1. Institute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia 2. Institute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia; Meshalkin National Medical Research Center, Ministry of Health of the Russian Federation, Novosibirsk, Russia 3. Institute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia; Novosibirsk State University, Novosibirsk, Russia 4. Novosibirsk Regional Oncological Dispensary, Novosibirsk, Russia
Smoking is a risk factor for non-small cell lung cancer (NSCLC). The most common subtypes of NSCLC are lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). The cigarette smoke contains aryl hydrocarbon receptor (AhR) ligands, such as benzo(a)pyrene (BaP). By activating the AhR, BaP can change the expression of many genes, including miRNA-encoding genes. In this study, we have evaluated the expression of few miRNAs potentially regulated by AhR (miR-21, -342, -93, -181a, -146a), as well as CYP1A1, a known AhR target gene, in lung tumor samples from smoking (n=40) and non-smoking (n=30) patients with LAC and from smoking patients with SCC (n=40). We have also collected macroscopically normal lung tissue >5 cm from the tumor margin. We compared the obtained data on the miRNA expression in tumors with data from The Cancer Genome Atlas (TCGA). We found that in 76.7% of non-smoking LAC patients, CYP1A1 mRNA was not detected in tumor and normal lung tissues, while in smoking patients, CYP1A1 expression was detected in tumors in almost half of the cases (47.5% for SCC and 42.5% for LAC). The expression profile of AhR-regulated miRNAs differed between LAC and SCC and depended on the smoking status. In LAC patients, the expression of oncogenic miRNA-21 and miRNA-93 in tumors was higher than in normal lung tissue from the same patients. However, in SCC patients from our sample, the levels of these miRNAs in tumor and non-transformed lung tissue did not differ significantly. The results of our studies and TCGA data indicate that the expression levels of miRNA-181a and miRNA-146a in LAC are associated with smoking: expression of these miRNAs was significantly lower in tumors of smokers. It is possible that their expression is regulated by AhR and AhRR (AhR repressor), and inhibition of AhR by AhRR leads to a decrease in miRNA expression in tumors of smoking patients. Overall, these results confirm that smoking has an effect on the miRNA expression profile. This should be taken into account when searching for new diagnostic and therapeutic targets for NSCLC.
Kalinina T.S., Kononchuk V.V., Valembakhov I.S., Pustylnyak V.O., Kozlov V.V., Gulyaeva L.F. (2024) Expression of AhR-regulated miRNAs in non-small cell lung cancer in smokers and never smokers. Biomeditsinskaya Khimiya, 70(1), 52-60.
Kalinina T.S. et al. Expression of AhR-regulated miRNAs in non-small cell lung cancer in smokers and never smokers // Biomeditsinskaya Khimiya. - 2024. - V. 70. -N 1. - P. 52-60.
Kalinina T.S. et al., "Expression of AhR-regulated miRNAs in non-small cell lung cancer in smokers and never smokers." Biomeditsinskaya Khimiya 70.1 (2024): 52-60.
Kalinina, T. S., Kononchuk, V. V., Valembakhov, I. S., Pustylnyak, V. O., Kozlov, V. V., Gulyaeva, L. F. (2024). Expression of AhR-regulated miRNAs in non-small cell lung cancer in smokers and never smokers. Biomeditsinskaya Khimiya, 70(1), 52-60.
References
Pohjanvirta R. (ed.) (2012) The AH Receptor in Biology and Toxicology. John Wiley & Sons Ltd, New Jersey, 533 p. CrossRef Scholar google search
Poland A., Glover E., Kende A.S. (1976) Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem., 251(16), 4936-4946. CrossRef Scholar google search
Safe S., Jin U.H., Park H., Chapkin R.S., Jayaraman A. (2020) Aryl hydrocarbon receptor (AHR) ligands as selective AHR modulators (SAhRMs). Int. J. Mol. Sci., 21(18), 6654. CrossRef Scholar google search
Safe S., Han H., Goldsby J., Mohankumar K., Chapkin R.S. (2018) Aryl hydrocarbon receptor (AhR) ligands as selective AhR modulators: Genomic studies. Curr. Opin. Toxicol., 11-12, 10-20. CrossRef Scholar google search
Murray I.A., Patterson A.D., Perdew G.H. (2014) Aryl hydrocarbon receptor ligands in cancer: Friend and foe. Nat. Rev. Cancer, 14(12), 801-814. CrossRef Scholar google search
Kolluri S.K., Jin U.H., Safe S. (2017) Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch. Toxicol., 91(7), 2497-2513. CrossRef Scholar google search
Tsay J.J., Tchou-Wong K.M., Greenberg A.K., Pass H., Rom W.N. (2013) Aryl hydrocarbon receptor and lung cancer. Anticancer Res., 33(4), 1247-1256. Scholar google search
Li Y., Hecht S.S. (2022) Carcinogenic components of tobacco and tobacco smoke: A 2022 update. Food Chem. Toxicol., 165, 113179. CrossRef Scholar google search
Kaiserman M.J., Rickert W.S. (1992) Carcinogens in tobacco smoke: Benzo[a]pyrene from Canadian cigarettes and cigarette tobacco. Am. J. Public Health, 82(7), 1023-1026. CrossRef Scholar google search
Yang S.Y., Ahmed S., Satheesh S.V., Matthews J. (2018) Genome-wide mapping and analysis of aryl hydrocarbon receptor (AHR)- and aryl hydrocarbon receptor repressor (AHRR)-binding sites in human breast cancer cells. Arch. Toxicol., 92(1), 225-240. CrossRef Scholar google search
O'Brien J., Hayder H., Zayed Y., Peng C. (2018) Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol., 9, 402. CrossRef Scholar google search
Ovchinnikov V.Y., Antonets D.V., Gulyaeva L.F. (2018) The search of CAR, AhR, ESRs binding sites in promoters of intronic and intergenic microRNAs. J. Bioinform. Comput. Biol., 16(1), 1750029. CrossRef Scholar google search
Han R., Guan Y., Tang M., Li M., Zhang B., Fei G., Zhou S., Wang R. (2023) High expression of PSRC1 predicts poor prognosis in lung adenocarcinoma. J. Cancer, 14(17), 3321-3334. CrossRef Scholar google search
Shi L., Middleton J., Jeon Y.J., Magee P., Veneziano D., Laganà A., Leong H.S., Sahoo S., Fassan M., Booton R., Shah R., Crosbie P.A.J., Garofalo M. (2018) KRAS induces lung tumorigenesis through microRNAs modulation. Cell Death Disease, 9(2), 219. CrossRef Scholar google search
Sluzhev M.I., Zaraisky M.I., Semiglazov V.V., Semiglazova T.Yu., Tkachenko E.V., Kondratev S.V., Brish N.A., Alekseeva Yu.V., Petrik I.V., Sidorova A.N. (2022) Comparative analysis of tumor control gene and microRNA expression profiles in tumor and adjacent tissues in patients with colorectal cancer. Siberian Journal of Oncology, 21(2), 55-64. CrossRef Scholar google search
Kalinina T.S., Kononchuk V.V., Yakovleva A.K., Alekseenok E.Y., Sidorov S.V., Gulyaeva L.F. (2020) Association between lymph node status and expression levels of androgen receptor, miR-185, miR-205, and miR-21 in breast cancer subtypes. Int. J. Breast Cancer, 2020, 3259393. CrossRef Scholar google search
Chen C., Ridzon D.A., Broomer A.J., Zhou Z., Lee D.H., Nguyen J.T., Barbisin M., Xu N.L., Mahuvakar V.R., Andersen M.R., Lao K.Q., Livak K.J., Guegler K.J. (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res., 33(20), e179. CrossRef Scholar google search
Rouillard A.D., Gundersen G.W., Fernandez N.F., Wang Z., Monteiro C.D., McDermott M.G., Ma'ayan A. (2016) The Harmonizome: A collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford), 2016, baw100. CrossRef Scholar google search
Chandrashekar D.S., Karthikeyan S.K., Korla P.K., Patel H., Shovon A.R., Athar M., Netto G.J., Qin Z.S., Kumar S., Manne U., Creighton C.J., Varambally S. (2022) UALCAN: An update to the integrated cancer data analysis platform. Neoplasia, 25, 18-27. CrossRef Scholar google search
van Rooij J.G., Veeger M.M., Bodelier-Bade M.M., Scheepers P.T., Jongeneelen F.J. (1994) Smoking and dietary intake of polycyclic aromatic hydrocarbons as sources of interindividual variability in the baseline excretion of 1-hydroxypyrene in urine. Int. Arch. Occup. Environ., 66(1), 55-65. CrossRef Scholar google search
Vu A.T., Taylor K.M., Holman M.R., Ding Y.S., Hearn B., Watson C.H. (2015) Polycyclic aromatic hydrocarbons in the mainstream smoke of popular U.S. cigarettes. Chem. Res. Toxicol., 28(8), 1616-1626. CrossRef Scholar google search
Stading R., Gastelum G., Chu C., Jiang W., Moorthy B. (2021) Molecular mechanisms of pulmonary carcinogenesis by polycyclic aromatic hydrocarbons (PAHs): Implications for human lung cancer. Semin. Cancer Biol., 76, 3-16. CrossRef Scholar google search
Das D.N., Ravi N. (2022) Influences of polycyclic aromatic hydrocarbon on the epigenome toxicity and its applicability in human health risk assessment. Environ. Res., 213, 113677. CrossRef Scholar google search
Chen Z., Ying J., Shang W., Ding D., Guo M., Wang H. (2021) miR-342-3p regulates the proliferation and apoptosis of NSCLC cells by targeting BCL-2. Technol. Cancer Res. Treat., 20, 15330338211041193. CrossRef Scholar google search
Simiene J., Dabkeviciene D., Stanciute D., Prokarenkaite R., Jablonskiene V., Askinis R., Normantaite K., Cicenas S., Suziedelis K. (2023) Potential of miR-181a-5p and miR-630 as clinical biomarkers in NSCLC. BMC Cancer, 23(1), 857. CrossRef Scholar google search
Bica-Pop C., Cojocneanu-Petric R., Magdo L., Raduly L., Gulei D., Berindan-Neagoe I. (2018) Overview upon miR-21 in lung cancer: Focus on NSCLC. Cell. Mol. Life Sci., 75(19), 3539-3551. CrossRef Scholar google search
Yang W., Bai J., Liu D., Wang S., Zhao N., Che R., Zhang H. (2018) MiR-93-5p up-regulation is involved in non-small cell lung cancer cells proliferation and migration and poor prognosis. Gene, 647, 13-20. CrossRef Scholar google search
Grieshober L., Graw S., Barnett M.J., Thornquist M.D., Goodman G.E., Chen C., Koestler D.C., Marsit C.J., Doherty J.A. (2020) AHRR methylation in heavy smokers: Associations with smoking, lung cancer risk, and lung cancer mortality. BMC Cancer, 20(1), 905. CrossRef Scholar google search
