MicroRNA-99a Induces G1-phase Cell Cycle Arrest and Suppresses Tumorigenicity in Renal Cell Carcinoma

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2012 Nov 24

PMID 23173671

Citations 58

Authors

Li Cui

Hua Zhou

Hu Zhao

Yaojun Zhou

Renfang Xu

Xianlin Xu

Lu Zheng

Zhong Xue

Wei Xia

Bo Zhang

Tao Ding

Yunjie Cao

Zinong Tian

Qianqian Shi

Xiaozhou He

Affiliations

Soon will be listed here.

Abstract

Background: A growing body of evidence suggests that microRNAs (miRNAs) play an important role in cancer diagnosis and therapy. MicroRNA-99a (miR-99a), a potential tumor suppressor, is downregulated in several human malignancies. The expression and function of miR-99a, however, have not been investigated in human renal cell carcinoma (RCC) so far. We therefore examined the expression of miR-99a in RCC cell lines and tissues, and assessed the impact of miR-99a on the tumorigenesis of RCC.

Methods: MiR-99a levels in 40 pairs of RCC and matched adjacent non-tumor tissues were assessed by real-time quantitative Reverse Transcription PCR (qRT-PCR). The RCC cell lines 786-O and OS-RC-2 were transfected with miR-99a mimics to restore the expression of miR-99a. The effects of miR-99a were then assessed by cell proliferation, cell cycle, transwell, and colony formation assay. A murine xenograft model of RCC was used to confirm the effect of miR-99a on tumorigenicity in vivo. Potential target genes were identified by western blotting and luciferase reporter assay.

Results: We found that miR-99a was remarkably downregulated in RCC and low expression level of miR-99a was correlated with poor survival of RCC patients. Restoration of miR-99a dramatically suppressed RCC cells growth, clonability, migration and invasion as well as induced G1-phase cell cycle arrest in vitro. Moreover, intratumoral delivery of miR-99a could inhibit tumor growth in murine xenograft models of human RCC. In addition, we also fond that mammalian target of rapamycin (mTOR) was a direct target of miR-99a in RCC cells. Furthermore, siRNA-mediated knockdown of mTOR partially phenocopied the effect of miR-99a overexpression, suggesting that the tumor suppressive role of miR-99a may be mediated primarily through mTOR regulation.

Conclusions: Collectively, these results demonstrate for the first time, to our knowledge, that deregulation of miR-99a is involved in the etiology of RCC partially via direct targeting mTOR pathway, which suggests that miR-99a may offer an attractive new target for diagnostic and therapeutic intervention in RCC.

Citing Articles

Renal cancer: signaling pathways and advances in targeted therapies.

Jiang A, Li J, He Z, Liu Y, Qiao K, Fang Y MedComm (2020). 2024; 5(8):e676.

PMID: 39092291 PMC: 11292401. DOI: 10.1002/mco2.676.

Expression of hsa-miRNA-15b, -99b, -181a and Their Relationship to Angiogenesis in Renal Cell Carcinoma.

Kiraly J, Szabo E, Fodor P, Vass A, Choudhury M, Gesztelyi R Biomedicines. 2024; 12(7).

PMID: 39062015 PMC: 11274182. DOI: 10.3390/biomedicines12071441.

Identification of microRNA editing sites in clear cell renal cell carcinoma.

Liu Y, Guo S, Xie W, Yang H, Li W, Zhou N Sci Rep. 2023; 13(1):15117.

PMID: 37704698 PMC: 10499803. DOI: 10.1038/s41598-023-42302-y.

Unraveling Therapeutic Opportunities and the Diagnostic Potential of microRNAs for Human Lung Cancer.

Sweef O, Zaabout E, Bakheet A, Halawa M, Gad I, Akela M Pharmaceutics. 2023; 15(8).

PMID: 37631277 PMC: 10459057. DOI: 10.3390/pharmaceutics15082061.

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy.

Jiang A, Song J, Fang X, Fang Y, Wang Z, Liu B Front Public Health. 2022; 10:1029509.

PMID: 36478716 PMC: 9720257. DOI: 10.3389/fpubh.2022.1029509.

References

White N, Yousef G . MicroRNAs: exploring a new dimension in the pathogenesis of kidney cancer. BMC Med. 2010; 8:65. PMC: 2978114. DOI: 10.1186/1741-7015-8-65. View

Schickel R, Boyerinas B, Park S, Peter M . MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene. 2008; 27(45):5959-74. DOI: 10.1038/onc.2008.274. View

Petroulakis E, Mamane Y, le Bacquer O, Shahbazian D, Sonenberg N . mTOR signaling: implications for cancer and anticancer therapy. Br J Cancer. 2007; 96 Suppl:R11-5. View

Grewe M, Gansauge F, Schmid R, Adler G, Seufferlein T . Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res. 1999; 59(15):3581-7. View

Guertin D, Sabatini D . Defining the role of mTOR in cancer. Cancer Cell. 2007; 12(1):9-22. DOI: 10.1016/j.ccr.2007.05.008. View

Shenouda S, Alahari S . MicroRNA function in cancer: oncogene or a tumor suppressor?. Cancer Metastasis Rev. 2009; 28(3-4):369-78. DOI: 10.1007/s10555-009-9188-5. View

Li D, Liu X, Lin L, Hou J, Li N, Wang C . MicroRNA-99a inhibits hepatocellular carcinoma growth and correlates with prognosis of patients with hepatocellular carcinoma. J Biol Chem. 2011; 286(42):36677-85. PMC: 3196113. DOI: 10.1074/jbc.M111.270561. View

van Spronsen D, de Weijer K, Mulders P, De Mulder P . Novel treatment strategies in clear-cell metastatic renal cell carcinoma. Anticancer Drugs. 2005; 16(7):709-17. DOI: 10.1097/01.cad.0000167901.58877.a3. View

Hummel R, Hussey D, Haier J . MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer. 2009; 46(2):298-311. DOI: 10.1016/j.ejca.2009.10.027. View

10.

Kapoor A . Inhibition of mTOR in kidney cancer. Curr Oncol. 2009; 16 Suppl 1:S33-9. PMC: 2687803. DOI: 10.3747/co.v16i0.419. View

11.

Yamada H, Yanagisawa K, Tokumaru S, Taguchi A, Nimura Y, Osada H . Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer. Genes Chromosomes Cancer. 2008; 47(9):810-8. DOI: 10.1002/gcc.20582. View

12.

Calin G, Croce C . MicroRNA signatures in human cancers. Nat Rev Cancer. 2006; 6(11):857-66. DOI: 10.1038/nrc1997. View

13.

Wong T, Liu X, Wong B, Ng R, Yuen A, Wei W . Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongue. Clin Cancer Res. 2008; 14(9):2588-92. DOI: 10.1158/1078-0432.CCR-07-0666. View

14.

Gao W, Shen H, Liu L, Xu J, Xu J, Shu Y . MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis. J Cancer Res Clin Oncol. 2010; 137(4):557-66. DOI: 10.1007/s00432-010-0918-4. View

15.

Huang Y, Dai Y, Yang J, Chen T, Yin Y, Tang M . Microarray analysis of microRNA expression in renal clear cell carcinoma. Eur J Surg Oncol. 2009; 35(10):1119-23. DOI: 10.1016/j.ejso.2009.04.010. View

16.

Fingar D, Richardson C, Tee A, Cheatham L, Tsou C, Blenis J . mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2003; 24(1):200-16. PMC: 303352. DOI: 10.1128/MCB.24.1.200-216.2004. View

17.

Iorio M, Croce C . MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol. 2009; 27(34):5848-56. PMC: 2793003. DOI: 10.1200/JCO.2009.24.0317. View

18.

Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W . Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res. 2010; 70(11):4666-75. PMC: 2880211. DOI: 10.1158/0008-5472.CAN-09-3970. View

19.

Chow T, Youssef Y, Lianidou E, Romaschin A, Honey R, Stewart R . Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis. Clin Biochem. 2009; 43(1-2):150-8. DOI: 10.1016/j.clinbiochem.2009.07.020. View

20.

Nagaraja A, Creighton C, Yu Z, Zhu H, Gunaratne P, Reid J . A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. Mol Endocrinol. 2010; 24(2):447-63. PMC: 2817607. DOI: 10.1210/me.2009-0295. View