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Long Non-coding RNAs in Pulmonary Neuroendocrine Neoplasms

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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.

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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).

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Authors and 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

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  1. Damodaran Narayanan
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  2. Rakesh Mandal
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  8. Ricardo V. Lloyd
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Correspondence to Ricardo V. Lloyd.

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

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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

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