Skip to main content
Top
Published in: Molecular Cancer 1/2020

Open Access 01-12-2020 | Renal Cancer | Research

Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA

Authors: Wei Wang, Wentao Hu, Ya Wang, Yong An, Lei Song, Panfeng Shang, Zhongjin Yue

Published in: Molecular Cancer | Issue 1/2020

Login to get access

Abstract

Background

Accumulating literatures have indicated that long non-coding RNAs (lncRNAs) are potential biomarkers that play key roles in tumor development and progression. Urothelial cancer associated 1 (UCA1) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancers. However, the molecular mechanism of UCA1 in renal cancer is still needed to further explore.

Methods

The relative expression level of UCA1 was determined by Real-Time qPCR in a total of 88 patients with urothelial renal cancer and in different renal cancer cell lines. Loss-of-function experiments were performed to investigate the biological roles of UCA1 and miR-182-5p on renal cancer cell proliferation, migration, apoptosis and tumorigenicity. Comprehensive transcriptional analysis, dual-luciferase reporter assay and western blot etc. were performed to explore the molecular mechanisms underlying the functions of UCA1.

Results

In this study, we found that UCA1 was significantly up-regulated in renal cancer. Moreover, increased UCA1 expression was positively correlated with differentiation and advanced TNM stage. Further experiments demonstrated that knockdown of UCA1 inhibited malignant phenotypes and Notch signal path of renal cancer cells, and miR-182-5p was reverse function as UCA1. UCA1 functioned as a miRNA sponge to positively regulate the expression of Delta-like ligand 4(DLL4) through sponging miR-182-5p and subsequently promoted malignant phenotypes of renal cancer cells, thus UCA1 playing an oncogenic role and miR-182-5p as an antioncogenic one in renal cancer pathogenesis.

Conclusion

UCA1-miR-182-5p-DLL4 axis is involved in proliferation and progression of renal cancer. Thus, this study demonstrated that UCA1 plays a critical regulatory role in renal cancer cell and UCA1 may serve as a potential diagnostic biomarker and therapeutic target of renal cancer.
Appendix
Available only for authorised users
Literature
1.
go back to reference Zhou H, Tang K, Liu H, et al. Regulatory network of two tumor-suppressive noncoding RNAs interferes with the growth and metastasis of renal cell carcinoma. Mol Ther Nucleic Acids. 2019;16:554–65.CrossRefPubMedPubMedCentral Zhou H, Tang K, Liu H, et al. Regulatory network of two tumor-suppressive noncoding RNAs interferes with the growth and metastasis of renal cell carcinoma. Mol Ther Nucleic Acids. 2019;16:554–65.CrossRefPubMedPubMedCentral
2.
go back to reference Li J, Zhuang C, Liu Y, et al. Synthetic tetracycline-controllable shRNA targeting long non-coding RNA HOXD-AS1 inhibits the progression of bladder cancer. J Exp Clin Cancer Res. 2016;35(1):99.CrossRefPubMedPubMedCentral Li J, Zhuang C, Liu Y, et al. Synthetic tetracycline-controllable shRNA targeting long non-coding RNA HOXD-AS1 inhibits the progression of bladder cancer. J Exp Clin Cancer Res. 2016;35(1):99.CrossRefPubMedPubMedCentral
3.
go back to reference Chen M, Zhuang C, Liu Y, et al. Tetracycline-inducible shRNA targeting antisense long non-coding RNA HIF1A-AS2 represses the malignant phenotypes of bladder cancer. Cancer Lett. 2016;376(1):155–64.CrossRefPubMed Chen M, Zhuang C, Liu Y, et al. Tetracycline-inducible shRNA targeting antisense long non-coding RNA HIF1A-AS2 represses the malignant phenotypes of bladder cancer. Cancer Lett. 2016;376(1):155–64.CrossRefPubMed
4.
go back to reference Li J, Zhuang C, Liu Y, et al. shRNA targeting long non-coding RNA CCAT2 controlled by tetracycline-inducible system inhibits progression of bladder cancer cells. Oncotarget. 2016;7(20):28989–97.CrossRefPubMedPubMedCentral Li J, Zhuang C, Liu Y, et al. shRNA targeting long non-coding RNA CCAT2 controlled by tetracycline-inducible system inhibits progression of bladder cancer cells. Oncotarget. 2016;7(20):28989–97.CrossRefPubMedPubMedCentral
5.
go back to reference Zhuang C, Li J, Liu Y, et al. Tetracycline-inducible shRNA targeting long non-coding RNA PVT1 inhibits cell growth and induces apoptosis in bladder cancer cells. Oncotarget. 2015;6(38):41194–203.CrossRefPubMedPubMedCentral Zhuang C, Li J, Liu Y, et al. Tetracycline-inducible shRNA targeting long non-coding RNA PVT1 inhibits cell growth and induces apoptosis in bladder cancer cells. Oncotarget. 2015;6(38):41194–203.CrossRefPubMedPubMedCentral
7.
go back to reference Zhuang C, Huang X, Zhuang C, et al. Synthetic regulatory RNAs selectively suppress the progression of bladder cancer. J Exp Clin Cancer Res. 2017;36(1):151.CrossRefPubMedPubMedCentral Zhuang C, Huang X, Zhuang C, et al. Synthetic regulatory RNAs selectively suppress the progression of bladder cancer. J Exp Clin Cancer Res. 2017;36(1):151.CrossRefPubMedPubMedCentral
8.
go back to reference Gu P, Chen X, Xie R, et al. A novel AR translational regulator lncRNA LBCS inhibits castration resistance of prostate cancer. Mol Cancer. 2019;18(1):109.CrossRefPubMedPubMedCentral Gu P, Chen X, Xie R, et al. A novel AR translational regulator lncRNA LBCS inhibits castration resistance of prostate cancer. Mol Cancer. 2019;18(1):109.CrossRefPubMedPubMedCentral
9.
go back to reference Zhang L, Meng X, Zhu XW, et al. Long non-coding RNAs in Oral squamous cell carcinoma: biologic function, mechanisms and clinical implications. Mol Cancer. 2019;18(1):102.CrossRefPubMedPubMedCentral Zhang L, Meng X, Zhu XW, et al. Long non-coding RNAs in Oral squamous cell carcinoma: biologic function, mechanisms and clinical implications. Mol Cancer. 2019;18(1):102.CrossRefPubMedPubMedCentral
10.
go back to reference Xu S, Wang P, Zhang J, et al. Ai-lncRNA EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions in human cancer. Mol Cancer. 2019;18(1):89.CrossRefPubMedPubMedCentral Xu S, Wang P, Zhang J, et al. Ai-lncRNA EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions in human cancer. Mol Cancer. 2019;18(1):89.CrossRefPubMedPubMedCentral
11.
go back to reference Wang X, Yang J, Guo G, et al. Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway. Mol Cancer. 2019;18(1):84.CrossRefPubMedPubMedCentral Wang X, Yang J, Guo G, et al. Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway. Mol Cancer. 2019;18(1):84.CrossRefPubMedPubMedCentral
12.
go back to reference Trimarchi T, Bilal E, Ntziachristos P, et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell. 2014;158(3):593–606.CrossRefPubMedPubMedCentral Trimarchi T, Bilal E, Ntziachristos P, et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell. 2014;158(3):593–606.CrossRefPubMedPubMedCentral
13.
go back to reference Kotzin JJ, Spencer SP, McCright SJ, et al. The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature. 2016;537(7619):239–43.CrossRefPubMedPubMedCentral Kotzin JJ, Spencer SP, McCright SJ, et al. The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature. 2016;537(7619):239–43.CrossRefPubMedPubMedCentral
14.
15.
go back to reference Sallam T, Jones MC, Gilliland T, et al. Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature. 2016;534(7605):124–8.CrossRefPubMedPubMedCentral Sallam T, Jones MC, Gilliland T, et al. Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature. 2016;534(7605):124–8.CrossRefPubMedPubMedCentral
16.
go back to reference Wang CJ, Zhu CC, Xu J, et al. The lncRNA UCA1 promotes proliferation, migration, immune escape and inhibits apoptosis in gastric cancer by sponging anti-tumor miRNAs. Mol Cancer. 2019;18(1):115.CrossRefPubMedPubMedCentral Wang CJ, Zhu CC, Xu J, et al. The lncRNA UCA1 promotes proliferation, migration, immune escape and inhibits apoptosis in gastric cancer by sponging anti-tumor miRNAs. Mol Cancer. 2019;18(1):115.CrossRefPubMedPubMedCentral
17.
go back to reference Wang XS, Zhang Z, Wang HC, et al. Rapid identification of UCA1 as a very sensitive and specific unique marker for human renal carcinoma. Clin Cancer Res. 2006;12(16):4851–8.CrossRefPubMed Wang XS, Zhang Z, Wang HC, et al. Rapid identification of UCA1 as a very sensitive and specific unique marker for human renal carcinoma. Clin Cancer Res. 2006;12(16):4851–8.CrossRefPubMed
18.
go back to reference Wang F, Li X, Xie X, et al. UCA1, a non-protein-coding RNA up-regulated in renal carcinoma and embryo, influencing cell growth and promoting invasion. FEBS Lett. 2008;582(13):1919–27.CrossRefPubMed Wang F, Li X, Xie X, et al. UCA1, a non-protein-coding RNA up-regulated in renal carcinoma and embryo, influencing cell growth and promoting invasion. FEBS Lett. 2008;582(13):1919–27.CrossRefPubMed
19.
go back to reference Li JY, Ma X. Overexpression of long non-coding RNA UCA1 predicts a poor prognosis in patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7(11):7938–44.PubMedPubMedCentral Li JY, Ma X. Overexpression of long non-coding RNA UCA1 predicts a poor prognosis in patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7(11):7938–44.PubMedPubMedCentral
20.
go back to reference Li Z, Niu H, Qin Q, et al. lncRNA UCA1 mediates resistance to cisplatin by regulating the miR-143/FOSL2-signaling pathway in ovarian cancer. Mol Ther Nucleic Acids. 2019;17:92–101.CrossRefPubMedPubMedCentral Li Z, Niu H, Qin Q, et al. lncRNA UCA1 mediates resistance to cisplatin by regulating the miR-143/FOSL2-signaling pathway in ovarian cancer. Mol Ther Nucleic Acids. 2019;17:92–101.CrossRefPubMedPubMedCentral
21.
go back to reference Kong L, Wu Q, Zhao L, et al. Upregulated lncRNA-UCA1 contributes to metastasis of bile duct carcinoma through regulation of miR-122/ and activation of the ERK/MAPK signaling pathway. Cell Cycle. 2019;18(11):1212–28.CrossRefPubMedPubMedCentral Kong L, Wu Q, Zhao L, et al. Upregulated lncRNA-UCA1 contributes to metastasis of bile duct carcinoma through regulation of miR-122/ and activation of the ERK/MAPK signaling pathway. Cell Cycle. 2019;18(11):1212–28.CrossRefPubMedPubMedCentral
22.
go back to reference Han C, Tang F, Chen J, et al. Knockdown of lncRNA-UCA1 inhibits the proliferation and migration of melanoma cells through modulating the miR-28-5p/HOXB3 axis. Exp Ther Med. 2019;17(5):4294–302.PubMedPubMedCentral Han C, Tang F, Chen J, et al. Knockdown of lncRNA-UCA1 inhibits the proliferation and migration of melanoma cells through modulating the miR-28-5p/HOXB3 axis. Exp Ther Med. 2019;17(5):4294–302.PubMedPubMedCentral
25.
go back to reference Li O, Yi W, Yang P, et al. Long non-coding RNA UCA1 promotes proliferation and invasion of intrahepatic cholangiocarcinoma cells through targeting microRNA-122. Exp Ther Med. 2019;18(1):25–32.PubMedPubMedCentral Li O, Yi W, Yang P, et al. Long non-coding RNA UCA1 promotes proliferation and invasion of intrahepatic cholangiocarcinoma cells through targeting microRNA-122. Exp Ther Med. 2019;18(1):25–32.PubMedPubMedCentral
29.
go back to reference Li D, Hao S. Long non-coding RNA UCA1 exerts growth modulation by miR-15a in human thyroid cancer TPC-1 cells. Artif Cells, Nanomed Biotechnol. 2019;47(1):1815–22.CrossRef Li D, Hao S. Long non-coding RNA UCA1 exerts growth modulation by miR-15a in human thyroid cancer TPC-1 cells. Artif Cells, Nanomed Biotechnol. 2019;47(1):1815–22.CrossRef
30.
go back to reference Gong J, Lu X, Xu J, et al. Coexpression of UCA1 and ITGA2 in pancreatic cancer cells target the expression of miR-107 through focal adhesion pathway. J Cell Physiol. 2019;234(8):12884–96.CrossRefPubMed Gong J, Lu X, Xu J, et al. Coexpression of UCA1 and ITGA2 in pancreatic cancer cells target the expression of miR-107 through focal adhesion pathway. J Cell Physiol. 2019;234(8):12884–96.CrossRefPubMed
32.
33.
go back to reference Qin SB, Peng DY, Lu JM. MiR-182-5p inhibited oxidative stress and apoptosis triggered by oxidized low-density lipoprotein via targeting toll-like receptor 4. J Cell Physiol. 2018;233(10):6630–7.CrossRefPubMed Qin SB, Peng DY, Lu JM. MiR-182-5p inhibited oxidative stress and apoptosis triggered by oxidized low-density lipoprotein via targeting toll-like receptor 4. J Cell Physiol. 2018;233(10):6630–7.CrossRefPubMed
35.
go back to reference Liang Q, Chen H, Xu X. miR-182-5p attenuates high-fat -diet-induced nonalcoholic steatohepatitis in mice. Ann Hepatol. 2019;18(1):116–25 10.560.CrossRefPubMed Liang Q, Chen H, Xu X. miR-182-5p attenuates high-fat -diet-induced nonalcoholic steatohepatitis in mice. Ann Hepatol. 2019;18(1):116–25 10.560.CrossRefPubMed
36.
go back to reference Jia XN, Yin SD, Wei Y. MiR-182-5p inhibited proliferation and migration of ovarian cancer cells by targeting BNIP3. Eur Rev Med Pharmacol Sci. 2019;23(8):3270–6. Jia XN, Yin SD, Wei Y. MiR-182-5p inhibited proliferation and migration of ovarian cancer cells by targeting BNIP3. Eur Rev Med Pharmacol Sci. 2019;23(8):3270–6.
37.
go back to reference Miles KM,Seshadri M,Ciamporcero E, et al. Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts .PloS One. 2014;9(11):e112371. Miles KM,Seshadri M,Ciamporcero E, et al. Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts .PloS One. 2014;9(11):e112371.
38.
go back to reference McClements L, Annett S, Yakkundi A, et al. FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. BMC Cancer. 2019;19(1):351.CrossRefPubMedPubMedCentral McClements L, Annett S, Yakkundi A, et al. FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. BMC Cancer. 2019;19(1):351.CrossRefPubMedPubMedCentral
39.
40.
go back to reference Zheng X, Narayanan S, Sunkari VG, et al. Triggering of a Dll4-Notch1 loop impairs wound healing in diabetes. Proc Natl Acad Sci U S A. 2019;116(14):6985–94.CrossRefPubMedPubMedCentral Zheng X, Narayanan S, Sunkari VG, et al. Triggering of a Dll4-Notch1 loop impairs wound healing in diabetes. Proc Natl Acad Sci U S A. 2019;116(14):6985–94.CrossRefPubMedPubMedCentral
42.
go back to reference Boardman R, Pang V, Malhi N, et al. Activation of Notch signaling by soluble Dll4 decreases vascular permeability via a cAMP/PKA-dependent pathway. Am J Physiol Heart Circ Physiol. 2019;316(5):H1065–75.CrossRefPubMedPubMedCentral Boardman R, Pang V, Malhi N, et al. Activation of Notch signaling by soluble Dll4 decreases vascular permeability via a cAMP/PKA-dependent pathway. Am J Physiol Heart Circ Physiol. 2019;316(5):H1065–75.CrossRefPubMedPubMedCentral
43.
go back to reference Un W, Li J, Li Y, et al. Gamma-secretase inhibitor, DAPT, prevents the development of retinopathy of prematurity in a rat model by regulating the Delta-like ligand 4/Notch Homolog-1 (DLL4/Notch-1) pathway. Med Sci Monit. 2019;25:492–9.CrossRef Un W, Li J, Li Y, et al. Gamma-secretase inhibitor, DAPT, prevents the development of retinopathy of prematurity in a rat model by regulating the Delta-like ligand 4/Notch Homolog-1 (DLL4/Notch-1) pathway. Med Sci Monit. 2019;25:492–9.CrossRef
44.
go back to reference Nakano T, Katsuki S, Chen M, et al. Uremic toxin Indoxyl sulfate promotes Proinflammatory macrophage activation via the interplay of OATP2B1 and Dll4-Notch signaling. Circulation. 2019;139(1):78–96 10.1161.CrossRefPubMedPubMedCentral Nakano T, Katsuki S, Chen M, et al. Uremic toxin Indoxyl sulfate promotes Proinflammatory macrophage activation via the interplay of OATP2B1 and Dll4-Notch signaling. Circulation. 2019;139(1):78–96 10.1161.CrossRefPubMedPubMedCentral
46.
go back to reference Minuzzo S, Agnusdei V, Pusceddu I, et al. DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD/SCID mice. Carcinogenesis. 2015;36(1):115–21.CrossRefPubMed Minuzzo S, Agnusdei V, Pusceddu I, et al. DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD/SCID mice. Carcinogenesis. 2015;36(1):115–21.CrossRefPubMed
47.
go back to reference Qiu XX, Chen L, Wang CH, et al. High delta-like ligand 4 (DLL4) is correlated with peritumoral brain edema and predicts poor prognosis in primary glioblastoma. Medicine. 2014;93(8):e57.CrossRefPubMedPubMedCentral Qiu XX, Chen L, Wang CH, et al. High delta-like ligand 4 (DLL4) is correlated with peritumoral brain edema and predicts poor prognosis in primary glioblastoma. Medicine. 2014;93(8):e57.CrossRefPubMedPubMedCentral
49.
Metadata
Title
Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA
Authors
Wei Wang
Wentao Hu
Ya Wang
Yong An
Lei Song
Panfeng Shang
Zhongjin Yue
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Renal Cancer
Published in
Molecular Cancer / Issue 1/2020
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-020-1132-x

Other articles of this Issue 1/2020

Molecular Cancer 1/2020 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine