article : Google Scholar : PubMed/NCBI
43	Fatima R, Akhade VS, Pal D and Rao SM: Long noncoding RNAs in development and cancer: Potential biomarkers and therapeutic targets. Mol Cell Ther. 3:52015. View Article : Google Scholar : PubMed/NCBI
44	Cheetham SW, Gruhl F, Mattick JS and Dinger ME: Long noncoding RNAs and the genetics of cancer. Br J Cancer. 108:2419–2425. 2013. View Article : Google Scholar : PubMed/NCBI
45	Ouyang D, Li R, Li Y and Zhu X: A 7-lncRNA signature predict prognosis of uterine corpus endometrial carcinoma. J Cell Biochem. 120:18465–18477. 2019. View Article : Google Scholar : PubMed/NCBI
46	Yuan C, Zhu X, Han Y, Song C, Liu C, Lu S, Zhang M, Yu F, Peng Z and Zhou C: Elevated HOXA1 expression correlates with accelerated tumor cell proliferation and poor prognosis in gastric cancer partly via cyclin D1. J Exp Clin Cancer Res. 35:152016. View Article : Google Scholar : PubMed/NCBI
47	Park GH, Song HM and Jeong JB: The coffee diterpene kahweol suppresses the cell proliferation by inducing cyclin D1 proteasomal degradation via ERK1/2, JNK and GKS3β-dependent threonine-286 phosphorylation in human colorectal cancer cells. Food Chem Toxicol. 95:142–148. 2016. View Article : Google Scholar : PubMed/NCBI
48	Liu H, Zeng Z, Wang S, Li T, Mastriani E, Li QH, Bao HX, Zhou YJ, Wang X, Liu Y, et al: Main components of pomegranate, ellagic acid and luteolin, inhibit metastasis of ovarian cancer by down-regulating MMP2 and MMP9. Cancer Biol Ther. 18:990–999. 2017. View Article : Google Scholar : PubMed/NCBI
49	Wang X, Yang B, She Y and Ye Y: The lncRNA TP73-AS1 promotes ovarian cancer cell proliferation and metastasis via modulation of MMP2 and MMP9. J Cell Biochem. 119:7790–7799. 2018. View Article : Google Scholar : PubMed/NCBI
50	Wang Y, Zhu Y, Zhang L, Tian W, Hua S, Zhao J, Zhang H and Xue F: Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway. Cancer Lett. 322:223–231. 2012. View Article : Google Scholar : PubMed/NCBI
51	Wang F, Chen Q, Huang G, Guo X, Li N, Li Y and Li B: BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway. BMC Cancer. 18:11282018. View Article : Google Scholar : PubMed/NCBI
52	Zhao Z, Sun W, Guo Z, Zhang J, Yu H and Liu B: Mechanisms of lncRNA/microRNA interactions in angiogenesis. Life Sci. 254:1169002020. View Article : Google Scholar : PubMed/NCBI
53	Paraskevopoulou MD and Hatzigeorgiou AG: Analyzing MiRNA-LncRNA interactions. Methods Mol Biol. 1402:271–286. 2016. View Article : Google Scholar : PubMed/NCBI
54	Liu C, Zhang YH, Deng Q, Li Y, Huang T, Zhou S and Cai YD: Cancer-related triplets of mRNA-lncRNA-miRNA revealed by integrative network in uterine corpus endometrial carcinoma. Biomed Res Int. 2017:38595822017.PubMed/NCBI
55	Kong D, Hou Y, Li W, Ma X and Jiang J: LncRNA-ZXF1 regulates P21 expression in endometrioid endometrial carcinoma by managing ubiquitination-mediated degradation and miR-378a-3p/PCDHA3 axis. Mol Oncol. 16:813–829. 2021. View Article : Google Scholar : PubMed/NCBI
56	Rong D, Dong Q, Qu H, Deng X, Gao F, Li Q and Sun P: m⁶A-induced LINC00958 promotes breast cancer tumorigenesis via the miR-378a-3p/YY1 axis. Cell Death Discov. 7:272021. View Article : Google Scholar : PubMed/NCBI
57	Painter JN, Kaufmann S, O'Mara TA, Hillman KM, Sivakumaran H, Darabi H, Cheng THT, Pearson J, Kazakoff S, Waddell N, et al: A common variant at the 14q32 endometrial cancer risk locus activates AKT1 through YY1 binding. Am J Hum Genet. 98:1159–1169. 2016. View Article : Google Scholar : PubMed/NCBI
58	Bhaskar Rao D, Panneerpandian P, Balakrishnan K and Ganesan K: YY1 regulated transcription-based stratification of gastric tumors and identification of potential therapeutic candidates. J Cell Commun Signal. 15:251–267. 2021. View Article : Google Scholar : PubMed/NCBI