There is a perception that long noncoding RNA (lncRNA) has relationship with carcinogenesis. Many studies have previously identified and validated that the section of chromosome 11p13 is associated with high incidence of tumor. In this study, we investigated a new lncRNA, named lncPRRG4-4, mapped to 11p13 and suspected that lncPRRG4-4 was a potential lung cancer-related gene. To explore its role in carcinogenesis, we first demonstrated that lncPRRG4-4 was upregulated in lung cancer tissues compared with adjacent nontumor tissues and functioned as an oncogene in lung cancer cells. The lncPRRG4-4 was significantly upregulated in lung cancer tissues compared with adjacent normal counterparts (mean ± standard deviation: 0.12 ± 0.84 vs. 0.05 ± 0.22; p < 0.001). Patients with metastasis exhibited high levels of lncPRRG4-4 expression than those without metastasis in both the southern samples (p = 0.045) and eastern samples (p = 0.030), total samples (p = 0.004). In addition, downregulation of lncPRRG4-4 expression inhibited lung cancer proliferation, viability, migration, and invasion ability, arrested cell cycle, facilitated apoptosis, and vice versa. Taken together, these observations suggested that the lncPRRG4-4 functions as an oncogene in lung cancer cells.
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References
1.
CheethamS.W., GruhlF., MattickJ.S., and DingerM.E. (2013). Long noncoding RNAs and the genetics of cancer. Br J Cancer, 108, 2419–2425.
2.
ChenW., ZhengR., BaadeP.D., ZhangS., ZengH., BrayF., et al. (2016a). Cancer statistics in China, 2015. CA Cancer J Clin, 66, 115–132.
3.
ChenW., ZhengR., ZengH., and ZhangS. (2015). Epidemiology of lung cancer in China. Thorac Cancer, 6, 209–215.
4.
ChenX., WuR., WangS., DuanQ., and XuanY. (2016b). RNA-Seq analysis for the potential targets and molecular mechanisms of 17 beta-estradiol in squamous cell lung carcinoma. Neoplasma, 63, 394–401.
5.
CrinoL., WederW., van MeerbeeckJ., and FelipE. (2010). Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 21(Suppl 5), v103–v115.
6.
EastonD.F., PharoahP.D., AntoniouA.C., TischkowitzM., TavtigianS.V., NathansonK.L., et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med, 372, 2243–2257.
7.
FaticaA., and BozzoniI. (2014). Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet, 15, 7–21.
8.
FinkelsteinS.D., HasegawaT., ColbyT., and YousemS.A. (1999). 11q13 allelic imbalance discriminates pulmonary carcinoids from tumorlets. A microdissection-based genotyping approach useful in clinical practice. Am J Pathol, 155, 633–640.
9.
FukudaY., KuriharaN., ImotoI., YasuiK., YoshidaM., YanagiharaK., et al. (2000). CD44 is a potential target of amplification within the 11p13 amplicon detected in gastric cancer cell lines. Genes Chromosomes Cancer, 29, 315–324.
10.
GaoA.C., LouW., DongJ.T., and IsaacsJ.T. (1997). CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p13. Cancer Res, 57, 846–849.
11.
GaoY., NiuY., WangX., WeiL., ZhangR., LvS., et al. (2011). Chromosome aberrations associated with centrosome defects: a study of comparative genomic hybridization in breast cancer. Hum Pathol, 42, 1693–1701.
12.
GeschwindD.H., and StateM.W. (2015). Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol, 14, 1109–1120.
13.
GibbE.A., BrownC.J., and LamW.L. (2011). The functional role of long non-coding RNA in human carcinomas. Mol Cancer, 10, 38.
14.
GutschnerT., HammerleM., EissmannM., HsuJ., KimY., HungG., et al. (2013). The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res, 73, 1180–1189.
15.
JusticeE.D., BarnumS.J., and KiddT. (2017). The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene. PLoS Genet, 13, e1006865.
16.
KashimotoK., KomatsuS., IchikawaD., AritaT., KonishiH., NagataH., et al. (2012). Overexpression of TRIM44 contributes to malignant outcome in gastric carcinoma. Cancer Sci, 103, 2021–2026.
17.
KlingbeilP., NatrajanR., EverittG., VatchevaR., MarchioC., PalaciosJ., et al. (2010). CD44 is overexpressed in basal-like breast cancers but is not a driver of 11p13 amplification. Breast Cancer Res Treat, 120, 95–109.
18.
LiS., WangQ., QiangQ., ShanH., ShiM., ChenB., et al. (2015). Sp1-mediated transcriptional regulation of MALAT1 plays a critical role in tumor. J Cancer Res Clin Oncol, 141, 1909–1920.
19.
LiZ., GaoB., HaoS., TianW., ChenY., WangL., et al. (2017). Knockdown of lncRNA-PANDAR suppresses the proliferation, cell cycle and promotes apoptosis in thyroid cancer cells. EXCLI J, 16, 354–362.
20.
LiuY., LuoF., XuY., WangB., ZhaoY., XuW., et al. (2015). Epithelial-mesenchymal transition and cancer stem cells, mediated by a long non-coding RNA, HOTAIR, are involved in cell malignant transformation induced by cigarette smoke extract. Toxicol Appl Pharmacol, 282, 9–19.
21.
MarshallK.W., MohrS., KhettabiF.E., NossovaN., ChaoS., BaoW., et al. (2010). A blood-based biomarker panel for stratifying current risk for colorectal cancer. Int J Cancer, 126, 1177–1186.
22.
MendellJ.T. (2016). Targeting a long noncoding RNA in breast cancer. N Engl J Med, 374, 2287–2289.
23.
OkudaT., TakiT., NishidaK., ChinenY., NagoshiH., SakakuraC., et al. (2017). Molecular heterogeneity in the novel fusion gene APIP-FGFR2: diversity of genomic breakpoints in gastric cancer with high-level amplifications at 11p13 and 10q26. Oncol Lett, 13, 215–221.
24.
OngC.A., ShannonN.B., Ross-InnesC.S., O'DonovanM., RuedaO.M., HuD.E., et al. (2014). Amplification of TRIM44: pairing a prognostic target with potential therapeutic strategy. J Natl Cancer Inst, 106, dju050.
25.
OxnardG.R., BinderA., and JanneP.A. (2013). New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol, 31, 1097–1104.
26.
PakzadR., Mohammadian-HafshejaniA., GhonchehM., PakzadI., and SalehiniyaH. (2015). The incidence and mortality of lung cancer and their relationship to development in Asia. Transl Lung Cancer Res, 4, 763–774.
27.
PanZ., LiuL., NieW., MigginS., QiuF., CaoY., et al. (2017). Long non-coding RNA AGER-1 functionally upregulates the innate immunity gene AGER and approximates its anti-tumor effect in lung cancer. Mol Carcinog, 57, 305–318.
28.
SeabraC.M., QuentalS., NetoA.P., CarvalhoF., GoncalvesJ., OliveiraJ.P., et al. (2014). A novel Alu-mediated microdeletion at 11p13 removes WT1 in a patient with cryptorchidism and azoospermia. Reprod Biomed Online, 29, 388–391.
29.
ShipmanR., SchramlP., ColombiM., and LudwigC.U. (1998). Allelic deletion at chromosome 11p13 defines a tumour suppressor region between the catalase gene and D11S935 in human non-small cell lung carcinoma. Int J Oncol, 12, 107–111.
30.
SidranskyE., and LopezG. (2012). The link between the GBA gene and parkinsonism. Lancet Neurol, 11, 986–998.
31.
SiegelR.L., MillerK.D., and JemalA. (2017). Cancer statistics, 2017. CA Cancer J Clin, 67, 7–30.
32.
SungJ.S., ParkK.H., and KimY.H. (2010). Genomic alterations of chromosome region 11p as predictive marker by array comparative genomic hybridization in lung adenocarcinoma patients. Cancer Genet Cytogenet, 198, 27–34.
33.
TorreL.A., BrayF., SiegelR.L., FerlayJ., Lortet-TieulentJ., and JemalA. (2015). Global cancer statistics, 2012. CA Cancer J Clin, 65, 87–108.
34.
VeltriW.R. (2014). Non-coding RNAs as biomarkers for metastatic prostate cancer. Lancet Oncol, 15, 1412–1413.
35.
WaoH., MhaskarR., KumarA., MiladinovicB., and DjulbegovicB. (2013). Survival of patients with non-small cell lung cancer without treatment: a systematic review and meta-analysis. Syst Rev, 2, 10.
36.
XieX., LiuH.T., MeiJ., DingF.B., XiaoH.B., HuF.Q., et al. (2014). LncRNA HMlincRNA717 is down-regulated in non-small cell lung cancer and associated with poor prognosis. Int J Clin Exp Pathol, 7, 8881–8886.
37.
XuS., HanJ.C., MoralesA., MenzieC.M., WilliamsK., and FanY.S. (2008). Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism. Cytogenet Genome Res, 122, 181–187.
38.
YamamotoT., TogawaM., ShimadaS., SanguN., ShimojimaK., and OkamotoN. (2014). Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4. Am J Med Genet A, 164a, 634–638.
39.
YangJ., LinJ., LiuT., ChenT., PanS., HuangW., et al. (2014). Analysis of lncRNA expression profiles in non-small cell lung cancers (NSCLC) and their clinical subtypes. Lung Cancer (Amsterdam, Netherlands), 85, 110–115.
40.
YipK.T., DasP.K., SuriaD., LimC.R., NgG.H., and LiewC.C. (2010). A case-controlled validation study of a blood-based seven-gene biomarker panel for colorectal cancer in Malaysia. J Exp Clin Cancer Res, 29, 128.
41.
ZaretskyJ.M., Garcia-DiazA., ShinD.S., Escuin-OrdinasH., HugoW., Hu-LieskovanS., et al. (2016). Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med, 375, 819–829.
42.
ZhangJ., WalshM.F., WuG., EdmonsonM.N., GruberT.A., EastonJ., et al. (2015). Germline mutations in predisposition genes in pediatric cancer. N Engl J Med, 373, 2336–2346.
43.
ZhouJ., NgA.Y., TymmsM.J., JermiinL.S., SethA.K., ThomasR.S., et al. (1998). A novel transcription factor, ELF5, belongs to the ELF subfamily of ETS genes and maps to human chromosome 11p13-15, a region subject to LOH and rearrangement in human carcinoma cell lines. Oncogene, 17, 2719–2732.
44.
ZhouM., GuoM., HeD., WangX., CuiY., YangH., et al. (2015). A potential signature of eight long non-coding RNAs predicts survival in patients with non-small cell lung cancer. J Transl Med, 13, 231.
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