Identification of exosomal microRNA panel as diagnostic and prognostic biomarker for small cell lung cancer

Dong Ha Kim; Hyojeong Park; Yun Jung Choi; Kyungtaek Im; Chae Won Lee; Da-Som Kim; Chan-Gi Pack; Hyun-Yi Kim; Chang-Min Choi; Jae Cheol Lee; Wonjun Ji; Jin Kyung Rho

doi:10.1186/s40364-023-00517-1

Identification of exosomal microRNA panel as diagnostic and prognostic biomarker for small cell lung cancer

Biomark Res. 2023 Sep 13;11(1):80. doi: 10.1186/s40364-023-00517-1.

Authors

Dong Ha Kim¹, Hyojeong Park², Yun Jung Choi¹, Kyungtaek Im¹, Chae Won Lee², Da-Som Kim², Chan-Gi Pack³, Hyun-Yi Kim⁴, Chang-Min Choi^{5

6}, Jae Cheol Lee⁶, Wonjun Ji⁷, Jin Kyung Rho⁸

Affiliations

¹ Asan Institute for Life Sciences, 05505, Seoul, South Korea.
² Department of Biomedical Sciences, AMIST, 05505, Seoul, South Korea.
³ Department of Convergence Medicine, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
⁴ NGeneS Inc, Asan-Si, Gyeonggi-do, South Korea.
⁵ Department of Pulmonary Critical and Care Medicine, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
⁶ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 05505, Seoul, South Korea.
⁷ Department of Pulmonary Critical and Care Medicine, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea. jack1097@naver.com.
⁸ Department of Convergence Medicine, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea. jkrho@amc.seoul.kr.

Abstract

Background: Small cell lung cancer (SCLC) has an exceptionally poor prognosis; as most of the cases are initially diagnosed as extensive disease with hematogenous metastasis. Therefore, the early diagnosis of SCLC is very important and may improve its prognosis.

Methods: To investigate the feasibility of early diagnosis of SCLC, we examined exosomal microRNAs (miRNAs) present in serum obtained from patients with SCLC. First, exosomes were isolated in serum from patients with SCLC and healthy individuals and were characterized using particle size and protein markers. Additionally, miRNA array was performed to define SCLC-specific exosomal miRNAs. Second, the obtained miRNAs were further validated employing a large cohort. Finally, the ability to diagnose SCLC was estimated by area under the curve (AUC), and intracellular mRNA change patterns were verified through validated miRNAs.

Results: From the miRNA array results, we selected 51-miRNAs based on p-values and top 10 differentially expressed genes, and 25-miRNAs were validated using quantitative reverse transcription-polymerase chain reaction. The 25-miRNAs were further validated employing a large cohort. Among them, 7-miRNAs showed significant differences. Furthermore, 6-miRNAs (miR-3565, miR-3124-5p, miR-200b-3p, miR-6515, miR-3126-3p and miR-9-5p) were up-regulated and 1-miRNA (miR-92b-5p) was down-regulated. The AUC value of each miRNA sets between 0.64 and 0.76, however the combined application of 3-miRNAs (miR-200b-3p, miR-3124-5p and miR-92b-5p) remarkably improved the diagnostic value (AUC = 0.93). Gene ontology analysis revealed that the 3-miRNA panel is linked to various oncogene pathways and nervous system development. When the 3-miRNAs were introduced to cells, the resulting changes in total mRNA expression strongly indicated the presence of lung diseases, including lung cancer. In addition, the 3-miRNA panel was significantly associated with a poorer prognosis, although individual miRNAs have not been validated as prognostic markers.

Conclusion: Our study identified SCLC-specific exosomal miRNAs, and the 3-miRNAs panel (miR-200b-3p, miR-3124-5p and miR-92b-5p) may serve as a diagnostic and prognostic marker for SCLC.

Keywords: Diagnosis; Exosomal miRNA; Exosome; Prognosis; SCLC.

Abstract

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