Browse > Article
http://dx.doi.org/10.7314/APJCP.2013.14.1.387

Let-7c Inhibits NSCLC Cell Proliferation by Targeting HOXA1  

Zhan, Min (Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University)
Qu, Qiang (Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University)
Wang, Guo (Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University)
Liu, Ying-Zi (Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University)
Tan, Sheng-Lan (Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University)
Lou, Xiao-Ya (Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University)
Yu, Jing (Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University)
Zhou, Hong-Hao (Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.14, no.1, 2013 , pp. 387-392 More about this Journal
Abstract
Objective: The aim of the present study was to explore mechanisms by which let-7c suppresses NSCLC cell proliferation. Methods: The expression level of let-7c was quantified by qRT-PCR. A549 and H1299 cells were transfected with let-7c mimics to restore the expression of let-7c. The effects of let-7c were then assessed by cell proliferation, colony formation and cell cycle assay. Mouse experiments were used to confirm the effect of let-7c on tumorigenicity in vivo. Luciferase reporter assays and Western blotting were performed to identify target genes for let-7c. Results: HOXA1 was identified as a novel target of let-7c. MTS, colony formation and flow cytometry assays demonstrated that forced expression of let-7c inhibited NSCLC cell proliferation by inducing G1 arrest in vitro, consistent with inhibitory effects induced by knockdown of HOXA1. Mouse experiments demonstrated that let-7c expression suppressed tumorigenesis. Furthermore, we found that let-7c could regulate the expression of HOXA1 downstream effectors CCND1, CDC25A and CDK2. Conclusions: Collectively, these results demonstrate let-7c inhibits NSCLC cell proliferation and tumorigenesis by partial direct targeting of the HOXA1 pathway, which suggests that restoration of let-7c expression may thus offer a potential therapeutic intervention strategy for NSCLC.
Keywords
Let-7c; NSCLC; HOXA1; G1 arrest;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Pasquinelli AE, Reinhart BJ, Slack F, et al (2000). Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature, 408, 86-9.   DOI   ScienceOn
2 Pelosi A, Careccia S, Lulli V, et al (2012). miRNA let-7c promotes granulocytic differentiation in acute myeloid leukemia. Oncogene.
3 Roush S, Slack FJ (2008). The let-7 family of microRNAs. Trends Cell Biol, 18, 505-16.   DOI   ScienceOn
4 Schultz J, Lorenz P, Gross G, et al (2008). MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth. Cell Res, 18, 549-57.   DOI   ScienceOn
5 Shimizu S, Takehara T, Hikita H, et al (2010). The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol, 52, 698-704.   DOI   ScienceOn
6 Simoncini T, Hafezi-Moghadam A, Brazil DP, et al (2000). Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature, 407, 538-41.   DOI   ScienceOn
7 Suzuki R, Takemura K, Tsutsumi M, et al (2001). Detection of cyclin D1 overexpression by real-time reverse-transcriptase-mediated quantitative polymerase chain reaction for the diagnosis of mantle cell lymphoma. Am J Pathol, 159, 425-9.   DOI   ScienceOn
8 Takamizawa J, Konishi H, Yanagisawa K, et al (2004). Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res, 64, 3753-6.   DOI   ScienceOn
9 Wang M, Wu L, Wang L, et al (2010). Down-regulation of Notch1 by gamma-secretase inhibition contributes to cell growth inhibition and apoptosis in ovarian cancer cells A2780. Biochem Biophys Res Commun, 393, 144-9.   DOI   ScienceOn
10 Yamada H, Yanagisawa K, Tokumaru S, et al (2008). Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer. Genes Chromosomes Cancer, 47, 810-8.   DOI   ScienceOn
11 Yin R, Bao W, Xing Y, et al (2012). MiR-19b-1 inhibits angiogenesis by blocking cell cycle progression of endothelial cells. Biochem Biophys Res Commun, 417, 771-6.   DOI   ScienceOn
12 Zha TZ, Hu BS, Yu HF, et al (2012). Overexpression of HOXA1 correlates with poor prognosis in patients with hepatocellular carcinoma. Tumour Biol, 33, 2125-34.   DOI   ScienceOn
13 Zhu T, Starling-Emerald B, Zhang X, et al (2005). Oncogenic transformation of human mammary epithelial cells by autocrine human growth hormone. Cancer Res, 65, 317-24.
14 Cho HS, Toyokawa G, Daigo Y, et al (2012). The JmjC domain-containing histone demethylase KDM3A is a positive regulator of the G1/S transition in cancer cells via transcriptional regulation of the HOXA1 gene. Int J Cancer, 131, E179-89.   DOI   ScienceOn
15 Esquela-Kerscher A, Trang P, Wiggins JF, et al (2008). The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle, 7, 759-64.   DOI
16 Feng X, Wu Z, Wu Y, et al (2011). Cdc25A regulates matrix metalloprotease 1 through Foxo1 and mediates metastasis of breast cancer cells. Mol Cell Biol, 31, 3457-71.   DOI   ScienceOn
17 Jinno S, Suto K, Nagata A, et al (1994). Cdc25A is a novel phosphatase functioning early in the cell cycle. EMBO J, 13, 1549-56.
18 Gong FX, Xia JL, Yang BW, et al (2011). Effect of let-7c on the proliferation of human hepatocellular carcinoma cell HCCLM3. Zhonghua Gan Zang Bing Za Zhi, 19, 853-6.
19 Han HB, Gu J, Zuo HJ, et al (2012). Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer. J Pathol, 226, 544-55.   DOI   ScienceOn
20 Jemal A, Siegel R, Ward E, et al (2007). Cancer statistics, 2007. CA Cancer J Clin, 57, 43-66.   DOI   ScienceOn
21 Johnson CD, Esquela-Kerscher A, Stefani G, et al (2007). The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res, 67, 7713-22.   DOI   ScienceOn
22 Johnson SM, Grosshans H, Shingara J, et al (2005). RAS is regulated by the let-7 microRNA family. Cell, 120, 635-47.   DOI   ScienceOn
23 Kim HH, Kuwano Y, Srikantan S, et al (2009). HuR recruits let-7/RISC to repress c-Myc expression. Genes Dev, 23, 1743-8.   DOI   ScienceOn
24 Kumar MS, Erkeland SJ, Pester RE, et al (2008). Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci U S A, 105, 3903-8.   DOI   ScienceOn
25 Liu Q, Fu H, Sun F, et al (2008). miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Res, 36, 5391-404.   DOI   ScienceOn
26 Mayr C, Hemann MT, Bartel DP. (2007). Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science, 315, 1576-9.   DOI   ScienceOn
27 Mohankumar KM, Xu XQ, Zhu T, et al (2007). HOXA1-stimulated oncogenicity is mediated by selective upregulation of components of the p44/42 MAP kinase pathway in human mammary carcinoma cells. Oncogene, 26, 3998-4008.   DOI   ScienceOn
28 Ohuchida K, Mizumoto K, Lin C, et al (2012). MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 gene. Ann Surg Oncol, 19, 2394-402.   DOI   ScienceOn
29 Nadiminty N, Tummala R, Lou W, et al (2012). MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. PLoS One, 7, e32832.   DOI   ScienceOn
30 Navarro A, Marrades RM, Vinolas N, et al (2009). MicroRNAs expressed during lung cancer development are expressed in human pseudoglandular lung embryogenesis. Oncology-Basel, 76, 162-9.   DOI   ScienceOn
31 Abe M, Hamada J, Takahashi O, et al (2006). Disordered expression of HOX genes in human non-small cell lung cancer. Oncol Rep, 15, 797-802.
32 Aleem E, Kiyokawa H, Kaldis P (2005). Cdc2-cyclin E complexes regulate the G1/S phase transition. Nat Cell Biol, 7, 831-6.   DOI   ScienceOn
33 Barh D, Malhotra R, Ravi B, et al (2010). MicroRNA let-7: an emerging next-generation cancer therapeutic. Curr Oncol, 17, 70-80.
34 Bartel DP (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116, 281-97.   DOI   ScienceOn
35 Bitu CC, Destro MF, Carrera M, et al (2012). HOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis. BMC Cancer, 12, 146.   DOI   ScienceOn
36 Chariot A, Castronovo V. (1996). Detection of HOXA1 expression in human breast cancer. Biochem Biophys Res Commun, 222, 292-7.   DOI   ScienceOn
37 Chen H, Sukumar S (2003). Role of homeobox genes in normal mammary gland development and breast tumorigenesis. J Mammary Gland Biol Neoplasia, 8, 159-75.   DOI   ScienceOn