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Cancer Cell International
Published in: Cancer Cell International 1/2020

01-12-2020 | Endometrial Cancer | Primary research

HOXA-AS2 promotes type I endometrial carcinoma via miRNA-302c-3p-mediated regulation of ZFX

Authors: Ning Song, Ying Zhang, Fanfei Kong, Hui Yang, Xiaoxin Ma

Published in: Cancer Cell International | Issue 1/2020

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Abstract

Background

HOXA cluster antisense RNA2 (HOXA-AS2), a long-chain non-coding RNA, plays an important role in the behavior of various malignant tumors. The roles of HOXA-AS2 in endometrial cancer remain unclear.

Methods

We test expression levels of HOXA-AS2, miRNA-302c-3p, the transcription factor zinc finger X-chromosomal protein (ZFX), and the chitinase-like protein YKL-40 in endometrial carcinoma by qRT-PCR and western blotting. Luciferase reporter and qRT-PCR assays were conducted to identify potential binding sites of HOXA-AS2 to miRNA-302c-3p. Cell cycle, migration and invasion ability of endometrial cancer cells were investigated using flow-cytometric analysis, CCK-8 and transwell assays, respectively.

Results

HOXA-AS2 levels were significantly increased in endometrial cancer specimens compared to normal endometrial specimens. Upregulated HOXA-AS2 promoted invasion and proliferation of type I endometrial cancer cells. HOXA-AS2 silenced miRNA-302c-3p by binding to it. MiRNA-302c-3p negatively regulates ZFX and YKL-40. Thus HOXA-AS2 promotes the development of type I endometrial cancer via miRNA-302c-3p-mediated regulation of ZFX.

Conclusions

These findings suggest that HOXA-AS2 can act as a new therapeutic target for type I endometrial cancer.
Appendix
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Literature
1.
Bray F, Ferlay J, Soerjomataram I. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. A Cancer J Clinic. 2018;68:394–424.CrossRef
2.
Jeggo PA, Pearl LH, Cart AM. DNA repair, genome stability and cancer:a historical perspective. Nat Rev Cancer. 2016;16:35–42.PubMedCrossRef
3.
4.
Zhang W, Huang C, Gong Z, Zhao Y, Tang K, Li X, et al. Expression of LINC00312, a long intergenic non-coding RNA, is negatively correlated with tumor size but positively correlated with lymph node metastasis in nasopharyngeal carcinoma. J Mol Histol. 2013;44:545–54.PubMedCrossRef
5.
Gong Z, Zhang S, Zeng Z, Wu H, Yang Q, Xiong F, et al. LOC401317, a p53-regulated long non-coding RNA, inhibits cell proliferation and induces apoptosis in nasopharyngeal carcinoma cell line HNE2. PLoS ONE. 2014;9:e110674.PubMedPubMedCentralCrossRef
6.
Zhai W, Li X, Wu S, Zhang Y, Pang H, Chen W. Microarray expression profile of lncRNAs and the upregulated ASLNC04080 lncRNA in human endometrial carcinoma. Int J Oncol. 2015;46:2125–37.PubMedCrossRef
7.
Huang J, Ke P, Guo L, Wang W, Tan H, Liang Y, et al. Lentivirus-mediated RNA interference targeting the long noncoding RNA HOTAIR inhibits proliferat and invasion of endometrial carcinoma cells in vitro and in vivo. Int J Gynecol Cancer. 2014;24:635–42.PubMedCrossRef
8.
Zhao H, Zhang X, Frazão JB, Condino-Neto A, Newburger PE. HOX antisense lincRNA HOXA-AS2 is an apoptosis repressor in all trans retinoic acid treated NB4 promyelocytic leukemia cells. J Cell Biochem. 2013;114:2375–83.PubMedPubMedCentralCrossRef
9.
Xie M, Sun M, Zhu YN, Xia R, Liu YW, Ding J, et al. Long noncoding RNA HOXA-AS2 promotes gastric cancer proliferation by epigenetically silencing P21/PLK3/DDIT3 expression. Oncotarget. 2015;6:33587–601.PubMedPubMedCentralCrossRef
10.
11.
Yan GJ, Yu F, Wang B, Zhou HJ, Ge QY, Su J, et al. MicroRNA miR-302 inhibits the tumorigenicity of endometrial cancer cells by suppression of Cyclin D1 and CDK1. Cancer Lett. 2014;345:39–47.PubMedCrossRef
12.
Leivonen SK, Mäkelä R, Ostling P, Kohonen P, Haapa-Paananen S, Kleivi K, et al. Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines. Oncogene. 2009;28:3926–36.PubMedCrossRef
13.
Yoshimoto N, Toyama T, Takahashi S, Sugiura H, Endo Y, Iwasa M, et al. Distinct expressions of microRNAs that directly target estrogen receptor alpha in human breast cancer. Breast Cancer Res Treat. 2011;130:331–9.PubMedCrossRef
14.
Shi SJ, Wang LJ, Yu B, Li YH, Jin Y, Bai XZ. LncRNA-ATB promotes trastuzumab resistance and invasion-metastasis cascade in breast cancer. Oncotarge. 2015;6:11652–63.CrossRef
15.
Fleuren ED, Versleijen-Jonkers YM, Roeffen MH, Franssen GM, Flucke UE, Houghton PJ, et al. Temsirolimus combined witll cisplatin or bevacizumab is active in osteosarcoma models. Int J Cancer. 2014;135:2770–82.PubMedCrossRef
16.
Qiao Q, Li H. LncRNA FER1L4 suppresses cancer cell proliferation and cycle by regulating PTEN expression in endometrial carcinoma. Biochem Biophys Res Commun. 2016;478:507–12.PubMedCrossRef
17.
Grignani G, Palmerini E, Ferraresi V, D’Ambrosio L, Bertulli R, Asaftei SD, et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment:a non-randomised phase 2 clinical trial. Lancet Oncol. 2015;16:98–107.PubMedCrossRef
18.
Baranski Z, Booij TH, Cleton-Jansen AM, Price LS, van de Water B, Bovée JV, et al. Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma. J Pathol. 2015;236:348–59.PubMedCrossRef
19.
Ding J, Xie M, Lian Y, Zhu Y, Peng P, Wang J, et al. Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expres-sion transcription by binding with EZH2, LSD1 in colorectal cancer. Oncogenesis. 2017;6:e288.PubMedPubMedCentralCrossRef
20.
Fang Y, Wang J, Wu F, Song Y, Zhao S, Zhang Q. Long non-coding RNA HOXA-AS2 pro-motes proliferation and invasion of breast can-cer by acting as a miR-520c-3p sponge. Oncotarget. 2017;8:46090–103.PubMedPubMedCentralCrossRef
21.
Wang F, Yang H, Deng Z, Su Y, Fang Q, Yin Z. HOX antisense lincRNA HOXA-AS2 promotes tumorigenesis of hepatocellular carcinoma. Cell Physiol Biochem. 2016;40:287–96.PubMedCrossRef
22.
Zhang P, Cao P, Zhu X, Pan M, Zhong K, He R, et al. Upregulation of long non-coding RNA HOXA-AS2 promotes proliferation and induces epithelial-mesenchymal transi-tion in gallbladder carcinoma. Oncotarget. 2017;8:33137–43.PubMedPubMedCentralCrossRef
23.
Lian Y, Li Z, Fan Y, Huang Q, Chen J, Liu W, et al. The lncRNA-HOXA-AS2/EZH2/LSD1 oncogene complex promotes cell proliferation in pancreatic cancer. Am J Transl Res. 2017;9:5496–506.PubMedPubMedCentral
24.
Nagano YK, Toiyama YJ, Okugawa Y. MicroRNA-7IS associated with malignant potential and poor prognosis in human colorectal cancer. Anticancer Res. 2016;36:6521–6.PubMedCrossRef
25.
Glover AR, Zhao JT, Gill AJ, Weiss J, Mugridge N, Kim E, et al. MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma. Oncotarget. 2015;6:36675–88.PubMedPubMedCentralCrossRef
26.
Bi Y, Shen W, Min M, Liu Y. MicroRNA -7functions as a tumor-suppressor gene by regulating ILF2 in pancreatic carcinoma. Int J Mol Med. 2017;39:900–6.PubMedPubMedCentralCrossRef
27.
Negrini M, Nicoloso MS, Calin G. MicroRNAs and cancer-New paradigms in molecular oncology. Curr Opin Cell Biol. 2009;21:470–9.PubMedCrossRef
28.
Ramón LA, Braza-Boïls A, Gilabert J, Chirivella M, España F, Estellés A, et al. microRNAs related to angiogenesis are dysregulated in endometrioid endometrial cancer. Human Reprod. 2012;27:3036–45.CrossRef
29.
Li BL, Lu C, Lu W, Yang TT, Qu J, Hong X, et al. miR-130b is an EMT-related microRNA that targets DICER1 for aggression in endometrial cancer. Med Oncol. 2013;30:484.PubMedCrossRef
30.
Park YA, Lee JW, Choi JJ, Jeon HK, Cho Y, Choi C, et al. The interactions between microRNA-200c and BRD7 in endometrial carcinoma. Gynecol Oncol. 2012;124:125–33.PubMedCrossRef
31.
Qin X, Yan L, Zhao X, Li C, Fu Y. microRNA-21 overexpression contributes to cell proliferation by targeting PTEN in endometrioid endometrial cancer. Oncol Lett. 2012;4(1290):1296.
32.
Mozos A, Catasús L, D’Angelo E, Serrano E, Espinosa I, Ferrer I, et al. The FOXO1- miR27 tandem regulates myometrial invasion in endometrioid endometrial adenocarcinoma. Human Pathol. 2014;45:942–51.CrossRef
33.
Dai Y, Xia W, Song T, Su X, Li J, Li S, et al. MicroRNA -200b is overexpressed in endometrial adenocarcinomas and enhances MMP2 activity by downregulating TIMP2 in human endometrial cancer cell line HEC-1A cells. Nucleic Acid Therapeutics. 2013;23:29–34.PubMedPubMedCentralCrossRef
34.
Yang L, Guo Y, Liu X, Wang T, Tong X, Lei K, et al. The tumor suppressive miR-302c-3p inhibits migration and invasion of hepatocellular carcinoma cells by targeting TRAF4. J Cancer. 2018;9:2693–701.PubMedPubMedCentralCrossRef
35.
Wang Y, Wei Y, Tong H, Chen L, Fan Y, Ji Y, et al. MiR-302c-3p suppresses invasion and proliferation of glioma cells via down-regulating metadherin (MTDH) expression. Cancer Biol Ther. 2015;16:1308–15.PubMedPubMedCentralCrossRef
36.
Zheng GD, Wang YU, Zhu XD. Evaluation of miR-302c-3p as prognostic biomarkers in glioma patients. Eur Rev Med Pharmacol Sci. 2016;20:1521–5.PubMed
37.
Chen L, Min L, Wang X, Zhao J, Chen H, Qin J, et al. Loss of RACK1 promotes metastasis of gastric cancer by inducing a miR-302c/IL8 signaling loop. Cancer Res. 2015;75:3832–41.PubMedCrossRef
38.
Ma G, Li Q, Dai W, Yang X, Sang A. Prognostic implications of miR-302a/b/c/d in human gastric cancer. Pathol Oncol Res. 2017;23:899–905.PubMedCrossRef
39.
Zhao L, Wang Y, Jiang L, He M, Bai X, Yu L, et al. MiR-302a/b/c/d cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein(P-gp) by targeting MAP/ERK kinase kinase 1 (MEKK1). J Exp Clin Cancer Res. 2016;35:25.PubMedPubMedCentralCrossRef
40.
Galoian K, Qureshi A, D’Ippolito G, Schiller PC, Molinari M, Johnstone AL, et al. Epigenetic regulation of embryonic stem cell marker miR302C in human chondrosarcoma as determinant of antiproliferative activity of proline-rich polypeptide. Int J Oncol. 2015;47:465–72.PubMedPubMedCentralCrossRef
41.
Iovanna J, Dusetti N. Speeding towards individualized treatment for pancreatic cancer by taking an alternative road. Cancer Lett. 2017;410:63–7.PubMedCrossRef
42.
Murn J, Zarnack K, Yang YJ, Durak O, Murphy EA, Cheloufi S, et al. Control of a neuronal morphology program by an RNA-binding zinc finger protein, Unkempt. Genes Dev. 2015;29:501–12.PubMedPubMedCentralCrossRef
43.
Wolf G, Yang P, Füchtbauer AC, Füchtbauer EM, Silva AM, Park C, et al. The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses. Genes Dev. 2015;29:538–54.PubMedPubMedCentralCrossRef
44.
Weng H, Wang X, Li M, Wu X, Wang Z, Wu W, et al. Zinc finger X-chromosomal protein (ZFX) is a significant prognostic indicator and promotes cellular malignant potential in gallbladder cancer. Cancer Biol Ther. 2015;16:1462–70.PubMedPubMedCentralCrossRef
45.
Yang H, Lu Y, Zheng Y, Yu X, Xia X, He X, et al. shRNA-mediated silencing of ZFX attenuated the proliferation of breast cancer cells. Cancer Chemother Pharmacol. 2014;73:569–76.PubMedCrossRef
46.
Li K, Zhu ZC, Liu YJ, Liu JW, Wang HT, Xiong ZQ, et al. ZFX knockdown inhibits growth and migration of non-small cell lung carcinoma cell line H1299. Int J Clin Exp Pathol. 2013;6:2460–7.PubMedPubMedCentral
47.
Liu TY, Gong W, Tan ZJ, Lu W, Wu XS, Weng H, et al. Baicalein inhibits progression of gallbladder cancer cells by downregulating ZFX. PLoS ONE. 2015;10:e0114851.PubMedPubMedCentralCrossRef
48.
Lai KP, Chen J, He M, Ching AK, Lau C, Lai PB, et al. Overexpression of ZFX confers self-renewal and chemoresistance properties in hepatocellular carcinoma. Int J Cancer. 2014;135:1790–9.PubMedCrossRef
49.
Fang J, Yu Z, Lian M, Ma H, Tai J, Zhang L, et al. Knockdown of zinc finger protein, X-linked (ZFX) inhibits cell proliferation and induces apoptosis in human laryngeal squamous cell carcinoma. Mol Cell Biochem. 2012;360:301–7.PubMedCrossRef
50.
Wu S, Lao XY, Sun TT, Ren LL, Kong X, Wang JL, et al. Knockdown of ZFX inhibits gastric cancer cell growth in vitro and in vivo via downregulating the ERKMAPK pathway. Cancer Lett. 2013;337:293–300.PubMedCrossRef
51.
Song X, Zhu M, Zhang F, Zhang F, Zhang Y, Hu Y, et al. ZFX promotes proliferation and metastasis of pancreatic cancer cells via the MAPK pathway. Cell Physiol Biochem. 2018;48:274–84.PubMedCrossRef
52.
Xu S, Duan P, Li J, Senkowski T, Guo F, Chen H, et al. Zinc finger and X-linked factor (ZFX) binds to human SET transcript 2 promoter and transactivates set expression. Int J Mol Sci. 2016;17:1737.PubMedCentralCrossRef
53.
Rhie SK, Yao L, Luo Z, Witt H, Schreiner S, Guo Y, et al. Farnham ZFX acts as a transcriptional activator in multiptypes of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters. Genome Res. 2018;28:310–20.PubMedCentralCrossRef
54.
Bao H, Li X, Li H, Xing H, Xu B, Zhang X, et al. MicroRNA-144 inhibits hepatocellular carcinoma cell proliferationinvasion and migration by targeting ZFX. J Biosci. 2017;42:103–11.PubMedCrossRef
55.
Shao R, Taylor SL, Oh DS, Schwartz LM. Vascular heterogeneity andtargeting: the role of YKL-40 in glioblastoma vascularization. Oncotarget. 2015;6:40507–18.PubMedPubMedCentralCrossRef
56.
Jefri M, Huang YN, Huang WC, Tai CS, Chen WL. YKL-40 regulated epithelial-mesenchymal transition and migration/invasion enhancement in non-small cell lung cancer. BMC Cancer. 2015;15:590.PubMedPubMedCentralCrossRef
57.
Thongsom S, Chaocharoen W, Silsirivanit A, Wongkham S, Sripa B, Choe H, et al. YKL-40/chitinase-3-like protein 1 is associated with poorprognosis and promotes cell growth and migration of cholangiocarcinoma. Tumour Biol. 2016;37:9451–63.PubMedCrossRef
58.
Li LL, Fan JT, Li DH, Liu Y. Effects of a small interfering RNA targeting YKL-40 gene on the proliferation and invasion of endometrial cancer HEC-1A cells. Gynecol Cancer. 2016;26:1190–5.CrossRef
59.
Chen HT, Zheng JM, Zhang YZ, Yang M, Wang YL, Man XH, et al. Overexpression of YKL-40 predicts poor prognosis in patients undergoing curative resection of pancreatic cancer. Pancreas. 2017;46:323–34.PubMedCrossRef
60.
Francescone R, Ngernyuang N, Yan W, Bentley B, Shao R. Tumor-derivedmural-like cells coordinate with endothelial cells role of YKL-40 in mural cell-mediated angiogenesis. Oncogene. 2014;33:2110–22.PubMedCrossRef
61.
Boisen MK, Madsen CV, Dehlendorff C, Jakobsen A, Johansen JS, Steffensen KD. The prognostic value of plasma YKL-40 in patients with chemotherapy-resistant ovarian cancer treated with Bevacizumab. Int J Gynecol Cancer. 2016;26:1390–8.PubMedCrossRef
62.
Low D, Subramaniam R, Lin L, Aomatsu T, Mizoguchi A, Ng A, et al. Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9. Oncotarget. 2015;6:36535–50.PubMedPubMedCentralCrossRef
63.
Chiang YC, Lin HW, Chang CF, Chang MC, Fu CF, Chen TC, et al. Overexpression of CHI3L1 is associated with chemoresistance and poor outcome of epithelial ovarian carcinoma. Oncotarget. 2015;6:39740–55.PubMedPubMedCentralCrossRef
64.
Ma JY, Li RH, Huang K, Tan G, Li C, Zhi FC. Increased expression and possible role of chitinase 3-like-1 in a colitis-associated carcinoma model. World J Gastroenterol. 2014;20:15736–44.PubMedPubMedCentralCrossRef
65.
Ngernyuang N, Francescone RA, Jearanaikoon P, Daduang J, Supoken A, Yan W, et al. Chitinase 3 like 1 is associated with tumor angiogenesis in cervical cancer. Int J Biochem Cell Biol. 2014;51:45–52.PubMedCrossRef
Metadata
Title
HOXA-AS2 promotes type I endometrial carcinoma via miRNA-302c-3p-mediated regulation of ZFX
Authors
Ning Song
Ying Zhang
Fanfei Kong
Hui Yang
Xiaoxin Ma
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01443-0

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