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Cancer Cell International
Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Primary research

Mechanistic study of lncRNA UCA1 promoting growth and cisplatin resistance in lung adenocarcinoma

Authors: Jiali Fu, Jingjing Pan, Xiang Yang, Yan Zhang, Fanggui Shao, Jie Chen, Kate Huang, Yumin Wang

Published in: Cancer Cell International | Issue 1/2021

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Abstract

Aim

This study aimed to explore the mechanism of LncRNA urothelial carcinoma-associated 1 (UCA1) promoting cisplatin resistance in lung adenocarcinoma (LUAD).

Method

The UCA1 expression level in LUAD cell lines was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). We overexpressed UCA1 in A549 cells and downregulated UCA1 in A549/DDP cells by the lentivirus‑mediated technique. Subsequently, in vitro, and in vivo functional experiments were performed to investigate the functional roles of UCA1 in the growth and metastasis of LUAD cell lines. Furthermore, RNA pulldown, mass spectrometry, and RNA immunoprecipitation technique were performed to analyze various downstream target factors regulated by UCA1.

Results

The results revealed a higher UCA1 expression level in A549/DDP cells and LUAD tissues than in A549 cells and adjacent cancer tissues. UCA1 expression was significantly associated with distant metastasis, clinical stage, and survival time of patients with LUAD. UCA1 overexpression significantly increased the proliferation, invasion, clone formation, and cisplatin resistance ability and enhanced the expression levels of proliferating cell nuclear antigen and excision repair cross-complementing gene 1 in A549 cells. However, these trends were mostly reversed after the knockdown of UCA1 in A549/DDP cells. Tumorigenic assays in nude mice showed that UCA1 knockdown significantly inhibited tumor growth and reduced cisplatin resistance. Enolase 1 was the RNA-binding protein (RBP) of UCA1.

Conclusion

Based on the results, we concluded that UCA1 promoted LUAD progression and cisplatin resistance and hence could be a potential diagnostic marker and therapeutic target in patients with LUAD.
Appendix
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Literature
1.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–429.CrossRefPubMed
2.
3.
Du L, Morgensztern D. Chemotherapy for advanced-stage non-small cell lung cancer. Cancer J. 2015;21(5):366–70.PubMedCrossRef
4.
Kibria G, Hatakeyama H, Harashima H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch Pharm Res. 2014;37(1):4–15.PubMedCrossRef
5.
Liang XJ, Finkel T, Shen DW, Yin JJ, Aszalos A, Gottesman MM. SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism. Mol Cancer Res. 2008;6(9):1499–506.PubMedPubMedCentralCrossRef
6.
Beretta GL, Benedetti V, Cossa G, et al. Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin. Biochem Pharmacol. 2010;79(8):1108–17.PubMedCrossRef
7.
Galluzzi L, Senovilla L, Vitale I, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31(15):1869–83.PubMedCrossRef
8.
Liu XH, Sun M, Nie FQ, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.PubMedPubMedCentralCrossRef
9.
Xue X, Yang YA, Zhang A, et al. LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene. 2016;35(21):2746–55.PubMedCrossRef
10.
Özeş AR, Miller DF, Özeş ON, et al. NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer. Oncogene. 2016;35(41):5350–61.PubMedPubMedCentralCrossRef
11.
Hong Q, Li O, Zheng W, et al. LncRNA HOTAIR regulates HIF-1α/AXL signaling through inhibition of miR-217 in renal cell carcinoma. Cell Death Dis. 2017;8(5):e2772.PubMedPubMedCentralCrossRef
12.
Cheng D, Deng J, Zhang B, et al. LncRNA HOTAIR epigenetically suppresses miR-122 expression in hepatocellular carcinoma via DNA methylation. EBioMedicine. 2018;36:159–70.PubMedPubMedCentralCrossRef
13.
Sun S, Wu Y, Guo W, et al. STAT3/HOTAIR signaling axis regulates HNSCC Growth in an EZH2-dependent Manner. Clin Cancer Res. 2018;24(11):2665–77.PubMedCrossRef
14.
Tan SK, Pastori C, Penas C, et al. Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme. Mol Cancer. 2018;17(1):74.PubMedPubMedCentralCrossRef
15.
Wu C, Yang L, Qi X, Wang T, Li M, Xu K. Inhibition of long non-coding RNA HOTAIR enhances radiosensitivity via regulating autophagy in pancreatic cancer. Cancer Manag Res. 2018;10:5261–71.PubMedPubMedCentralCrossRef
16.
Wang XS, Zhang Z, Wang HC, et al. Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma. Clin Cancer Res. 2006;12(16):4851–8.PubMedCrossRef
17.
Bian Z, Jin L, Zhang J, et al. LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p. Sci Rep. 2016;6:23892.PubMedPubMedCentralCrossRef
18.
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.PubMedPubMedCentralCrossRef
19.
Pan J, Li X, Wu W, et al. Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR-196a-5p in bladder cancer cells. Cancer Lett. 2016;382(1):64–76.PubMedCrossRef
20.
Li C, Fan K, Qu Y, Zhai W, Huang A, Sun X, et al. Deregulation of UCA1 expression may be involved in the development of chemoresistance to cisplatin in the treatment of non-small-cell lung cancer via regulating the signaling pathway of microRNA-495/NRF2. J Cell Physiol. 2020;235:3721–30.PubMedCrossRef
21.
Liu X, Huang Z, Qian W, Zhang Q, Sun J. Silence of lncRNA UCA1 rescues drug resistance of cisplatin to non-small-cell lung cancer cells. J Cell Biochem. 2019;120(6):9243–9.PubMedCrossRef
22.
Chandrashekar DS, Bashel B, Balasubramanya S, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649–58.PubMedPubMedCentralCrossRef
23.
Madsen P, Celis JE. S-phase patterns of cyclin (PCNA) antigen staining resemble topographical patterns of DNA synthesis. A role for cyclin in DNA replication. FEBS Lett. 1985;193(1):5–11.PubMedCrossRef
24.
Kowalska E, Bartnicki F, Fujisawa R, et al. Inhibition of DNA replication by an anti-PCNA aptamer/PCNA complex. Nucleic Acids Res. 2018;46(1):25–41.PubMedCrossRef
25.
Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett. 2006;244(2):164–71.PubMedCrossRef
26.
Phadke MS, Krynetskaia NF, Mishra AK, Krynetskiy E. Glyceraldehyde 3-phosphate dehydrogenase depletion induces cell cycle arrest and resistance to antimetabolites in human carcinoma cell lines. J Pharmacol Exp Ther. 2009;331:77–86.PubMedPubMedCentralCrossRef
27.
Roque DM, Buza N, Glasgow M, Bellone S, Bortolomai I, Gasparrini S, et al. Class III β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel. Clin Exp Metastasis. 2014;31:101–10.PubMedCrossRef
28.
Shin YK, Yoo BC, Chang HJ, Jeon E, Hong SH, Jung MS, et al. Down-regulation of mitochondrial F1F0-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance. Cancer Res. 2005;65:3162–70.PubMedCrossRef
29.
Wang X, Lu Y, Yang J, Shi Y, Lan M, Liu Z, et al. Identification of triosephosphate isomerase as an anti-drug resistance agent in human gastric cancer cells using functional proteomic analysis. J Cancer Res Clin Oncol. 2008;134:995–1003.PubMedCrossRef
30.
Muramatsu H, Sumitomo M, Morinaga S, Kajikawa K, Kobayashi I, Nishikawa G, et al. Targeting lactate dehydrogenase-A promotes docetaxel-induced cytotoxicity predominantly in castration-resistant prostate cancer cells. Oncol Rep. 2019;42:224–30.PubMed
31.
Zaidi AH, Raviprakash N, Mokhamatam RB, Gupta P, Manna SK. Profilin potentiates chemotherapeutic agents mediated cell death via suppression of NF-κB and upregulation of p53. Apoptosis. 2016;21:502–13.PubMedCrossRef
32.
Stark M, Bram EE, Akerman M, Mandel-Gutfreund Y, Assaraf YG. Heterogeneous nuclear ribonucleoprotein H1/H2-dependent unsplicing of thymidine phosphorylase results in anticancer drug resistance. J Biol Chem. 2011;286:3741–54.PubMedCrossRef
33.
Wei L, Lee D, Law CT, Zhang MS, Shen J, Chin DW, et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun. 2019;10:4681.PubMedPubMedCentralCrossRef
34.
Yang L, Chen Y, Cui T, Knösel T, Zhang Q, Albring KF, et al. Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/β-catenin signaling pathway in human lung cancer. Carcinogenesis. 2012;33:1863–70.PubMedCrossRef
35.
Kong XX, Jiang S, Liu T, Liu GF, Dong M. Paclitaxel increases sensitivity of SKOV3 cells to hyperthermia by inhibiting heat shock protein 27. Biomed Pharmacother. 2020;132:110907.PubMedCrossRef
36.
Chen R, Li D, Zheng M, Chen B, Wei T, Wang Y, Li M, Huang W, Tong Q, Wang Q, et al. FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1. J Cell Mol Med. 2020;24:2123–34.PubMedPubMedCentralCrossRef
37.
Kim HJ, Moon SJ, Kim SH, Heo K, Kim JH. DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer. Cell Death Dis. 2018;9:831.PubMedPubMedCentralCrossRef
38.
Akbari Moqadam F, Lange-Turenhout EA, Ariës IM, Pieters R, den Boer ML. MiR-125b, miR-100 and miR-99a co-regulate vincristine resistance in childhood acute lymphoblastic leukemia. Leuk Res. 2013;37:1315–21.PubMedCrossRef
39.
Azimi A, Tuominen R, Costa Svedman F, Caramuta S, Pernemalm M, Frostvik Stolt M, et al. Silencing FLI or targeting CD13/ANPEP lead to dephosphorylation of EPHA2, a mediator of BRAF inhibitor resistance, and induce growth arrest or apoptosis in melanoma cells. Cell Death Dis. 2017;8:e3029.PubMedPubMedCentralCrossRef
40.
Jin X, Liao M, Zhang L, Yang M, Zhao J. Role of the novel gene BZW2 in the development of hepatocellular carcinoma. J Cell Physiol. 2019;234(9):16592–600.CrossRef
41.
Yan XD, Pan LY, Yuan Y, Lang JH, Mao N. Identification of platinum-resistance associated proteins through proteomic analysis of human ovarian cancer cells and their platinum-resistant sublines. J Proteome Res. 2007;6:772–80.PubMedCrossRef
42.
Blanch A, Robinson F, Watson IR, Cheng LS, Irwin MS. Eukaryotic translation elongation factor 1-alpha 1 inhibits p53 and p73 dependent apoptosis and chemotherapy sensitivity. PLoS ONE. 2013;8:e66436.PubMedPubMedCentralCrossRef
43.
Fritsche P, Seidler B, Schüler S, Schnieke A, Göttlicher M, Schmid RM, et al. HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA. Gut. 2009;58:1399–409.PubMedCrossRef
44.
Smith L, Welham KJ, Watson MB, Drew PJ, Lind MJ, Cawkwell L. The proteomic analysis of cisplatin resistance in breast cancer cells. Oncol Res. 2007;16:497–506.PubMedCrossRef
45.
Liang Z, Li W, Liu J, Li J, He F, Jiang Y, et al. Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast cancer cells. Sci Rep. 2017;7:41776.PubMedPubMedCentralCrossRef
46.
Wang Q, Zhao D, Xian M, Wang Z, Bi E, Su P, et al. MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma. Blood. 2020;136:2557–73.PubMedCrossRefPubMedCentral
47.
Marsh LA, Carrera S, Shandilya J, Heesom KJ, Davidson AD, Medler KF, et al. BASP1 interacts with oestrogen receptor α and modifies the tamoxifen response. Cell Death Dis. 2017;8:e2771.PubMedPubMedCentralCrossRef
48.
Hu W, Lei L, Xie X, Huang L, Cui Q, Dang T, et al. Heterogeneous nuclear ribonucleoprotein L facilitates recruitment of 53BP1 and BRCA1 at the DNA break sites induced by oxaliplatin in colorectal cancer. Cell Death Dis. 2019;10:550.PubMedPubMedCentralCrossRef
49.
50.
Romeo C, Weber MC, Zarei M, DeCicco D, Chand SN, Lobo AD, et al. HuR contributes to TRAIL resistance by restricting death receptor 4 expression in pancreatic cancer cells. Mol Cancer Res. 2016;14:599–611.PubMedPubMedCentralCrossRef
51.
Ma Y, Lai W, Zhao M, Yue C, Shi F, Li R, et al. Plastin 3 down-regulation augments the sensitivity of MDA-MB-231 cells to paclitaxel via the p38 MAPK signalling pathway. Artif Cells Nanomed Biotechnol. 2019;47:685–95.PubMed
52.
Zhao P, Ma W, Hu Z, Zang L, Tian Z, Zhang K. Filamin A (FLNA) modulates chemosensitivity to docetaxel in triple-negative breast cancer through the MAPK/ERK pathway. Tumour Biol. 2016;37:5107–15.PubMedCrossRef
53.
Li J, Zhi X, Shen X, Chen C, Yuan L, Dong X, et al. Depletion of UBE2C reduces ovarian cancer malignancy and reverses cisplatin resistance via downregulating CDK1. Biochem Biophys Res Commun. 2020;523:434–40.PubMedCrossRef
54.
Matsukawa S, Morita K, Negishi A, Harada H, Nakajima Y, Shimamoto H, et al. Galectin-7 as a potential predictive marker of chemo- and/or radio-therapy resistance in oral squamous cell carcinoma. Cancer Med. 2014;3:349–61.PubMedPubMedCentralCrossRef
55.
Zhou Y, Liu F, Xu Q, Yang B, Li X, Jiang S, et al. Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer. Oncogene. 2020;39:5633–48.PubMedPubMedCentralCrossRef
56.
Wu N, Ren D, Li S, Ma W, Hu S, Jin Y, et al. RCC2 over-expression in tumor cells alters apoptosis and drug sensitivity by regulating Rac1 activation. BMC Cancer. 2018;18:67.PubMedPubMedCentralCrossRef
57.
58.
Zhou J, Zhang S, Chen Z, He Z, Xu Y, Li Z. CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1. Cell Death Dis. 2019;10(12):885.PubMedPubMedCentralCrossRef
59.
Li W, Xie P, Ruan WH. Overexpression of lncRNA UCA1 promotes osteosarcoma progression and correlates with poor prognosis. J Bone Oncol. 2016;5(2):80–5.PubMedPubMedCentralCrossRef
60.
Lebrun L, Milowich D, Le Mercier M, et al. UCA1 overexpression is associated with less aggressive subtypes of bladder cancer. Oncol Rep. 2018;40(5):2497–506.PubMedPubMedCentral
61.
He X, Wang J, Chen J, et al. lncRNA UCA1 predicts a poor prognosis and regulates cell proliferation and migration by repressing p21 and SPRY1 expression in GC. Mol Ther Nucleic Acids. 2019;18:605–16.PubMedPubMedCentralCrossRef
62.
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.PubMedPubMedCentralCrossRef
63.
Xin H, Liu N, Xu X, et al. Knockdown of lncRNA-UCA1 inhibits cell viability and migration of human glioma cells by miR-193a-mediated downregulation of CDK6. J Cell Biochem. 2019;120(9):15157–69.PubMedCrossRef
64.
Dreyfuss G, Kim VN, Kataoka N. Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol. 2002;3(3):195–205.PubMedCrossRef
65.
Wang L, Bi R, Yin H, Liu H, Li L. ENO1 silencing impaires hypoxia-induced gemcitabine chemoresistance associated with redox modulation in pancreatic cancer cells. Am J Transl Res. 2019;11:4470–80.PubMedPubMedCentral
66.
Zhu X, Miao X, Wu Y, Li C, Guo Y, Liu Y, Chen Y, Lu X, Wang Y, He S. ENO1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) in Non-Hodgkin’s Lymphomas. Exp Cell Res. 2015;335:216–23.PubMedCrossRef
Metadata
Title
Mechanistic study of lncRNA UCA1 promoting growth and cisplatin resistance in lung adenocarcinoma
Authors
Jiali Fu
Jingjing Pan
Xiang Yang
Yan Zhang
Fanggui Shao
Jie Chen
Kate Huang
Yumin Wang
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-02207-0

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