Skip to main content
Log in

AFAP1-AS1, a long noncoding RNA upregulated in lung cancer and promotes invasion and metastasis

  • Original Article
  • Published:
Tumor Biology

Abstract

Long noncoding RNAs (lncRNAs) have emerged as a major regulator of cancer. Significant fraction of lncRNAs is represented on widely used microarray platforms; however, many of which have no known function. To discover novel lung cancer-related lncRNAs, we analyzed the lncRNA expression patterns in five sets of previously published lung cancer gene expression profile data that were represented on Affymetrix HG-U133 Plus 2.0 array, and identified dysregulated lncRNAs in lung cancer. One lncRNA, actin filament associated protein 1 antisense RNA1 (AFAP1-AS1), was the most significantly upregulated in lung cancer and associated with poor prognosis. In vitro experiments demonstrated that AFAP1-AS1 knockdown significantly inhibited the cell invasive and migration capability in lung cancer cells. AFAP1-AS1 knockdown also increased the expression of its antisense protein coding gene, actin filament associated protein 1 (AFAP1), and affected the expression levels of several small GTPase family members and molecules in the actin cytokeratin signaling pathway, which suggested that AFAP1-AS1 promoted cancer cell metastasis via regulation of actin filament integrity. Our findings extend the number of noncoding RNAs functionally implicated in lung cancer progression and highlight the role of AFAP1-AS1 as potential prognostic biomarker and therapeutic target of lung cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.

    Article  PubMed  Google Scholar 

  2. Wang M, Cao JX, Pan JH, Liu YS, Xu BL, et al. Adoptive immunotherapy of cytokine-induced killer cell therapy in the treatment of non-small cell lung cancer. PLoS One. 2014;9:e112662.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhang NN, Liu YT, Ma L, Wang L, Hao XZ, et al. The molecular detection and clinical significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK targeted therapy. PLoS One. 2014;9:e84501.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Aggarwal C. Targeted therapy for lung cancer: present and future. Ann Palliat Med. 2014;3:229–35.

    PubMed  Google Scholar 

  5. Lu JY, Zhang M, Jin HL, Zhu JL, Wei JL, et al. Advances on molecular mechanism of chronic inflammation-driven lung cancer induced by environmental carcinogens. Prog Biochem Biophys. 2014;41:41–51.

    CAS  Google Scholar 

  6. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10:155–9.

    Article  CAS  PubMed  Google Scholar 

  7. Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15:7–21.

    Article  CAS  PubMed  Google Scholar 

  8. Muers M. RNA: Genome-wide views of long non-coding RNAs. Nat Rev Genet. 2011;12:742.

    Article  CAS  PubMed  Google Scholar 

  9. Gong Z, Zhang S, Zhang W, Huang H, Li Q, et al. Long non-coding RNAs in cancer. Sci China Life Sci. 2012;55:1120–4.

    Article  PubMed  Google Scholar 

  10. Gong Z, Zhang S, Zeng Z, Wu H, Yang Q, et al. LOC401317, a p53-regulated long non-coding RNA, inhibits cell proliferation and induces apoptosis in the nasopharyngeal carcinoma cell line HNE2. PLoS One. 2014;9:e110674.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ono H, Motoi N, Nagano H, Miyauchi E, Ushijima M, et al. Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer. Cancer Med. 2014;3:632–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhao W, An Y, Liang Y, Xie XW. Role of HOTAIR long noncoding RNA in metastatic progression of lung cancer. Eur Rev Med Pharmacol Sci. 2014;18:1930–6.

    CAS  PubMed  Google Scholar 

  13. Matouk IJ, Halle D, Gilon M, Hochberg A. The non-coding RNAs of the H19-IGF2 imprinted loci: a focus on biological roles and therapeutic potential in Lung Cancer. J Transl Med. 2015;13:113.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lin L, Gu ZT, Chen WH, Cao KJ. Increased expression of the long non-coding RNA ANRIL promotes lung cancer cell metastasis and correlates with poor prognosis. Diagn Pathol. 2015;10:14.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Shen L, Chen L, Wang Y, Jiang X, Xia H, et al. Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer. J Neurooncol. 2015;121:101–8.

    Article  CAS  PubMed  Google Scholar 

  16. Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73:1180–9.

    Article  CAS  PubMed  Google Scholar 

  17. Weber DG, Johnen G, Casjens S, Bryk O, Pesch B, et al. Evaluation of long noncoding RNA MALAT1 as a candidate blood-based biomarker for the diagnosis of non-small cell lung cancer. BMC Res Notes. 2013;6:518.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dong S, Qu X, Li W, Zhong X, Li P, et al. The long non-coding RNA, GAS5, enhances gefitinib-induced cell death in innate EGFR tyrosine kinase inhibitor-resistant lung adenocarcinoma cells with wide-type EGFR via downregulation of the IGF-1R expression. J Hematol Oncol. 2015;8:43.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shi X, Sun M, Liu H, Yao Y, Kong R, et al. A critical role for the long non-coding RNA GAS5 in proliferation and apoptosis in non-small-cell lung cancer. Mol Carcinog. 2015;54 Suppl 1:E1–E12.

    Article  CAS  PubMed  Google Scholar 

  20. Okayama H, Kohno T, Ishii Y, Shimada Y, Shiraishi K, et al. Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. Cancer Res. 2012;72:100–11.

    Article  CAS  PubMed  Google Scholar 

  21. Lu TP, Tsai MH, Lee JM, Hsu CP, Chen PC, et al. Identification of a novel biomarker, SEMA5A, for non-small cell lung carcinoma in nonsmoking women. Cancer Epidemiol Biomarkers Prev. 2010;19:2590–7.

    Article  CAS  PubMed  Google Scholar 

  22. Wei TY, Hsia JY, Chiu SC, Su LJ, Juan CC, et al. Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis. Cell Signal. 2014;26:2940–50.

    Article  CAS  PubMed  Google Scholar 

  23. Sanchez-Palencia A, Gomez-Morales M, Gomez-Capilla JA, Pedraza V, Boyero L, et al. Gene expression profiling reveals novel biomarkers in nonsmall cell lung cancer. Int J Cancer. 2011;129:355–64.

    Article  CAS  PubMed  Google Scholar 

  24. Botling J, Edlund K, Lohr M, Hellwig B, Holmberg L, et al. Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis, and tissue microarray validation. Clin Cancer Res. 2013;19:194–204.

    Article  CAS  PubMed  Google Scholar 

  25. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98:5116–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zeng Z, Zhou Y, Xiong W, Luo X, Zhang W, et al. Analysis of gene expression identifies candidate molecular markers in nasopharyngeal carcinoma using microdissection and cDNA microarray. J Cancer Res Clin Oncol. 2007;133:71–81.

    Article  CAS  PubMed  Google Scholar 

  27. Liao Q, Zeng Z, Guo X, Li X, Wei F, et al. LPLUNC1 suppresses IL-6-induced nasopharyngeal carcinoma cell proliferation via inhibiting the Stat3 activation. Oncogene. 2014;33:2098–109.

    Article  CAS  PubMed  Google Scholar 

  28. Yang Y, Liao Q, Wei F, Li X, Zhang W, et al. LPLUNC1 inhibits nasopharyngeal carcinoma cell growth via down-regulation of the MAP kinase and cyclin D1/E2F pathways. PLoS One. 2013;8:e62869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xiong W, Wu X, Starnes S, Johnson SK, Haessler J, et al. An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Blood. 2008;112:4235–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dorfleutner A, Cho Y, Vincent D, Cunnick J, Lin H, et al. Phosphorylation of AFAP-110 affects podosome lifespan in A7r5 cells. J Cell Sci. 2008;121:2394–405.

    Article  CAS  PubMed  Google Scholar 

  31. Walker VG, Ammer A, Cao Z, Clump AC, Jiang BH, et al. PI3K activation is required for PMA-directed activation of cSrc by AFAP-110. Am J Physiol Cell Physiol. 2007;293:C119–32.

    Article  CAS  PubMed  Google Scholar 

  32. Qian Y, Gatesman AS, Baisden JM, Zot HG, Cherezova L, et al. Analysis of the role of the leucine zipper motif in regulating the ability of AFAP-110 to alter actin filament integrity. J Cell Biochem. 2004;91:602–20.

    Article  CAS  PubMed  Google Scholar 

  33. Ambriz-Pena X, Garcia-Zepeda EA, Meza I, Soldevila G. Jak3 enables chemokine-dependent actin cytoskeleton reorganization by regulating cofilin and Rac/Rhoa GTPases activation. PLoS One. 2014;9:e88014.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sit ST, Manser E. Rho GTPases and their role in organizing the actin cytoskeleton. J Cell Sci. 2011;124:679–83.

    Article  CAS  PubMed  Google Scholar 

  35. Yang Y, Li H, Hou S, Hu B, Liu J, et al. The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell. PLoS One. 2013;8:e65309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang X, Gao L, Guo X, Shi X, Wu H, et al. A network based method for analysis of lncRNA-disease associations and prediction of lncRNAs implicated in diseases. PLoS One. 2014;9:e87797.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Negishi M, Wongpalee SP, Sarkar S, Park J, Lee KY, et al. A new lncRNA, APTR, associates with and represses the CDKN1A/p21 promoter by recruiting polycomb proteins. PLoS One. 2014;9:e95216.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Li YW, Wang YM, Zhang XY, Xue D, Kuang B, et al. Progress of long noncoding RNA HOTAIR in human cancer. Progress in Biochemistry and Biophysics. 2015;42:228–35.

    CAS  Google Scholar 

  39. Tang K, Wei F, Bo H, Huang HB, Zhang WL, et al. Cloning and functional characterization of a novel long non-coding RNA gene associated with hepatocellular carcinoma. Prog Biochem Biophys. 2014;41:153–62.

    CAS  Google Scholar 

  40. Zhang W, Fan S, Zou G, Shi L, Zeng Z, et al. Lactotransferrin could be a novel independent molecular prognosticator of nasopharyngeal carcinoma. Tumour Biol. 2015;36:675–83.

    Article  PubMed  Google Scholar 

  41. Zhang HM, Yang FQ, Chen SJ, Che J, Zheng JH. Upregulation of long non-coding RNA MALAT1 correlates with tumor progression and poor prognosis in clear cell renal cell carcinoma. Tumour Biol. 2015;36:2947–55.

    Article  CAS  PubMed  Google Scholar 

  42. Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet. 2013;9:e1003368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pang EJ, Yang R, Fu XB, Liu YF. Overexpression of long non-coding RNA MALAT1 is correlated with clinical progression and unfavorable prognosis in pancreatic cancer. Tumour Biol. 2015;36:2403–7.

    Article  CAS  PubMed  Google Scholar 

  44. Ma KX, Wang HJ, Li XR, Li T, Su G, et al. Long noncoding RNA MALAT1 associates with the malignant status and poor prognosis in glioma. Tumour Biol. 2015;36:3355–9.

    Article  CAS  PubMed  Google Scholar 

  45. Ji Q, Liu X, Fu X, Zhang L, Sui H, et al. Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/beta-catenin signal pathway. PLoS One. 2013;8:e78700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dong Y, Liang G, Yuan B, Yang C, Gao R, et al. MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumour Biol. 2015;36:1477–86.

    Article  CAS  PubMed  Google Scholar 

  47. Guan Y, Kuo WL, Stilwell JL, Takano H, Lapuk AV, et al. Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clin Cancer Res. 2007;13:5745–55.

    Article  CAS  PubMed  Google Scholar 

  48. Kong R, Zhang EB, Yin DD, You LH, Xu TP, et al. Long noncoding RNA PVT1 indicates a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically regulating p15 and p16. Mol Cancer. 2015;14:82.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Wang F, Yuan JH, Wang SB, Yang F, Yuan SX, 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.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang W, Huang C, Gong Z, Zhao Y, Tang K, 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.

    Article  CAS  PubMed  Google Scholar 

  51. Wu W, Bhagat TD, Yang X, Song JH, Cheng Y, et al. Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett’s esophagus and esophageal adenocarcinoma. Gastroenterology. 2013;144(956–966):e954.

    Google Scholar 

  52. Yuan SX, Tao QF, Wang J, Yang F, Liu L, et al. Antisense long non-coding RNA PCNA-AS1 promotes tumor growth by regulating proliferating cell nuclear antigen in hepatocellular carcinoma. Cancer Lett. 2014;349:87–94.

    Article  CAS  PubMed  Google Scholar 

  53. Sehgal L, Mathur R, Braun FK, Wise JF, Berkova Z, et al. FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma. Leukemia. 2014;28:2376–87.

    Article  CAS  PubMed  Google Scholar 

  54. Baisden JM, Gatesman AS, Cherezova L, Jiang BH, Flynn DC. The intrinsic ability of AFAP-110 to alter actin filament integrity is linked with its ability to also activate cellular tyrosine kinases. Oncogene. 2001;20:6607–16.

    Article  CAS  PubMed  Google Scholar 

  55. Baisden JM, Qian Y, Zot HM, Flynn DC. The actin filament-associated protein AFAP-110 is an adaptor protein that modulates changes in actin filament integrity. Oncogene. 2001;20:6435–47.

    Article  CAS  PubMed  Google Scholar 

  56. Dorfleutner A, Stehlik C, Zhang J, Gallick GE, Flynn DC. AFAP-110 is required for actin stress fiber formation and cell adhesion in MDA-MB-231 breast cancer cells. J Cell Physiol. 2007;213:740–9.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang J, Park SI, Artime MC, Summy JM, Shah AN, et al. AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts. J Clin Invest. 2007;117:2962–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported in part by grants from the National Natural Science Foundation of China (81172189, 81272298, 81372907, 81301757, 81472531, and 81402009) and the Natural Science Foundation of Hunan Province (14JJ1010 and 2015JJ1022).

Conflicts of interest

None

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Guiyuan Li or Wei Xiong.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zeng, Z., Bo, H., Gong, Z. et al. AFAP1-AS1, a long noncoding RNA upregulated in lung cancer and promotes invasion and metastasis. Tumor Biol. 37, 729–737 (2016). https://doi.org/10.1007/s13277-015-3860-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3860-x

Keywords

Navigation