Let-7g and miR-21 expression in non-small cell lung cancer: Correlation with clinicopathological and molecular features

Capodanno,Alessandra; Boldrini,Laura; Proietti,Agnese; Alì,Greta; Pelliccioni,Serena; Niccoli,Cristina; D'Incecco,Armida; Cappuzzo,Federico; Chella,Antonio; Lucchi,Marco; Mussi,Alfredo; Fontanini,Gabriella

doi:10.3892/ijo.2013.2003

Let-7g and miR-21 expression in non-small cell lung cancer: Correlation with clinicopathological and molecular features

Authors:
- Alessandra Capodanno
- Laura Boldrini
- Agnese Proietti
- Greta Alì
- Serena Pelliccioni
- Cristina Niccoli
- Armida D'Incecco
- Federico Cappuzzo
- Antonio Chella
- Marco Lucchi
- Alfredo Mussi
- Gabriella Fontanini
View Affiliations

Affiliations: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, I-56126 Pisa, Italy, Unit of Pathological Anatomy III, A.O.U.P., I-56126 Pisa, Italy, Unit of Medical Oncology, Civil Hospital, I-57125 Livorno, Italy, Division of Pneumology II, A.O.U.P., I-56126 Pisa, Italy, Unit of Thoracic Surgery, A.O.U.P., I-56126 Pisa, Italy
Published online on: July 2, 2013 https://doi.org/10.3892/ijo.2013.2003
Pages: 765-774

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

MicroRNAs (miRNAs) play a key role in cancer pathogenesis and are involved in several human cancers, including non-small cell lung cancer (NSCLC). This study evaluated Let-7g and miR-21 expression by quantitative real-time PCR in 80 NSCLC patients and correlated the results with their main clinicopathological and molecular features. MiR-21 expression was significantly higher in NSCLC tissues compared to non-cancer lung tissues (p<0.0001), while no significant changes in Let-7g expression were observed between the tumor and normal lung tissues. Target prediction analysis led to the identification of 26 miR-21 and 24 Let-7g putative target genes that play important roles in cancer pathogenesis and progression. No significant association was observed between the analysed miRNAs and the main clinicopathological or molecular characteristics of the NSCLC patients, although both miRNAs were downregulated in squamous cell carcinomas compared to adenocarcinomas. Noteworthy, we observed a significant association between low Let-7g expression and metastatic lymph nodes at diagnosis (p=0.046), as well as between high miR-21 expression and K-Ras mutations (p=0.0003). Survival analysis did not show any significant correlation between prognosis and the analysed miRNAs, although the patients with a high Let-7g and miR-21 expression showed a significantly lower short-term progression-free survival (p=0.01 and p=0.0003, respectively) and overall survival (p=0.023 and p=0.0045, respectively). In conclusion, we showed that Let-7g and miR-21 expression was deregulated in NSCLC and we demonstrated a strong relationship between miR-21 overexpression and K-Ras mutations. Our data indicate that Let-7g and miR-21 profiling combined with the determination of K-Ras mutational status may be considered a useful biomarker for a more effective molecular characterization and clinical management of NSCLC patients.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
2	Travis WD, Brambilla E, Muller-Hemerlink HK and Harris CC; World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press; Lyon: 2004
3	Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M and Yankelewitz D: International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6:244–285. 2011. View Article : Google Scholar
4	Travis WD, Brambilla E, Noguchi M, Nicholson A, Geisinger K, Yatabe Y, Ishikawa Y, Wistuba I, Flieder DB, Franklin W, Gazdar A, Hasleton PS, Henderson DW, Kerr KM, Petersen I, Roggli V, Thunnissen E and Tsao M: Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification. Arch Pathol Lab Med. 137:668–684. 2012. View Article : Google Scholar
5	Bronte G, Rizzo S, La Paglia L, Adamo V, Siragusa S, Ficorella C, Santini D, Bazan V, Colucci G, Gebbia N and Russo A: Driver mutations and differential sensitivity to targeted therapies: a new approach to the treatment of lung adenocarcinoma. Cancer Treat Rev. 36:S21–S29. 2010. View Article : Google Scholar : PubMed/NCBI
6	Pao W and Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol. 12:175–180. 2011. View Article : Google Scholar : PubMed/NCBI
7	Saintigny P and Burger JA: Recent advances in non-small cell lung cancer biology and clinical management. Discov Med. 13:287–297. 2012.PubMed/NCBI
8	He L and Hannon GJ: MicroRNAs: small RNAs with big role in gene regulation. Nat Rev Genet. 5:522–531. 2002. View Article : Google Scholar
9	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
10	Schmittgen TD: Regulation of microRNA processing in development, differentiation and cancer. J Cell Mol Med. 12:1811–1819. 2008. View Article : Google Scholar : PubMed/NCBI
11	Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM and Zhang GZ: Biological functions of microRNAs: a review. J Physiol Biochem. 67:129–139. 2011. View Article : Google Scholar : PubMed/NCBI
12	Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M and Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 101:2999–3004. 2004. View Article : Google Scholar
13	Zhang B, Pan X, Cobb GP and Anderson TA: microRNAs as oncogenes and tumor suppressors. Dev Biol. 302:1–12. 2007. View Article : Google Scholar : PubMed/NCBI
14	Bartels CL and Tsongalis GJ: MicroRNAs: novel biomarkers for human cancer. Clin Chem. 55:623–631. 2009. View Article : Google Scholar : PubMed/NCBI
15	Farazi TA, Spitzer JI, Morozov P and Tuschl T: miRNAs in human cancer. J Pathol. 223:102–115. 2011. View Article : Google Scholar
16	Iorio MV and Croce CM: MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 4:143–159. 2012. View Article : Google Scholar : PubMed/NCBI
17	Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T and Takahashi T: Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64:3753–3756. 2004. View Article : Google Scholar : PubMed/NCBI
18	Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D, Wilson M, Wang X, Shelton J, Shingara J, Chin L, Brown D and Slack FJ: The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 67:7713–7722. 2007. View Article : Google Scholar : PubMed/NCBI
19	Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA and Jacks T: Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA. 105:3903–3908. 2008. View Article : Google Scholar : PubMed/NCBI
20	Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D and Slack FJ: RAS is regulated by the let-7 microRNA family. Cell. 120:635–647. 2005. View Article : Google Scholar : PubMed/NCBI
21	Roush S and Slack FJ: The let-7 family of microRNAs. Trends Cell Biol. 18:505–516. 2008. View Article : Google Scholar
22	Krichevsky AM and Gabriely G: miR-21: a small multi-faceted RNA. J Cell Mol Med. 13:39–53. 2009. View Article : Google Scholar : PubMed/NCBI
23	Gao W, Yu Y, Cao H, Shen H, Li X, Pan S and Shu Y: Deregulated expression of miR-21, miR-143 and miR-181a in non small cell lung cancer is related to clinicopathologic characteristics or patient prognosis. Biomed Pharmacother. 64:399–408. 2010. View Article : Google Scholar : PubMed/NCBI
24	Moore LM and Zhang W: Targeting miR-21 in glioma: a small RNA with big potential. Expert Opin Ther Targets. 14:1247–1257. 2010. View Article : Google Scholar : PubMed/NCBI
25	Pan X, Wang ZX and Wang R: MicroRNA-21: a novel therapeutic target in human cancer. Cancer Biol Ther. 10:1224–1232. 2011. View Article : Google Scholar : PubMed/NCBI
26	Seike M, Goto A, Okano T, Bowman ED, Schetter AJ, Horikawa I, Mathe EA, Jen J, Yang P, Sugimura H, Gemma A, Kudoh S, Croce CM and Harris CC: MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci USA. 106:12085–12090. 2009. View Article : Google Scholar : PubMed/NCBI
27	Selcuklu SD, Donoghue MT and Spillane C: miR-21 as a key regulator of oncogenic processes. Biochem Soc Trans. 37:918–925. 2009. View Article : Google Scholar : PubMed/NCBI
28	Capodanno A, Boldrini L, Alì G, Pelliccioni S, Mussi A and Fontanini G: Phosphatidylinositol-3-kinase α catalytic subunit gene somatic mutations in bronchopulmonary neuroendocrine tumours. Oncol Rep. 28:1559–1566. 2012.
29	Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC and Croce CM: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI
30	Landi MT, Zhao Y, Rotunno M, Koshiol J, Liu H, Bergen AW, Rubagotti M, Goldstein AM, Linnoila I, Marincola FM, Tucker MA, Bertazzi PA, Pesatori AC, Caporaso NE, McShane LM and Wang E: MicroRNA expression differentiates histology and predicts survival of lung cancer. Clin Cancer Res. 16:430–441. 2010. View Article : Google Scholar : PubMed/NCBI
31	Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 133:647–658. 2007. View Article : Google Scholar : PubMed/NCBI
32	Mitsudomi T, Oyama T, Nishida K, Ogami A, Osaki T, Sugio K, Yasumoto K, Sugimachi K and Gazdar AF: Loss of heterozygosity at 3p in non-small cell lung cancer and its prognostic implication. Clin Cancer Res. 2:1185–1189. 1996.PubMed/NCBI
33	Zabarovsky ER, Lerman MI and Minna JD: Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene. 21:6915–6935. 2002. View Article : Google Scholar : PubMed/NCBI
34	Riely GJ, Marks J and Pao W: KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 6:201–205. 2009. View Article : Google Scholar : PubMed/NCBI
35	Mao C, Qiu LX, Liao RY, Du FB, Ding H, Yang WC, Li J and Chen Q: KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer. 69:272–278. 2010. View Article : Google Scholar : PubMed/NCBI
36	Yatabe Y and Mitsudomi T: Epidermal growth factor receptor mutations in lung cancers. Pathol Int. 57:233–244. 2007. View Article : Google Scholar : PubMed/NCBI
37	Ladanyi M and Pao W: Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol. 21:S16–S22. 2008. View Article : Google Scholar : PubMed/NCBI
38	Dacic S: Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 135:622–629. 2011.PubMed/NCBI
39	Dacic S, Kelly L, Shuai Y and Nikiforova MN: miRNA expression profiling of lung adenocarcinomas: correlation with mutational status. Mod Pathol. 23:1577–1582. 2010. View Article : Google Scholar : PubMed/NCBI
40	Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller RU, Straka E, Su L, Burki EA, Crowell RE, Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DC, Belinsky SA, Slack FJ and Weidhaas JB: A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk. Cancer Res. 68:8535–8540. 2008.PubMed/NCBI
41	Boutros T, Chevet E and Metrakos P: Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death and cancer. Pharmacol Rev. 60:261–310. 2008. View Article : Google Scholar : PubMed/NCBI
42	Hatley ME, Patrick DM, Garcia MR, Richardson JA, Bassel-Duby R, van Rooij E and Olson EN: Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell. 18:282–293. 2010. View Article : Google Scholar : PubMed/NCBI
43	Lu Z, Liu M, Stribinskis V, Klinge CM, Ramos KS, Colburn NH and Li Y: MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene. 27:4373–4379. 2008. View Article : Google Scholar : PubMed/NCBI
44	Hwang SK, Jin H, Kwon JT, Chang SH, Kim TH, Cho CS, Lee KH, Young MR, Colburn NH, Beck GR Jr, Yang HS and Cho MH: Aerosol-delivered programmed cell death 4 enhanced apoptosis, controlled cell cycle and suppressed AP-1 activity in the lungs of AP-1 luciferase reporter mice. Gene Ther. 14:1353–1361. 2007.PubMed/NCBI
45	Talotta F, Cimmino A, Matarazzo MR, Casalino L, De Vita G, D'Esposito M, Di Lauro R and Verde P: An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation. Oncogene. 28:73–84. 2009. View Article : Google Scholar : PubMed/NCBI
46	Markou A, Tsaroucha EG, Kaklamanis L, Fotinou M, Georgoulias V and Lianidou ES: Prognostic value of mature microRNA-21 and microRNA-205 overexpression in non-small cell lung cancer by quantitative real-time RT-PCR. Clin Chem. 54:1696–1704. 2008. View Article : Google Scholar : PubMed/NCBI