Abstract
Our original microRNA (miRNA) expression signatures (based on RNA sequencing) revealed that both strands of the miR-145 duplex (miR-145-5p, the guide strand, and miR-145-3p, the passenger strand) were downregulated in several types of cancer tissues. Involvement of passenger strands of miRNAs in cancer pathogenesis is a new concept in miRNA biogenesis. In our continuing analysis of lung adenocarcinoma (LUAD) pathogenesis, we aimed here to identify important oncogenes that were controlled by miR-145-5p and miR-145-3p. Downregulation of miR-145-5p and miR-145-3p was confirmed in LUAD clinical specimens. Functional assays showed that miR-145-3p significantly blocked the malignant abilities in LUAD cells, e.g., cancer cell proliferation, migration and invasion. Thus, the data showed that expression of the passenger strand of the miR-145-duplex acted as an anti-tumor miRNA. In LUAD cells, we identified four possible target genes (LMNB2, NLN, SIX4, and DDC) that might be regulated by both strands of miR-145. Among the possible targets, high expression of LMNB2 predicted a significantly poorer prognosis of LUAD patients (disease-free survival, p = 0.0353 and overall survival, p = 0.0017). Overexpression of LMNB2 was detected in LUAD clinical specimens and its aberrant expression promoted malignant transformation of LUAD cells. Genes regulated by anti-tumor miR-145-5p and miR-145-3p are closely involved in the molecular pathogenesis of LUAD. We suggest that they are promising prognostic markers for this disease. Our approach, based on the roles of anti-tumor miRNAs, will contribute to improved understanding of the molecular pathogenesis of LUAD.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Global Burden of Disease Cancer Consortium. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol. 2017;3:524–48.
Travis WD. Pathology of lung cancer. Clin Chest Med. 2011;32:669–92.
Arai T, Kuroishi T, Saito Y, Kurita Y, Naruke T, Kaneko M. Tumor doubling time and prognosis in lung cancer patients: evaluation from chest films and clinical follow-up study. Jpn J Clin Oncol. 1994;24:199–204.
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.
Gulyaeva LF, Kushlinskiy NE. Regulatory mechanisms of microRNA expression. J Transl Med. 2016;14:143.
Peng Y, Croce CM. The role of microRNAs in human cancer. Signal Transduct Target Ther. 2016;1:15004.
Ramassone A, Pagotto S, Veronese A, Visone R. Epigenetics and microRNAs in cancer. Int J Mol Sci. 2018;19:E459.
Koshizuka K, Nohata N, Hanazawa T, Kikkawa N, Arai T, Okato A, et al. Deep sequencing-based microRNA expression signatures in head and neck squamous cell carcinoma: dual strands of pre-miR-150 as antitumor miRNAs. Oncotarget. 2017;8:30288–304.
Mizuno K, Mataki H, Arai T, Okato A, Kamikawaji K, Kumamoto T, et al. The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes. J Hum Genet. 2017;62:671–8.
Arai T, Okato A, Yamada Y, Sugawara S, Kurozumi A, Kojima S, et al. Regulation of NCAPG by miR-99a-3p (passenger strand) inhibits cancer cell aggressiveness and is involved in CRPC. Cancer Med. 2018;7:1988–2002.
Goto Y, Kurozumi A, Arai T, Nohata N, Kojima S, Okato A, et al. Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer. Br J Cancer. 2017;117:409–20.
Koshizuka K, Hanazawa T, Kikkawa N, Arai T, Okato A, Kurozumi A, et al. Regulation of ITGA3 by the anti-tumor miR-199 family inhibits cancer cell migration and invasion in head and neck cancer. Cancer Sci. 2017;108:1681–92.
Okato A, Arai T, Kojima S, Koshizuka K, Osako Y, Idichi T, et al. Dual strands of pre-miR150 (miR1505p and miR1503p) act as antitumor miRNAs targeting SPOCK1 in naive and castration-resistant prostate cancer. Int J Oncol. 2017;51:245–56.
Yamada Y, Koshizuka K, Hanazawa T, Kikkawa N, Okato A, Idichi T, et al. Passenger strand of miR-145-3p acts as a tumor-suppressor by targeting MYO1B in head and neck squamous cell carcinoma. Int J Oncol. 2018;52:166–78.
Yonemori K, Seki N, Idichi T, Kurahara H, Osako Y, Koshizuka K, et al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget. 2017;8:70097–115.
Mataki H, Seki N, Mizuno K, Nohata N, Kamikawaji K, Kumamoto T, et al. Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma. Oncotarget. 2016;7:72084–98.
Matsushita R, Yoshino H, Enokida H, Goto Y, Miyamoto K, Yonemori M, et al. Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p): Inhibition of bladder cancer cell aggressiveness. Oncotarget. 2016;7:28460–87.
Kamikawaji K, Seki N, Watanabe M, Mataki H, Kumamoto T, Takagi K, et al. Regulation of LOXL2 and SERPINH1 by antitumor microRNA-29a in lung cancer with idiopathic pulmonary fibrosis. J Hum Genet. 2016;61:985–93.
Suetsugu T, Koshizuka K, Seki N, Mizuno K, Okato A, Arai T, et al. Downregulation of matrix metalloproteinase 14 by the antitumor miRNA, miR-150-5p, inhibits the aggressiveness of lung squamous cell carcinoma cells. Int J Oncol. 2018;52:913–24.
Mataki H, Enokida H, Chiyomaru T, Mizuno K, Matsushita R, Goto Y, et al. Downregulation of the microRNA-1/133a cluster enhances cancer cell migration and invasion in lung-squamous cell carcinoma via regulation of Coronin1C. J Hum Genet. 2015;60:53–61.
Mizuno K, Seki N, Mataki H, Matsushita R, Kamikawaji K, Kumamoto T, et al. Tumor-suppressive microRNA-29 family inhibits cancer cell migration and invasion directly targeting LOXL2 in lung squamous cell carcinoma. Int J Oncol. 2016;48:450–60.
Osako Y, Seki N, Koshizuka K, Okato A, Idichi T, Arai T, et al. Regulation of SPOCK1 by dual strands of pre-miR-150 inhibit cancer cell migration and invasion in esophageal squamous cell carcinoma. J Hum Genet. 2017;62:935–44.
Kumamoto T, Seki N, Mataki H, Mizuno K, Kamikawaji K, Samukawa T, et al. Regulation of TPD52 by antitumor microRNA-218 suppresses cancer cell migration and invasion in lung squamous cell carcinoma. Int J Oncol. 2016;49:1870–80.
Anaya J. OncoLnc: linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. PeerJ Comput Sci. 2016;2:e67.
Kent OA, McCall MN, Cornish TC, Halushka MK. Lessons from miR-143/145: the importance of cell-type localization of miRNAs. Nucleic Acids Res. 2014;42:7528–38.
Morgado AL, Rodrigues CM, Sola S. MicroRNA-145 regulates neural stem cell differentiation through the Sox2-Lin28/let-7 signaling pathway. Stem Cells. 2016;34:1386–95.
Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell. 2009;137:647–58.
Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, et al. miR-145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 2010;127:2804–14.
Liu SY, Li XY, Chen WQ, Hu H, Luo B, Shi YX, et al. Demethylation of the MIR145 promoter suppresses migration and invasion in breast cancer. Oncotarget. 2017;8:61731–41.
Mei LL, Wang WJ, Qiu YT, Xie XF, Bai J, Shi ZZ. miR-145-5p suppresses tumor cell migration, invasion and epithelial to mesenchymal transition by regulating the Sp1/NF-kappaB signaling pathway in esophageal squamous cell carcinoma. Int J Mol Sci. 2017;18:E1833.
Sachdeva M, Zhu S, Wu F, Wu H, Walia V, Kumar S, et al. p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci USA. 2009;106:3207–12.
Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005;436:740–4.
Hutvagner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002;297:2056–60.
Matranga C, Tomari Y, Shin C, Bartel DP, Zamore PD. Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell. 2005;123:607–20.
Kojima S, Enokida H, Yoshino H, Itesako T, Chiyomaru T, Kinoshita T, et al. The tumor-suppressive microRNA-143/145 cluster inhibits cell migration and invasion by targeting GOLM1 in prostate cancer. J Hum Genet. 2014;59:78–87.
Yoshino H, Enokida H, Itesako T, Kojima S, Kinoshita T, Tatarano S, et al. Tumor-suppressive microRNA-143/145 cluster targets hexokinase-2 in renal cell carcinoma. Cancer Sci. 2013;104:1567–74.
Prokocimer M, Davidovich M, Nissim-Rafinia M, Wiesel-Motiuk N, Bar DZ, Barkan R, et al. Nuclear lamins: key regulators of nuclear structure and activities. J Cell Mol Med. 2009;13:1059–85.
Broers JL, Ramaekers FC. The role of the nuclear lamina in cancer and apoptosis. Adv Exp Med Biol. 2014;773:27–48.
Butin-Israeli V, Adam SA, Goldman AE, Goldman RD. Nuclear lamin functions and disease. Trends Genet. 2012;28:464–71.
Irianto J, Pfeifer CR, Ivanovska IL, Swift J, Discher DE. Nuclear lamins in cancer. Cell Mol Bioeng. 2016;9:258–67.
Kong L, Schafer G, Bu H, Zhang Y, Zhang Y, Klocker H. Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway. Carcinogenesis. 2012;33:751–9.
Sakthivel KM, Sehgal P. A novel role of lamins from genetic disease to cancer biomarkers. Oncol Rev. 2016;10:309.
Deng W, Yan M, Yu T, Ge H, Lin H, Li J, et al. Quantitative proteomic analysis of the metastasis-inhibitory mechanism of miR-193a-3p in non-small cell lung cancer. Cell Physiol Biochem. 2015;35:1677–88.
Ma Y, Fei L, Zhang M, Zhang W, Liu X, Wang C, et al. Lamin B2 binding to minichromosome maintenance complex component 7 promotes non-small cell lung carcinogenesis. Oncotarget. 2017;8:104813–30.
Liu YZ, Wang BS, Jiang YY, Cao J, Hao JJ, Zhang Y, et al. MCMs expression in lung cancer: implication of prognostic significance. J Cancer. 2017;8:3641–7.
Nishihara K, Shomori K, Fujioka S, Tokuyasu N, Inaba A, Osaki M, et al. Minichromosome maintenance protein 7 in colorectal cancer: implication of prognostic significance. Int J Oncol. 2008;33:245–51.
Simon NE, Schwacha A. The Mcm2-7 replicative helicase: a promising chemotherapeutic target. Biomed Res Int. 2014;2014:549719.
Acknowledgements
The present study was supported by KAKENHI grants 17K09660 and 18K09338.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Misono, S., Seki, N., Mizuno, K. et al. Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis. J Hum Genet 63, 1015–1028 (2018). https://doi.org/10.1038/s10038-018-0497-9
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s10038-018-0497-9
This article is cited by
-
Expression and gene regulatory network of SNHG1 in hepatocellular carcinoma
BMC Medical Genomics (2021)
-
Molecular pathogenesis of breast cancer: impact of miR-99a-5p and miR-99a-3p regulation on oncogenic genes
Journal of Human Genetics (2021)
-
Regulation of aberrantly expressed SERPINH1 by antitumor miR-148a-5p inhibits cancer cell aggressiveness in gastric cancer
Journal of Human Genetics (2020)
-
RNA sequencing-based microRNA expression signature in esophageal squamous cell carcinoma: oncogenic targets by antitumor miR-143-5p and miR-143-3p regulation
Journal of Human Genetics (2020)
-
Pan-cancer analysis reveals cooperativity of both strands of microRNA that regulate tumorigenesis and patient survival
Nature Communications (2020)
