Identification of Exosomal MicroRNA Panel As Diagnostic and Prognostic Biomarker for Small Cell Lung Cancer

Overview

Journal Biomark Res

Publisher Biomed Central

Date 2023 Sep 13

PMID 37705067

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Exosome tropism and various pathways in lung cancer metastasis.

Chen H, Liu L, Xing G, Zhang D, A N, Huang J Front Immunol. 2025; 16:1517495.

PMID: 40028322 PMC: 11868168. DOI: 10.3389/fimmu.2025.1517495.

Clinical value of miR-200b in diagnosis and prognosis of childhood pneumonia.

Qi W, Teng B, Zhang F, Chen Y, Xu J, Luan J BMC Pediatr. 2025; 25(1):42.

PMID: 39825267 PMC: 11748587. DOI: 10.1186/s12887-024-05370-1.

Improved Predictability of Diagnosis and Prognosis Using Serum- and Tissue-Derived Extracellular Vesicles From Bulk mRNA Sequencing in Pancreatic Ductal Adenocarcinoma.

Zhu Q, Chen Z, Tian M, Yan X, Gongye X, Liu Z Cancer Med. 2025; 14(2):e70538.

PMID: 39812156 PMC: 11733676. DOI: 10.1002/cam4.70538.

Exosome-Derived miRNAs in Liquid Biopsy for Lung Cancer.

Martinez-Espinosa I, Serrato J, Cabello-Gutierrez C, Carlos-Reyes A, Ortiz-Quintero B Life (Basel). 2025; 14(12.

PMID: 39768316 PMC: 11678223. DOI: 10.3390/life14121608.

Exosomes in esophageal cancer: a promising frontier for liquid biopsy in diagnosis and therapeutic monitoring.

Zihan R, Jingsi C, Lingwen D, Xin L, Yan Z Front Pharmacol. 2025; 15:1459938.

PMID: 39741631 PMC: 11685219. DOI: 10.3389/fphar.2024.1459938.

References

Skog J, Wurdinger T, van Rijn S, Meijer D, Gainche L, Sena-Esteves M . Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008; 10(12):1470-6. PMC: 3423894. DOI: 10.1038/ncb1800. View

Batagov A, Kurochkin I . Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3'-untranslated regions. Biol Direct. 2013; 8:12. PMC: 3732077. DOI: 10.1186/1745-6150-8-12. View

Li B, Cao Y, Sun M, Feng H . Expression, regulation, and function of exosome-derived miRNAs in cancer progression and therapy. FASEB J. 2021; 35(10):e21916. DOI: 10.1096/fj.202100294RR. View

Roberts A, Pimentel H, Trapnell C, Pachter L . Identification of novel transcripts in annotated genomes using RNA-Seq. Bioinformatics. 2011; 27(17):2325-9. DOI: 10.1093/bioinformatics/btr355. View

Kim D, Kim H, Choi Y, Kim S, Lee J, Sung K . Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer. Exp Mol Med. 2019; 51(8):1-13. PMC: 6802663. DOI: 10.1038/s12276-019-0295-2. View

Bolukbasi M, Mizrak A, Ozdener G, Madlener S, Strobel T, Erkan E . miR-1289 and "Zipcode"-like Sequence Enrich mRNAs in Microvesicles. Mol Ther Nucleic Acids. 2013; 1:e10. PMC: 3381601. DOI: 10.1038/mtna.2011.2. View

Zhou W, Wang H, Zhang J, Dai H, Yao Z, Zheng Z . NEAT1/miR-200b-3p/SMAD2 axis promotes progression of melanoma. Aging (Albany NY). 2020; 12(22):22759-22775. PMC: 7746346. DOI: 10.18632/aging.103909. View

Obuchowski N . ROC analysis. AJR Am J Roentgenol. 2005; 184(2):364-72. DOI: 10.2214/ajr.184.2.01840364. View

Castellana D, Zobairi F, Martinez M, Panaro M, Mitolo V, Freyssinet J . Membrane microvesicles as actors in the establishment of a favorable prostatic tumoral niche: a role for activated fibroblasts and CX3CL1-CX3CR1 axis. Cancer Res. 2009; 69(3):785-93. DOI: 10.1158/0008-5472.CAN-08-1946. View

10.

Liu J, Cao L, Meng J, Li Y, Deng P, Pan P . The fibrotic microenvironment promotes the metastatic seeding of tumor cells into the lungs via mediating the ZEB1-AS1/miR-200b-3p/ZEB1 signaling. Cell Cycle. 2020; 19(20):2701-2719. PMC: 7644172. DOI: 10.1080/15384101.2020.1826236. View

11.

Munagala R, Aqil F, Jeyabalan J, Gupta R . Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2015; 371(1):48-61. PMC: 4706492. DOI: 10.1016/j.canlet.2015.10.020. View

12.

Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P . Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology. 2005; 128(7):1796-804. DOI: 10.1053/j.gastro.2005.03.045. View

13.

Aqil F, Munagala R, Jeyabalan J, Agrawal A, Gupta R . Exosomes for the Enhanced Tissue Bioavailability and Efficacy of Curcumin. AAPS J. 2017; 19(6):1691-1702. DOI: 10.1208/s12248-017-0154-9. View

14.

Bebelman M, Smit M, Pegtel D, Baglio S . Biogenesis and function of extracellular vesicles in cancer. Pharmacol Ther. 2018; 188:1-11. DOI: 10.1016/j.pharmthera.2018.02.013. View

15.

Liu M, Mo F, Song X, He Y, Yuan Y, Yan J . Exosomal hsa-miR-21-5p is a biomarker for breast cancer diagnosis. PeerJ. 2021; 9:e12147. PMC: 8451442. DOI: 10.7717/peerj.12147. View

16.

Nabhan J, Hu R, Oh R, Cohen S, Lu Q . Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proc Natl Acad Sci U S A. 2012; 109(11):4146-51. PMC: 3306724. DOI: 10.1073/pnas.1200448109. View

17.

Matsumura T, Sugimachi K, Iinuma H, Takahashi Y, Kurashige J, Sawada G . Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer. 2015; 113(2):275-81. PMC: 4506387. DOI: 10.1038/bjc.2015.201. View

18.

Hu X, Li J, Fu M, Zhao X, Wang W . The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021; 6(1):402. PMC: 8617206. DOI: 10.1038/s41392-021-00791-1. View

19.

Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P . Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med. 2002; 195(10):1303-16. PMC: 2193755. DOI: 10.1084/jem.20011624. View

20.

Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A . Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009; 284(49):34211-22. PMC: 2797191. DOI: 10.1074/jbc.M109.041152. View