Diagnostic Potential of miR-551b-3p in Lung Cancer: In Vitro and In Silico Experiments

Öz

Lung cancer is a leading cause of cancer deaths worldwide. miRNAs have attracted attention as promising biomarkers in lung cancer diagnosis and prognosis. This study investigated the molecular mechanism of miR-551b-3p in lung cancer cells. The gene expression level of miR-551b-3p was investigated using qRT-PCR in healthy and cancerous lung cell lines. The target genes of miR-551b-3p and its function in cancer pathogenesis were also determined by in silico analyses. miR-551b-3p expression was higher in cancer cells compared to healthy lung cells (p<0.01). The expression level of miR-551b-3p was confirmed in silico in cancerous lung tissue. ERBB4 was identified as a target gene of miR-551b-3p and was down-regulated in cancer cells in comparison to healthy cells. Overexpression of miR-551b-3p and under expression of the ERBB4 gene decreased overall survival in cancer patients. A negative correlation was observed between miR-551b-3p and ERBB4 gene. miR-551b-3p expression was found to be closely associated with clinicopathological factors such as distant metastasis status, lymph node metastasis status and gender. miR-551b-3p target genes were enriched in cancer-related cellular processes. In conclusion, miR-551b-3p may be a potential alternative in treatment strategies as a therapeutic target in lung cancers.

Anahtar Kelimeler

• ERBB4
• Lung cancer
• miR-551b-3p
• qRT-PCR

Kaynakça

1. [1]. Leiter, A., Veluswamy, R.R., Wisnivesky, J. 2023. The global burden of lung cancer: current status and future trends. Nature Reviews Clinical Oncology; 20(9):624-639.
2. [2]. Çakmak, E. 2022. A bioinformatics approach to identify potential biomarkers in non-small cell lung cancer. Cumhuriyet Science Journal; 43(1):6-13.
3. [3]. Yang, Q., Wang, W., Cheng, D., Wang, Y., Han, Y., Huang, J. 2024. Non-coding RNA in exosomes: Regulating bone metastasis of lung cancer and its clinical application prospect. Translational Oncology; 46:102002.
4. [4]. Lahiri, A., Maji, A., Potdar, P.D., Singh, N., Parikh, P. 2023. Lung cancer immunotherapy: progress, pitfalls, and promises. Molecular Cancer; 22(1):40.
5. [5]. Chakrabortty, A., Patton, D., Smith, B.F. 2023. miRNAs: potential as biomarkers and therapeutic targets for cancer. Genes; 14(7):1375.
6. [6]. Çakmak, E. 2020. Computational and experimental tools of miRNAs in cancer. Middle East Journal of Cancer; 11(4):381-389.
7. [7]. Zhang, Q., Pan, J., Xiong, D., Zheng, J., McPherson, K.N., Lee, S., You, M. 2023. Aerosolized miR-138-5p and miR-200c targets PD-L1 for lung cancer prevention. Frontiers in Immunology; 14:1166951.
8. [8]. Cui, Y., Wu, X., Jin, J., Man, W. et al. 2023. CircHERC1 promotes non-small cell lung cancer cell progression by sequestering FOXO1 in the cytoplasm and regulating the miR-142-3p-HMGB1 axis. Molecular Cancer; 22(1):179.

9. [9]. Yang, F., Yan, Y., Yang, Y., Hong, X., Wang, M., Yang, Z. et al. 2020. MiR-210 in exosomes derived from CAFs promotes non-small cell lung cancer migration and invasion through PTEN/PI3K/AKT pathway. Cell signal; 73:109675.
10. [10]. Parashar, D., Geethadevi, A., Aure, M.R., Mishra, J., George, J. et al. 2019. miRNA551b-3p activates an oncostatin signaling module for the progression of triple-negative breast cancer. Cell reports; 29(13), 4389-4406.
11. [11]. Wang, X., Cheng, Z., Dai, L., Jiang, T., Li, P., Jia, L. et al. 2021. LncRNA PVT1 facilitates proliferation, migration and invasion of NSCLC cells via miR-551b/FGFR1 axis. OncoTargets and therapy; 3555-3565.
12. [12]. Yuan, H., Chen, Z., Bai, S., Wei, H., Wang, Y. et al. 2018. Molecular mechanisms of lncRNA SMARCC2/miR-551b-3p/TMPRSS4 axis in gastric cancer. Cancer Letters; 418, 84-96.
13. [13]. Karanam, N.K., Ding, L., Vo, D.T., Giri, U., Yordy, J.S. et al.2023. miR-551a and miR-551b-3p target GLIPR2 and promote tumor growth in high-risk head and neck cancer by modulating autophagy. Advances in Cancer Biology-Metastasis; 7:100085.
14. [14]. Thomas, P.D., Ebert, D., Muruganujan, A., Mushayahama, T. et al. 2022. PANTHER: Making genome‐scale phylogenetics accessible to all. Protein Science; 31(1):8-22.
15. [15]. An, J., Zhang, M., Fu, Y., Zhang, D. et al. 2024. Emerging electrochemical biosensors for lung cancer-associated protein biomarker and miRNA detection. International Journal of Biological Macromolecules; 280(3):135972.
16. [16]. Singh, S., Saxena, S., Sharma, H., Paudel, K.R., Chakraborty, A. et al. 2024. Emerging role of tumor suppressing microRNAs as therapeutics in managing Non-small cell lung cancer. Pathology - Research and Practice; 155222.
17. [17]. Dong, Z.R., Cai, J.B., Shi, G.M., Yang, Y.F. et al. 2023. Oncogenic miR-93-5p/Gal-9 axis drives CD8 (+) T-cell inactivation and is a therapeutic target for hepatocellular carcinoma immunotherapy. Cancer Letter; 564:216186.
18. [18]. Hsu, C.Y., Allela, O.Q.B., Mahdi, S.A.H., Doshi, O.P., Adil, M. et al. 2023. miR-136-5p: A key player in human cancers with diagnostic, prognostic and therapeutic implications. Pathology - Research and Practice; 54794.
19. [19]. Liu, S., Ruan, Y., Chen, X., He, B., Chen, Q. 2024. miR-137: a potential therapeutic target for lung cancer. Frontiers in Cell and Developmental Biology; 12:1427724.
20. [20]. Kim, K.S., Jeong, D., Sari, I.N., Wijaya, Y.T. et al. 2019. miR551b regulates colorectal cancer progression by targeting the ZEB1 signaling axis. Cancers; 11(5):735.
21. [21]. Bai, S.Y., Ji, R., Wei, H., Guo, Q.H., Yuan H. et al. 2019. Serum miR-551b-3p is a potential diagnostic biomarker for gastric cancer. Turkish Journal of Gastroenterology; 30(5):415.
22. [22]. Yang, Z., Xu, B., Wu, S., Yang, W., Luo, R., Geng, S. et al. 2022. Exosomal microRNA-551b-3p from bone marrow-derived mesenchymal stromal cells inhibits breast cancer progression via regulating TRIM31/Akt signaling. Human Cell; 235(6):1797-1812.
23. [23]. Chang, W., Wang, Y., Li, W., Shi, L., Geng, Z. 2019. Micro RNA‐551b‐3p inhibits tumor growth of human cholangiocarcinoma by targeting Cyclin D1. Journal of Cellular and Molecular Medicine; 23(8):4945-4954.
24. [24]. Chaluvally-Raghavan, P., Jeong, K.J., Pradeep, S., Silva, A.M., et al. 2016. Direct upregulation of STAT3 by MicroRNA-551b-3p deregulates growth and metastasis of ovarian cancer. Cell Reports; 15(7):1493-1504.
25. [25]. Çaglar, H.O., Aytatli, A., Karatas, O.F. 2024. In silico identification of differentially expressed microRNAs in thyroid cancer. Human Gene; 201306.
26. [26]. Yu, H., Pang, Z., Li, G., Gu, T. 2021. Bioinformatics analysis of differentially expressed miRNAs in non‐small cell lung cancer. Journal of Clinical Laboratory Analysis; 35(2):e23588.
27. [27]. Lin, K., Xu, T., He, B.S., Pan, Y.Q., Sun, H.L., Peng, H.X. et al. 2016. MicroRNA expression profiles predict progression and clinical outcome in lung adenocarcinoma. OncoTargets and therapy; 5679-5692.
28. [28]. Charkiewicz, R., Sulewska, A., Mroz, R., Charkiewicz, A., Naumnik, W. et al. 2023. Serum Insights: Leveraging the Power of miRNA Profiling as an Early Diagnostic Tool for Non-Small Cell Lung Cancer. Cancers; 15(20), 4910.
29. [29]. Pandey, M., Mukhopadhyay, A., Sharawat, S. K., & Kumar, S.2021. Role of microRNAs in regulating cell proliferation, metastasis and chemoresistance and their applications as cancer biomarkers in small cell lung cancer. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer; 1876(1), 188552.
30. [30]. Schegoleva, A. A., Khozyainova, A. A., Fedorov, A. A., Gerashchenko, T. S., Rodionov, E. O., Topolnitsky, E. B., ... & Denisov, E. V. 2021. Prognosis of different types of non-small cell lung cancer progression: current state and perspectives. Cell Physiol Biochem; 55(S2), 29-48.
31. [31]. Han, L., Huang, Z., Liu, Y., Ye, L., Li, D., Yao, Z., ... & Yang, Z. 2021. MicroRNA-106a regulates autophagy-related cell death and EMT by targeting TP53INP1 in lung cancer with bone metastasis. Cell death & disease; 12(11), 1037.
32. [32]. Pourdavoud, P., Pakzad, B., Mosallaei, M., Saadatian, Z., Esmaeilzadeh, E. et al. 2020. MiR-196: emerging of a new potential therapeutic target and biomarker in colorectal cancer. Molecular Biology Reports; 47:9913-9920.
33. [33]. Ji, T., Gao, L., Yu, Z. 2021. Tumor-suppressive microRNA-551b-3p targets H6PD to inhibit gallbladder cancer progression. Cancer Gene Therapy; 28(6), 693-705.
34. [34]. Song, G., Zhang, H., Chen, C., Gong, L., Chen, B., Zhao, S. et al. 2017. miR-551b regulates epithelial-mesenchymal transition and metastasis of gastric cancer by inhibiting ERBB4 expression. Oncotarget; 8(28):45725.
35. [35]. Liu, Y., Song, L., Ni, H., Sun, L., Jiao, W., Chen, L. 2017. ERBB4 acts as a suppressor in the development of hepatocellular carcinoma. Carcinogenesis; 38(4):465-473.