Skip to main content

Long Non-coding RNAs in Pulmonary Neuroendocrine Neoplasms

Endocrine Pathology volume 31, pages 254–263 (2020)Cite this article

Abstract

Pulmonary neuroendocrine neoplasms (NENs) are classified into low-grade neuroendocrine tumors and high-grade neuroendocrine carcinomas (NECs). There are significant differences in therapeutic strategies of the different NEN subtypes, and therefore, precise classification of pulmonary NENs is critical. However, challenges in pulmonary NEN classification include overlap of diagnostic histological features among the subtypes and reduced or negative expression of neuroendocrine markers in poorly differentiated pulmonary NECs. Recently, transcription factor insulinoma-associated protein 1 (INSM1) was identified as a sensitive marker of neuroendocrine and neuroepithelial differentiation. In this study, INSM1 expression was detected by immunohistochemistry in greater than 94% of pulmonary NENs, indicating that it is a highly sensitive marker of pulmonary NENs and is useful to detect poorly differentiated pulmonary NECs. Although there are well-established morphological and immunohistologic criteria to diagnose pulmonary NENs, there is no universal consensus regarding prognostic markers of pulmonary NENs. Studies have shown that non–small cell lung cancers express long non-coding RNAs (lncRNAs), which regulate gene expression, epithelial-to-mesenchymal transition, and carcinogenesis. We characterized expression and function of lncRNAs, including HOX transcript antisense RNA (HOTAIR), maternally expressed 3 (MEG3), and prostate cancer antigen 3 (PCA3) in pulmonary NENs, including typical carcinoid tumors, atypical carcinoid tumors, small cell lung carcinoma (SCLC/NEC), and large cell neuroendocrine carcinoma (LCNEC/NEC). In situ hybridization and real-time polymerase chain reaction studies showed higher expression (p < 0.01) of all lncRNAs in SCLC/NEC. Small interfering RNA studies indicated a role for MEG3 and PCA3 in tumor proliferation. Therefore, these lncRNAs may serve as prognostic indicators of pulmonary NEN aggressiveness and as possible therapeutic targets.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113:5–21.

    CAS  Article  Google Scholar 

  2. Bertino EM, Confer PD, Colonna JE, Ross P, Otterson GA. Pulmonary neuroendocrine/carcinoid tumors: a review article. Cancer. 2009;115:4434–41.

    Article  Google Scholar 

  3. Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol. 2010;21 Suppl 7:vii65-71.

    Article  Google Scholar 

  4. Pelosi G, Sonzogni A, Harari S, Albini A, Bresaola E, Marchiò C, et al. Classification of pulmonary neuroendocrine tumors: new insights. Transl Lung Cancer Res. 2017;6:513–29.

    CAS  Article  Google Scholar 

  5. Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31:1770–86.

    Article  Google Scholar 

  6. Jensen SM, Gazdar AF, Cuttitta F, Russell EK, Linnoila RI. A comparison of synaptophysin, chromogranin, and L-dopa decarboxylase as markers for neuroendocrine differentiation in lung cancer cell lines. Cancer Res. 1990;50:6068–74.

    CAS  PubMed  Google Scholar 

  7. Rosenbaum JN, Guo Z, Baus RM, Werner H, Rehrauer WM, Lloyd RV. INSM1: A novel immunohistochemical and molecular marker for neuroendocrine and neuroepithelial neoplasms. Am J Clin Pathol. 2015;144:579–91.

    CAS  Article  Google Scholar 

  8. Kim D, Viswanathan K, Goyal A, Rao R. Insulinoma-associated protein 1 (INSM1) is a robust marker for identifying and grading pancreatic neuroendocrine tumors. Cancer Cytopathol. 2020

  9. Staaf J, Tran L, Söderlund L, Nodin B, Jirström K, Vidarsdottir H, et al. Diagnostic value of insulinoma-associated protein 1 (INSM1) and comparison with established neuroendocrine markers in pulmonary cancers: a comprehensive study and review of the literature. Arch Pathol Lab Med. 2020

  10. Kim IE, Amin A, Wang LJ, Cheng L, Perrino CM. Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract. Appl Immunohistochem Mol Morphol. 2019

  11. Viswanathan K, Siddiqui MT, Borczuk AC. Insulinoma-associated protein 1 is a sensitive and specific marker for lung neuroendocrine tumors in cytologic and surgical specimens. J Am Soc Cytopathol. 2019;8:299–308.

    Article  Google Scholar 

  12. Yang C, Gonzalez I, Zhang L, Cao D. Neuroendocrine markers insulinoma-associated protein 1, chromogranin, synaptophysin, and CD56 show rare positivity in adenocarcinoma ex-goblet cell carcinoids. Gastroenterology Res. 2019;12:120–7.

    Article  Google Scholar 

  13. Leblebici C, Yeni B, Savli TC, Aydın Ö, Güneş P, Cinel L, et al. A new immunohistochemical marker, insulinoma-associated protein 1 (INSM1), for merkel cell carcinoma: evaluation of 24 cases. Ann Diagn Pathol. 2019;40:53–8.

    Article  Google Scholar 

  14. Dermawan JK, Mukhopadhyay S. Insulinoma-associated protein 1 (INSM1) differentiates carcinoid tumourlets of the lung from pulmonary meningothelial-like nodules. Histopathology. 2018;72:1067–9.

    Article  Google Scholar 

  15. Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF. Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol. 2019;32:100–9.

    CAS  Article  Google Scholar 

  16. Fujino K, Motooka Y, Hassan WA, Ali Abdalla MO, Sato Y, Kudoh S, et al. Insulinoma-associated protein 1 is a crucial regulator of neuroendocrine differentiation in lung cancer. Am J Pathol. 2015;185:3164–77.

    CAS  Article  Google Scholar 

  17. Nakra T, Nambirajan A, Guleria P, Phulware RH, Jain D. Insulinoma-associated protein 1 is a robust nuclear immunostain for the diagnosis of small cell lung carcinoma in cytology smears. Cancer Cytopathol. 2019;127:539–48.

    CAS  Article  Google Scholar 

  18. Roy M, Buehler DG, Zhang R, Schwalbe ML, Baus RM, Salamat MS, et al. Expression of Insulinoma-Associated Protein 1 (INSM1) and Orthopedia Homeobox (OTP) in Tumors with Neuroendocrine Differentiation at Rare Sites. Endocr Pathol. 2019;30:35–42.

    CAS  Article  Google Scholar 

  19. Rush PS, Rosenbaum JN, Roy M, Baus RM, Bennett DD, Lloyd RV. Insulinoma-associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma). J Cutan Pathol. 2018;45:129–35.

    Article  Google Scholar 

  20. Xue M, Zhuo Y, Shan B. MicroRNAs, long noncoding RNAs, and their functions in human disease. Methods Mol Biol. 2017;1617:1–25.

    Google Scholar 

  21. Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: a new paradigm. Cancer Res. 2017;77:3965–81.

    CAS  Article  Google Scholar 

  22. Wu C-H, Hsu C-L, Lu P-C, Lin W-C, Juan H-F, Huang H-C. Identification of lncRNA functions in lung cancer based on associated protein-protein interaction modules. Sci Rep. 2016;6:35939.

    CAS  Article  Google Scholar 

  23. Peng Z, Zhang C, Duan C. Functions and mechanisms of long noncoding RNAs in lung cancer. Onco Targets Ther. 2016;9:4411–24.

    CAS  Article  Google Scholar 

  24. Zhang R, Hardin H, Huang W, Buehler D, Lloyd RV. Long non-coding RNA Linc-ROR is upregulated in papillary thyroid carcinoma. Endocr Pathol. 2018;29:1–8.

    Article  Google Scholar 

  25. Wang Y, Hardin H, Chu Y-H, Esbona K, Zhang R, Lloyd RV. Long non-coding RNA expression in anaplastic thyroid carcinomas. Endocr Pathol. 2019;30:262–9.

    CAS  Article  Google Scholar 

  26. Hardin H, Guo Z, Shan W, Montemayor-Garcia C, Asioli S, Yu X-M, et al. The roles of the epithelial-mesenchymal transition marker PRRX1 and miR-146b-5p in papillary thyroid carcinoma progression. Am J Pathol. 2014;184:2342–54.

    CAS  Article  Google Scholar 

  27. Hardin H, Yu X-M, Harrison AD, Larrain C, Zhang R, Chen J, et al. Generation of novel thyroid cancer stem-like cell clones: effects of resveratrol and valproic acid. Am J Pathol. 2016;186:1662–73.

    CAS  Article  Google Scholar 

  28. Taylor JE, Coy DH, Moreau JP. High affinity binding of [125I-Tyr11]somatostatin-14 to human small cell lung carcinoma (NCI-H69). Life Sci. 1988;43:421–7.

    CAS  Article  Google Scholar 

  29. Kasprzak A, Zabel M, Biczysko W. Selected markers (chromogranin A, neuron-specific enolase, synaptophysin, protein gene product 9.5) in diagnosis and prognosis of neuroendocrine pulmonary tumours. Pol J Pathol. 2007;58:23–33.

    CAS  PubMed  Google Scholar 

  30. Rooper LM, Sharma R, Li QK, Illei PB, Westra WH. INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin and CD56 for diagnosing neuroendocrine tumors of the thoracic cavity. Am J Surg Pathol. 2017;41:1561–9.

    Article  Google Scholar 

  31. Hiroshima K, Iyoda A, Shida T, Shibuya K, Iizasa T, Kishi H, et al. Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis. Mod Pathol. 2006;19:1358–68.

    CAS  Article  Google Scholar 

  32. Derks JL, Dingemans A-MC, van Suylen R-J, den Bakker MA, Damhuis RAM, van den Broek EC, et al. Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens? Histopathology. 2019;74:555–66.

    Article  Google Scholar 

  33. Beermann J, Piccoli M-T, Viereck J, Thum T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016;96:1297–325.

    CAS  Article  Google Scholar 

  34. Yang S, Liu T, Sun Y, Liang X. The long noncoding RNA LINC00483 promotes lung adenocarcinoma progression by sponging miR-204-3p. Cell Mol Biol Lett. 2019;24:70.

    CAS  Article  Google Scholar 

  35. Wu L, Liu C, Zhang Z. Knockdown of lncRNA MIAT inhibits proliferation and cisplatin resistance in non-small cell lung cancer cells by increasing miR-184 expression. Oncol Lett. 2020;19:533–41.

    CAS  PubMed  Google Scholar 

  36. Moris D, Ntanasis-Stathopoulos I, Tsilimigras DI, Adam MA, Yang C-FJ, Harpole D, et al. Insights into novel prognostic and possible predictive biomarkers of lung neuroendocrine tumors. Cancer Genomics Proteomics. 2018;15:153–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Dermawan JKT, Farver CF. The role of histologic grading and Ki-67 index in predicting outcomes in pulmonary carcinoid tumors. Am J Surg Pathol. 2020;44:224–31.

    Article  Google Scholar 

  38. Mairinger FD, Ting S, Werner R, Walter RFH, Hager T, Vollbrecht C, et al. Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumors of the lung: results of a profiling study. Mod Pathol. 2014;27:1632–40.

    CAS  Article  Google Scholar 

  39. Demes M, Aszyk C, Bartsch H, Schirren J, Fisseler-Eckhoff A. Differential miRNA-expression as an adjunctive diagnostic tool in neuroendocrine tumors of the lung. Cancers (Basel). 2016;8.

  40. Fang S, Gao H, Tong Y, Yang J, Tang R, Niu Y, et al. Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells. Lab Invest. 2016;96:60–8.

    CAS  Article  Google Scholar 

  41. Ono H, Motoi N, Nagano H, Miyauchi E, Ushijima M, Matsuura 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.

    CAS  Article  Google Scholar 

  42. Loewen G, Jayawickramarajah J, Zhuo Y, Shan B. Functions of lncRNA HOTAIR in lung cancer. J Hematol Oncol. 2014;7:90.

    Article  Google Scholar 

  43. Lu K, Li W, Liu X, Sun M, Zhang M, Wu W, et al. Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer. 2013;13:461.

    Article  Google Scholar 

  44. Zhang A, Zhang J, Kaipainen A, Lucas JM, Yang H. Long non-coding RNA: A newly deciphered “code” in prostate cancer. Cancer Lett. 2016;375:323–30.

    CAS  Article  Google Scholar 

Download references

Acknowledgments

The authors thank the University of Wisconsin Translational Research Initiatives in Pathology (TRIP) laboratory, supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520), and the Office of the Director – NIH (S10OD023526) for the use of its facilities and services.

Funding

The authors thank the University of Wisconsin Translational Research in Pathology (TRIP) laboratory for technical assistance. Supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520) and the Office of the Director--NIH (S100DV23526).

Author information

Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI, 53792-8550, USA

    Damodaran Narayanan, Rakesh Mandal, Heather Hardin, Vishal Chanana, Michael Schwalbe, Jason Rosenbaum, Darya Buehler & Ricardo V. Lloyd

Authors
  1. Damodaran Narayanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rakesh Mandal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heather Hardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vishal Chanana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Schwalbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jason Rosenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Darya Buehler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ricardo V. Lloyd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ricardo V. Lloyd.

Ethics declarations

The study was approved by the Institutional Review Board at the University of Wisconsin-Madison.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Narayanan, D., Mandal, R., Hardin, H. et al. Long Non-coding RNAs in Pulmonary Neuroendocrine Neoplasms. Endocr Pathol 31, 254–263 (2020). https://doi.org/10.1007/s12022-020-09626-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12022-020-09626-1

Keywords

  • INSM1
  • Long non-coding RNA
  • Pulmonary neuroendocrine neoplasms