Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-03-2014 | Original Paper

miR-145 functions as tumor suppressor and targets two oncogenes, ANGPT2 and NEDD9, in renal cell carcinoma

Authors: Ruijing Lu, Ziliang Ji, Xiaoqing Li, Qingna Zhai, Chunjuan Zhao, Zhimao Jiang, Shiqiang Zhang, Liping Nie, Zhendong Yu

Published in: Journal of Cancer Research and Clinical Oncology | Issue 3/2014

Abstract

Purpose

Abnormal expression of miRNAs is closely related to a variety of human cancers. The purpose of this study is to identify new tumor suppressor miRNA and elucidate its physiological function and mechanism in renal cell carcinoma (RCC).

Methods

The expression of miR-145 in 45 RCC and adjacent normal tissues was performed by quantitative RT-PCR. Cell proliferation, migration, invasion, apoptosis and cycle assays were carried out for functional analysis after miR-145 transfection. Two target genes of miR-145 were identified by luciferase reporter assay. The altered expression of 84 epithelial to mesenchymal transition (EMT)-related genes after miR-145 transfection was detected by RT² Profiler EMT PCR array.

Results

The expression of miR-145 was downregulated in RCC compared to their normal adjacent tissues. Restoring miR-145 expression in RCC cell lines dramatically suppressed cell proliferation, migration and invasion, and induced cell apoptosis and G2-phase arrest. We further validated those miR-145 targets two oncogenes, ANGPT2 and NEDD9 in RCC. In addition, miR-145 was found to regulate numerous genes involved in the EMT.

Conclusions

These findings demonstrate that miR-145 functions as tumor suppressor in RCC, suggesting that miR-145 may be a potential therapeutic target for RCC.

Baldewijns M, Thijssen V, Van den Eynden G, Van Laere S, Bluekens A, Roskams T, Van Poppel H, De Bruine A, Griffioen A, Vermeulen P (2007) High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile. Br J Cancer 96(12):1888–1895PubMedCentralPubMedCrossRef

Berezikov E, Guryev V, van de Belt J, Wienholds E, Plasterk RH, Cuppen E (2005) Phylogenetic shadowing and computational identification of human micro RNA genes. Cell 120(1):21–24PubMedCrossRef

Bullock A, Zhang L, O’Neill A, Percy A, Sukhatme V, Mier J, Atkins M, Bhatt R (2010) Plasma angiopoietin-2 (ANG2) as an angiogenic biomarker in renal cell carcinoma (RCC). J Clin Oncol 2010(28):4630CrossRef

Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P (2010) Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer 10(12):858–870PubMedCrossRef

Chang J-X, Gao F, Zhao G-Q, Zhang G-J (2012) Expression and clinical significance of NEDD9 in lung tissues. Med Oncol 29(4):2654–2660PubMedCrossRef

Chen B, Li H, Zeng X, Yang P, Liu X, Zhao X, Liang S (2012) Roles of microRNA on cancer cell metabolism. J Transl Med 10:228. doi:10.1186/1479-5876-10-228 PubMedCentralPubMedCrossRef

Chiyomaru T, Enokida H, Tatarano S, Kawahara K, Uchida Y, Nishiyama K, Fujimura L, Kikkawa N, Seki N, Nakagawa M (2010) miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer 102(5):883–891PubMedCentralPubMedCrossRef

Cohen HT, McGovern FJ (2005) Renal-cell carcinoma. New Engl J Med 353(23):2477–2490PubMedCrossRef

Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M (2001) Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma possible in vivo regulation via induction of proteases. Cancer Res 61(5):2145–2153PubMed

Fuhrman SA, Lasky LC, Limas C (1982) Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6(7):655–664PubMedCrossRef

Ha T-Y (2011) MicroRNAs in human diseases: from cancer to cardiovascular disease. Immune Netw 11(3):135–154PubMedCentralPubMedCrossRef

Honda H, Oda H, Nakamoto T, Honda Z-I, Sakai R, Suzuki T, Saito T, Nakamura K, Nakao K, Ishikawa T (1998) Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas. Nat Genet 19(4):361–365PubMedCrossRef

Hu B, Cheng S-Y (2009) Angiopoietin-2: development of inhibitors for cancer therapy. Curr Oncol Rep 11(2):111–116PubMedCentralPubMedCrossRef

Inui M, Martello G, Piccolo S (2010) MicroRNA control of signal transduction. Nat Rev Mol Cell Bio 11(4):252–263

Izumchenko E, Singh MK, Plotnikova OV, Tikhmyanova N, Little JL, Serebriiskii IG, Seo S, Kurokawa M, Egleston BL, Klein-Szanto A (2009) NEDD9 promotes oncogenic signaling in mammary tumor development. Cancer Res 69(18):7198–7206PubMedCentralPubMedCrossRef

Kim M, Gans JD, Nogueira C, Wang A, Paik J-H, Feng B, Brennan C, Hahn WC, Cordon-Cardo C, Wagner SN (2006) Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell 125(7):1269–1281PubMedCrossRef

Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001) Identification of novel genes coding for small expressed RNAs. Science 294(5543):853–858PubMedCrossRef

Liang C–C, Park AY, Guan J-L (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2(2):329–333PubMedCrossRef

Natarajan M, Stewart J, Golemis EA, Pugacheva E, Alexandropoulos K, Cox BD, Wang W, Grammer J, Gladson C (2005) HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene 25(12):1721–1732CrossRef

Naumnik W, Naumnik B, Niewiarowska K, Ossolinska M, Chyczewska E (2013) Angiogenic axis angiopoietin-1 and angiopoietin-2/tie-2 in non-small cell lung cancer: a bronchoalveolar lavage and serum study. Neurobiol Respir Spring 341–348

Noh JH, Chang YG, Kim MG, Jung KH, Kim JK, Bae HJ, Eun JW, Shen Q, Kim S-J, Kwon SH (2013) miR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer. Cancer Lett 335(2):455–462PubMedCrossRef

Oliner J, Min H, Leal J, Yu D, Rao S, You E, Tang X, Kim H, Meyer S, Han SJ (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6(5):507–516PubMed

Pascual D, Borque A (2008) Epidemiology of kidney cancer. Adv Urol 2008:782381PubMedCentral

Redova M, Poprach A, Besse A, Iliev R, Nekvindova J, Lakomy R, Radova L, Svoboda M, Dolezel J, Vyzula R, Slaby O (2012) MiR-210 expression in tumor tissue and in vitro effects of its silencing in renal cell carcinoma. Tumor Biol 34(1):481–491. doi:10.1007/s13277-012-0573-2

Reeves DJ, Liu CY (2009) Treatment of metastatic renal cell carcinoma. Cancer Chemoth Pharm 64(1):11–25

Rini BI, Campbell SC, Escudier B (2009) Renal cell carcinoma. Lancet 373(9669):1119–1132PubMed

Speranza MC, Frattini V, Pisati F, Kapetis D, Porrati P, Eoli M, Pellegatta S, Finocchiaro G (2012) NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. Oncotarget 3(7):723PubMed

Thurston G, Daly C (2012) The complex role of angiopoietin-2 in the angiopoietin–tie signaling pathway. Cold Spring Harb Perspect Med 2(9):a006550PubMed

Zaman M, Chen Y, Deng G, Shahryari V, Suh S, Saini S, Majid S, Liu J, Khatri G, Tanaka Y (2010) The functional significance of microRNA-145 in prostate cancer. Br J Cancer 103(2):256–264PubMedCentralPubMed

Zhao L, Chen X, Cao Y (2011) New role of microRNA: carcinogenesis and clinical application in cancer. Acta Biochim Biophys Sin 43(11):831–839PubMed

Zhou L, Chen J, Li Z, Li X, Hu X, Huang Y, Zhao X, Liang C, Wang Y, Sun L (2010) Integrated profiling of microRNAs and mRNAs: microRNAs located on Xq27. 3 associate with clear cell renal cell carcinoma. PLoS ONE 5(12):e15224PubMedCentralPubMed

Title: miR-145 functions as tumor suppressor and targets two oncogenes, ANGPT2 and NEDD9, in renal cell carcinoma
Authors: Ruijing Lu
Ziliang Ji
Xiaoqing Li
Qingna Zhai
Chunjuan Zhao
Zhimao Jiang
Shiqiang Zhang
Liping Nie
Zhendong Yu
Publication date: 01-03-2014
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 3/2014
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-013-1577-z

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

miR-145 functions as tumor suppressor and targets two oncogenes, ANGPT2 and NEDD9, in renal cell carcinoma

Abstract

Purpose

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2014

Extracellular matrix metalloproteinase inducer (EMMPRIN) expression correlates positively with active angiogenesis and negatively with basic fibroblast growth factor expression in epithelial ovarian cancer

Prognostic factors associated with primary cancer in curatively resected stage IV colorectal cancer

Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer

Different treatment orders achieved similar clinical results: a retrospective study for retreatment of epidermal growth factor receptor tyrosine kinase inhibitors in 120 patients with non-small-cell lung cancer

High expression of metabotropic glutamate receptor 4: correlation with clinicopathologic characteristics and prognosis of osteosarcoma

Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page