MiR-486-5p Targets CD133+ Lung Cancer Stem Cells Through the P85/AKT Pathway

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2022 Mar 26

PMID 35337095

Authors

Massimo Moro

Orazio Fortunato

Giulia Bertolini

Mavis Mensah

Cristina Borzi

Giovanni Centonze

Francesca Andriani

Daniela Di Paolo

Patrizia Perri

Mirco Ponzoni

Ugo Pastorino

Gabriella Sozzi

Mattia Boeri

Affiliations

Soon will be listed here.

Abstract

Despite improvements in therapies and screening strategies, lung cancer prognosis still remains dismal, especially for metastatic tumors. Cancer stem cells (CSCs) are endowed with properties such as chemoresistance, dissemination, and stem-like features, that make them one of the main causes of the poor survival rate of lung cancer patients. MicroRNAs (miRNAs), small molecules regulating gene expression, have a role in lung cancer development and progression. In particular, miR-486-5p is an onco-suppressor miRNA found to be down-modulated in the tumor tissue of lung cancer patients. In this study, we investigate the role of this miRNA in CD133+ lung CSCs and evaluate the therapeutic efficacy of coated cationic lipid-nanoparticles entrapping the miR-486-5p miRNA mimic (CCL-486) using lung cancer patient-derived xenograft (PDX) models. In vitro, miR-486-5p overexpression impaired the PI3K/Akt pathway and decreased lung cancer cell viability. Moreover, miR-486-5p overexpression induced apoptosis also in CD133+ CSCs, thus affecting the in vivo tumor-initiating properties of these cells. Finally, we demonstrated that in vivo CCL-486 treatment decreased CD133+ percentage and inhibited tumor growth in PDX models. In conclusion, we provided insights on the efficacy of a novel miRNA-based compound to hit CD133+ lung CSCs, setting the basis for new combined therapeutic strategies.

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References

Yang Y, Ji C, Guo S, Su X, Zhao X, Zhang S . The miR-486-5p plays a causative role in prostate cancer through negative regulation of multiple tumor suppressor pathways. Oncotarget. 2017; 8(42):72835-72846. PMC: 5641172. DOI: 10.18632/oncotarget.20427. View

Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L . Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci U S A. 2009; 106(38):16281-6. PMC: 2741477. DOI: 10.1073/pnas.0905653106. View

Fortunato O, Boeri M, Moro M, Verri C, Mensah M, Conte D . Mir-660 is downregulated in lung cancer patients and its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction. Cell Death Dis. 2014; 5:e1564. PMC: 4454158. DOI: 10.1038/cddis.2014.507. View

Youness R, El-Tayebi H, Assal R, Hosny K, Esmat G, Abdelaziz A . MicroRNA-486-5p enhances hepatocellular carcinoma tumor suppression through repression of IGF-1R and its downstream mTOR, STAT3 and c-Myc. Oncol Lett. 2016; 12(4):2567-2573. PMC: 5038225. DOI: 10.3892/ol.2016.4914. View

Li H, Mou Q, Li P, Yang Z, Wang Z, Niu J . MiR-486-5p inhibits IL-22-induced epithelial-mesenchymal transition of breast cancer cell by repressing Dock1. J Cancer. 2019; 10(19):4695-4706. PMC: 6746125. DOI: 10.7150/jca.30596. View

Pastorino U, Sverzellati N, Sestini S, Silva M, Sabia F, Boeri M . Ten-year results of the Multicentric Italian Lung Detection trial demonstrate the safety and efficacy of biennial lung cancer screening. Eur J Cancer. 2019; 118:142-148. PMC: 6755135. DOI: 10.1016/j.ejca.2019.06.009. View

Conte D, Verri C, Borzi C, Suatoni P, Pastorino U, Sozzi G . Novel method to detect microRNAs using chip-based QuantStudio 3D digital PCR. BMC Genomics. 2015; 16:849. PMC: 4619272. DOI: 10.1186/s12864-015-2097-9. View

Prabavathy D, Ramadoss N . Heterogeneity of Small Cell Lung Cancer Stem Cells. Adv Exp Med Biol. 2019; 1139:41-57. DOI: 10.1007/978-3-030-14366-4_3. View

Yan X, Liu X, Wang Z, Cheng Q, Ji G, Yang H . MicroRNA‑486‑5p functions as a tumor suppressor of proliferation and cancer stem‑like cell properties by targeting Sirt1 in liver cancer. Oncol Rep. 2018; 41(3):1938-1948. DOI: 10.3892/or.2018.6930. View

10.

Pastorino U, Bellomi M, Landoni C, De Fiori E, Arnaldi P, Picchio M . Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet. 2003; 362(9384):593-7. DOI: 10.1016/S0140-6736(03)14188-8. View

11.

Peng Y, Dai Y, Hitchcock C, Yang X, Kassis E, Liu L . Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer. Proc Natl Acad Sci U S A. 2013; 110(37):15043-8. PMC: 3773758. DOI: 10.1073/pnas.1307107110. View

12.

Borzi C, Ganzinelli M, Caiola E, Colombo M, Centonze G, Boeri M . LKB1 Down-Modulation by miR-17 Identifies Patients With NSCLC Having Worse Prognosis Eligible for Energy-Stress-Based Treatments. J Thorac Oncol. 2021; 16(8):1298-1311. DOI: 10.1016/j.jtho.2021.04.005. View

13.

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

14.

Xing Y, Lin N, Maurer M, Chen H, Mahvash A, Sahin A . Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation. Breast Cancer Res. 2019; 21(1):78. PMC: 6612080. DOI: 10.1186/s13058-019-1154-8. View

15.

Rupaimoole R, Slack F . MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017; 16(3):203-222. DOI: 10.1038/nrd.2016.246. View

16.

Wang J, Tian X, Han R, Zhang X, Wang X, Shen H . Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer. Oncogene. 2013; 33(9):1181-9. PMC: 3883922. DOI: 10.1038/onc.2013.42. View

17.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

18.

Batlle E, Clevers H . Cancer stem cells revisited. Nat Med. 2017; 23(10):1124-1134. DOI: 10.1038/nm.4409. View

19.

Di Paolo D, Pontis F, Moro M, Centonze G, Bertolini G, Milione M . Cotargeting of miR-126-3p and miR-221-3p inhibits PIK3R2 and PTEN, reducing lung cancer growth and metastasis by blocking AKT and CXCR4 signalling. Mol Oncol. 2021; 15(11):2969-2988. PMC: 8564655. DOI: 10.1002/1878-0261.13036. View

20.

Iorio M, Croce C . MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 2012; 4(3):143-59. PMC: 3376845. DOI: 10.1002/emmm.201100209. View