Abstract
The functional effects of long noncoding RNAs (lncRNAs) in cancer have been widely recognized. However, there is little research on SCLC-related lncRNAs. Here, long intergenic nonprotein coding RNA 173 (Linc00173) was first shown to be involved in chemoresistance and progression of small-cell lung cancer (SCLC). We found that Linc00173 was highly expressed in SCLC chemoresistant cell lines, and promoted SCLC cells chemoresistance, proliferation, and migration-invasion. Animal studies validated that Linc00173 induced tumor chemoresistance and growth of SCLC in vivo. Moreover, Linc00173 upregulated Etk through functioning as a competitive endogenous RNA (ceRNA) by “sponging” miRNA-218 and led to the upregulation of GSKIP and NDRG1, resulting in the translocation of β-catenin. Importantly, expression analysis revealed that both Linc00173 and Etk were upregulated in SCLC patient samples and exhibiting positive Linc00173/Etk correlation. High expression of Linc00173 closely correlated with chemoresistance, extensive stage, and shorter survival in SCLC patients. Collectively, our study illustrated a Linc00173-mediated process that facilitated chemoresistance and progression in SCLC, which might provide treatment strategy against SCLC.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.
Sabari JK, Lok BH, Laird JH, Poirier JT, Rudin CM. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14:549–61.
Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172:393–407.
Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29:452–63.
Bartonicek N, Maag JL, Dinger ME. Long noncoding RNAs in cancer: mechanisms of action and technological advancements. Mol Cancer. 2016;15:43.
Bian Z, Zhang J, Li M, Feng Y, Wang X, Zhang J, et al. LncRNA-FEZF1-AS1 promotes tumor proliferation and metastasis in colorectal cancer by regulating PKM2 signaling. Clin Cancer Res. 2018;24:4808–19.
Cao C, Sun J, Zhang D, Guo X, Xie L, Li X, et al. The long intergenic noncoding RNA UFC1, a target of MicroRNA 34a, interacts with the mRNA stabilizing protein HuR to increase levels of β-catenin in HCC cells. Gastroenterology. 2015;148:415–26.
Kim SS, Harford JB, Moghe M, Rait A, Pirollo KF, Chang EH. Targeted nanocomplex carrying siRNA against MALAT1 sensitizes glioblastoma to temozolomide. Nucleic Acids Res. 2018;46:1424–40.
Sun Y, Hu B, Wang Q, Ye M, Qiu Q, Zhou Y, et al. Long non-coding RNA HOTTIP promotes BCL-2 expression and induces chemoresistance in small cell lung cancer by sponging miR-216a. Cell Death Dis. 2018;9:85.
Xiao L, Wu J, Wang JY, Chung HK, Kalakonda S, Rao JN, et al. Long noncoding RNA uc.173 promotes renewal of the intestinal mucosa by inducing degradation of MicroRNA 195. Gastroenterology. 2018;154:599–611.
Schwarzer A, Emmrich S, Schmidt F, Beck D, Ng M, Reimer C, et al. The non-coding RNA landscape of human hematopoiesis and leukemia. Nat Commun. 2017;8:218.
Mao Y, Fu Z, Zhang Y, Dong L, Zhang Y, Zhang Q, et al. A seven-lncRNA signature predicts overall survival in esophageal squamous cell carcinoma. Sci Rep. 2018;8:8823.
Guo L, Liu Y, Bai Y, Sun Y, Xiao F, Guo Y. Gene expression profiling of drug-resistant small cell lung cancer cells by combining microRNA and cDNA expression analysis. EUR J Cancer. 2010;46:1692–702.
Wang Q, Zeng F, Sun Y, Qiu Q, Zhang J, Huang W, et al. Etk interaction with PFKFB4 modulates chemoresistance of small cell lung cancer by regulating autophagy. Clin Cancer Res. 2017;24:1475–2017.
Guo L, Chen P, Zhou Y, Sun Y. Non-receptor tyrosine kinase Etk is involved in the apoptosis of small cell lung cancer cells. Exp Mol Pathol. 2010;88:401–6.
Guo L, Zhou Y, Sun Y, Zhang F. Non-receptor tyrosine kinase Etk regulation of drug resistance in small-cell lung cancer. Eur J Cancer. 2010;46:636–41.
Xiao J, Lv Y, Jin F, Liu Y, Ma Y, Xiong Y, et al. LncRNA HANR promotes tumorigenesis and increase of chemoresistance in hepatocellular carcinoma. Cell Physiol Biochem. 2017;43:1926–38.
Dema A, Schr ter MF, Perets E, Skroblin P, Moutty MC, De èk VA, et al. The A-kinase anchoring protein (AKAP) glycogen synthase kinase 3β interaction protein (GSKIP) regulates β-catenin through its interactions with both protein kinase A (PKA) and GSK3β. J Biol Chem. 2016;291:19618–30.
Wen J, Mei S, Wei W, Samuel K. NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3β and Nur77 to prevent β-catenin degradation. Oncotarget. 2015;6:29847–59.
Wang Y, Zhou Y, Tao F, Chai S, Xu X, Yang Y, et al. N-myc downstream regulated gene 1(NDRG1) promotes the stem-like properties of lung cancer cells through stabilized c-Myc. Cancer Lett. 2017;401:53–62.
Lin CC, Chou CH, Howng SL, Hsu CY, Hwang CC, Wang C, et al. GSKIP, an inhibitor of GSK3beta, mediates the N-cadherin/beta-catenin pool in the differentiation of SH-SY5Y cells. J Cell Biochem. 2009;108:1325–36.
Ma Y, Yang Y, Wang F, Moyer MP, Wei Q, Zhang P, et al. Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/beta-catenin signalling pathway via suppression of activator protein 2alpha. Gut. 2016;65:1494–504.
Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 2016;17:272–83.
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.
Huarte M. The emerging role of lncRNAs in cancer. NAT Med. 2015;21:1253–61.
Makarova JA, Shkurnikov MU, Wicklein D, Lange T, Samatov TR, Turchinovich AA, et al. Intracellular and extracellular microRNA: an update on localization and biological role. Prog Histochem Cytochem. 2016;51:33–49.
Leung AKL. The whereabouts of microRNA actions: cytoplasm and beyond. Trends Cell Biol. 2015;25:601–10.
Chen X, Liang H, Zhang CY, Zen K. miRNA regulates noncoding RNA: a noncanonical function model. Trends Biochem Sci. 2012;37:457–9.
Cazalla D, Yario T, Steitz JA. Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science. 2010;328:1563–6.
Hansen TB, Wiklund ED, Bramsen JB, Villadsen SB, Statham AL, Clark SJ, et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 2011;30:4414–22.
Tamagnone L, Lahtinen I, Mustonen T, Virtaneva K, Francis F, Muscatelli F, et al. BMX, a novel nonreceptor tyrosine kinase gene of the BTK/ITK/TEC/TXK family located in chromosome Xp22.2. Oncogene. 1994;9:3683–8.
Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99.
Yuchun N, Feng M, Weimei H, Fang S, Man L, Ting W, et al. Long non-coding RNA TUG1 is involved in cell growth and chemoresistance of small cell lung cancer by regulating LIMK2b via EZH2. Mol Cancer. 2017;16:5.
Wei T, Li Y, Zhuo E, Zhu W, Meng H, Zhang J. Down-regulation of GnT-V inhibits nasopharyngeal carcinoma cell CNE-2 malignancy in vitro and in vivo. Cancer Lett. 2011;309:151–61.
Wang F, Yuan JH, Wang SB, Yang F, Yuan SX, Ye C, et al. Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2. Hepatology. 2014;60:1278–90.
Wang K, Long B, Liu F, Wang JX, Liu CY, Zhao B, et al. A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur Heart J. 2016;37:2602–11.
Acknowledgements
The SCLC Human SCLC cell lines NCI-H82, H209 were obtained as a generous gift from Dr Ji Lin of MD Anderson Cancer Center. The flow cytometry analysis was supported by Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University.
Funding
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81572244, 81602631, and 81772458); Natural Science Foundation of Guangdong Province (key) (2015A030311028); The Clinical Research Initiative Project of Southern Medical University (LC2016ZD029); Major Basic Research Projects and Major Applied Research Projects of Educational Commission of Guangdong Province (2017KZDXM015).
Author information
Authors and Affiliations
Contributions
GL, ZW, and ZF conceived and designed the experiments. ZF, WQ, WS, HW, and GY performed the experiments. ZF, WQ, WS, HW, and LS analyzed the data. ZF, WQ, WS, LS, PJ, and LM wrote the paper. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zeng, F., Wang, Q., Wang, S. et al. Linc00173 promotes chemoresistance and progression of small cell lung cancer by sponging miR-218 to regulate Etk expression. Oncogene 39, 293–307 (2020). https://doi.org/10.1038/s41388-019-0984-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-019-0984-2
This article is cited by
-
LncRNA LUESCC promotes esophageal squamous cell carcinoma by targeting the miR-6785-5p/NRSN2 axis
Cellular and Molecular Life Sciences (2024)
-
Orchestrating smart therapeutics to achieve optimal treatment in small cell lung cancer: recent progress and future directions
Journal of Translational Medicine (2023)
-
The identification of a two-gene prognostic model based on cisplatin resistance-related ceRNA network in small cell lung cancer
BMC Medical Genomics (2023)
-
Novel insights into the multifaceted roles of m6A-modified LncRNAs in cancers: biological functions and therapeutic applications
Biomarker Research (2023)
-
Downregulation of Linc00173 increases BCL2 mRNA stability via the miR-1275/PROCA1/ZFP36L2 axis and induces acquired cisplatin resistance of lung adenocarcinoma
Journal of Experimental & Clinical Cancer Research (2023)