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The effects of lanthanum chloride on proliferation and apoptosis of cervical cancer cells: involvement of let-7a and miR-34a microRNAs

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Abstract

Lanthanide elements have been documented to possess various biologic effects, and their compounds have been studied intensely for their anti-cancer potential. However, the underlying mechanisms remain largely unknown. In the present study, we propose that the levels of proliferation and apoptosis related microRNAs (miRNAs), let-7a and miR-34a, which mediate the apoptosis of cervical cancer cells, can be affected by the lanthanum ion. Our data showed that LaCl3 inhibited the proliferation and induced the apoptosis of cervical cancer cells both in vivo and in vitro by regulating let-7a, miR-34a and their downstream genes. This study provides novel evidence demonstrating that the anticancer mechanism of lanthanum chloride is partially attributed to miRNAs regulation and establishes an experimental basis for the clinical application of lanthanum chloride as an anti-cancer drug.

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References

  • Antonini D, Russo MT, De Rosa L et al (2010) Transcriptional repression of miR-34 family contributes to p63-mediated cell cycle progression in epidermal cells. J Invest Dermatol 130:1249–1257

    Article  CAS  PubMed  Google Scholar 

  • Bandi N, Vassella E (2011) miR-34a and miR-15a/16 are co-regulated in non-small cell lung cancer and control cell cycle progression in a synergistic and Rb-dependent manner. Mol Cancer 10:55

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Barh D, Malhotra R, Ravi B et al (2010) MicroRNA let-7: an emerging next-generation cancer therapeutic. Curr Oncol 17:70–80

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bommer GT, Gerin I, Feng Y et al (2007) p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol 17:1298–1307

    Article  CAS  PubMed  Google Scholar 

  • Bu L, Yan S, Jin M et al (2002) The gamma S-crystallin gene is mutated in autosomal recessive cataract in mouse. Genomics 80:38–44

    Article  CAS  PubMed  Google Scholar 

  • Calin GA, Sevignani C, Dumitru CD et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101:2999–3004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Corney DC, Hwang C-I, Matoso A, Vogt M, Flesken-Nikitin A, Godwin AK, Kamat AA, Sood AK, Ellenson LH, Hermeking H, Nikitin AY (2010) Frequent downregulation of miR-34 family in human ovarian cancers. Clin Cancer Res 16:1119–1128

  • Dahiya N, Morin PJ (2010) MicroRNAs in ovarian carcinomas. Endocr-relat Cancer 17:F77–F89

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dai Y, Li J, Li J et al (2002) Effects of rare earth compounds on growth and apoptosis of leukemic cell lines. In vitro cellular & developmental biology. Animal 38:373–375

    CAS  Google Scholar 

  • Dong Q, Meng P, Wang T et al (2010) MicroRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2. PLoS One 5:e10147

    Article  PubMed Central  PubMed  Google Scholar 

  • Feng Z, Qiu Z, Li Y et al (2002) Protective immunity induced by the anti-idiotypic monoclonal antibody NP30 of Schistosoma japonicum. Chin Med J 115:576–579

    CAS  PubMed  Google Scholar 

  • He C, Xiong J, Xu X et al (2009) Functional elucidation of MiR-34 in osteosarcoma cells and primary tumor samples. Biochem Biophys Res Commun 388:35–40

    Article  CAS  PubMed  Google Scholar 

  • Heffeter P, Jakupec MA, Korner W et al (2006) Anticancer activity of the lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772; FFC24). Biochem Pharmacol 71:426–440

    Article  CAS  PubMed  Google Scholar 

  • Heffeter P, Jakupec MA, Korner W et al (2007) Multidrug-resistant cancer cells are preferential targets of the new antineoplastic lanthanum compound KP772 (FFC24). Biochem Pharmacol 73:1873–1886

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199

    Article  CAS  PubMed  Google Scholar 

  • Hwang HW, Mendell JT (2007) MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer 96(Suppl):R40–R44

    PubMed  Google Scholar 

  • JF Sun (2001) Experimental methodology in animals (Chinese). People Healthy House, Beijing

    Google Scholar 

  • Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647

    Article  CAS  PubMed  Google Scholar 

  • Krzeszinski JY, Wei W, Huynh H et al (2014) miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature 512:431–435

    Article  CAS  PubMed  Google Scholar 

  • Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21:1025–1030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liang Y, Ridzon D, Wong L et al (2007) Characterization of microRNA expression profiles in normal human tissues. BMC Genomics 8:166

    Article  PubMed Central  PubMed  Google Scholar 

  • Liu SS, Lu D, Miao LF et al (2010) Effects of lanthanum chloride on proliferation and migration of human cervical cancer cell line HeLa cells. Zhonghua fu chan ke za zhi 45:609–613

    PubMed  Google Scholar 

  • Liu X, Wei Q, Zhang J et al (2015) Derivation of embryonic stem cells from Kunming mice IVF blastocyst in feeder- and serum-free condition. In vitro Cell Dev Biol Anim 51:541–545

    Article  CAS  PubMed  Google Scholar 

  • Lou WJ, Chen Q, Liu L et al (2010) miR-34 s–a tumor suppression protein p53 highly related microRNA. Yi chuan = Hereditas/Zhongguo yi chuan xue hui bian ji 32:423–430

    Article  CAS  PubMed  Google Scholar 

  • Lu L, Schwartz P, Scarampi L et al (2011) MicroRNA let-7a: a potential marker for selection of paclitaxel in ovarian cancer management. Gynecol Oncol 122:366–371

    Article  CAS  PubMed  Google Scholar 

  • Lujambio A, Calin GA, Villanueva A et al (2008) A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA 105:13556–13561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Misso G, Di Martino MT, De Rosa G et al (2014) Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids 3:e194

    Article  CAS  PubMed  Google Scholar 

  • Nalls D, Tang SN, Rodova M et al (2011) Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One 6:e24099

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nikitina EG, Urazova LN, Stegny VN (2012) MicroRNAs and human cancer. Exp Oncol 34:2–8

    CAS  PubMed  Google Scholar 

  • Park EY, Chang E, Lee EJ et al (2014) Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance. Cancer Res 74:7573–7582

    Article  CAS  PubMed  Google Scholar 

  • Roush S, Slack FJ (2008) The let-7 family of microRNAs. Trends cell Biol 18:505–516

    Article  CAS  PubMed  Google Scholar 

  • Shen L, Lan Z, Sun X et al (2010) Proteomic analysis of lanthanum citrate-induced apoptosis in human cervical carcinoma SiHa cells. Biometals 23:1179–1189

    Article  CAS  PubMed  Google Scholar 

  • Shi P, Huang Z (2005) Proteomic detection of changes in protein synthesis induced by lanthanum in BGC-823 human gastric cancer cells. Biometals 18:89–95

    Article  CAS  PubMed  Google Scholar 

  • Shih KK, Qin LX, Tanner EJ et al (2011) A microRNA survival signature (MiSS) for advanced ovarian cancer. Gynecol Oncol 121:444–450

    Article  CAS  PubMed  Google Scholar 

  • Shishodia G, Verma G, Srivastava Y et al (2014) Deregulation of microRNAs Let-7a and miR-21 mediate aberrant STAT3 signaling during human papillomavirus-induced cervical carcinogenesis: role of E6 oncoprotein. BMC Cancer 14:996

    Article  PubMed Central  PubMed  Google Scholar 

  • Sun F, Fu H, Liu Q et al (2008) Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett 582:1564–1568

    Article  CAS  PubMed  Google Scholar 

  • Tarasov V, Jung P, Verdoodt B et al (2007) Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6:1586–1593

    Article  CAS  PubMed  Google Scholar 

  • Tomosugi M, Sowa Y, Yasuda S et al (2012) Retinoblastoma gene-independent G1 phase arrest by flavone, phosphatidylinositol 3-kinase inhibitor, and histone deacetylase inhibitor. Cancer Sci 103:2139–2143

    Article  CAS  PubMed  Google Scholar 

  • Tsang WP, Kwok TT (2008) Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis 13:1215–1222

    Article  CAS  PubMed  Google Scholar 

  • Vadla B, Kemper K, Alaimo J et al (2012) Lin-28 controls the succession of cell fate choices via two distinct activities. PLoS Genet 8:e1002588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vogt M, Munding J, Gruner M et al (2011) Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Archiv 458:313–322

    Article  PubMed  Google Scholar 

  • Wang X, Wang HK, McCoy JP et al (2009) Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA 15:637–647

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang X, Meyers C, Guo M et al (2011) Upregulation of p18Ink4c expression by oncogenic HPV E6 via p53-miR-34a pathway. Int J Cancer 129:1362–1372

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang DJ, Legesse-Miller A, Johnson EL et al (2012a) Regulation of the let-7a-3 promoter by NF-kappaB. PLoS One 7:e31240

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang X, Cao L, Wang Y et al (2012b) Regulation of let-7 and its target oncogenes (Review). Oncol Lett 3:955–960

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wang Y, Hu X, Greshock J et al (2012c) Genomic DNA copy-number alterations of the let-7 family in human cancers. PLoS One 7:e44399

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu Q, Guo R, Lin M et al (2011) MicroRNA-200a inhibits CD133/1+ ovarian cancer stem cells migration and invasion by targeting E-cadherin repressor ZEB2. Gynecol Oncol 122:149–154

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Yang J, Liu Q et al (2013) Lanthanum induced primary neuronal apoptosis through mitochondrial dysfunction modulated by Ca(2)(+) and Bcl-2 family. Biol Trace Elem Res 152:125–134

    Article  CAS  PubMed  Google Scholar 

  • Xu Z, Gao Y, Huang S et al (2011) A luminescent and mesoporous core–shell structured Gd2O3: Eu(3 +)@nSiO2@mSiO2 nanocomposite as a drug carrier. Dalton Trans 40:4846–4854

    Article  CAS  PubMed  Google Scholar 

  • Xu J, Zhang YX, Yu XQ et al (2013) Lanthanum carbonate for the treatment of hyperphosphatemia in CKD 5D: multicenter, double blind, randomized, controlled trial in mainland China. BMC Nephrol 14:29

    Article  PubMed Central  PubMed  Google Scholar 

  • Yang Q, Lu JT, Zhou AW et al (2001) Antinociceptive effect of astragalosides and its mechanism of action. Acta Pharmacol Sin 22:809–812

    CAS  PubMed  Google Scholar 

  • Yu T, Zhao Y, Shi W et al (1997) Effects of maternal oral administration of monosodium glutamate at a late stage of pregnancy on developing mouse fetal brain. Brain Res 747:195–206

    Article  CAS  PubMed  Google Scholar 

  • Yuan XM, Xie FP, Lu ZB et al (1995) The establishment of two cell lines from a mouse uterine cervical carcinoma (U14) and their metastatic phenotype changes. Clin Exp Metastasis 13:463–473

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Li Y, Hao X et al (2011) Recent progress in therapeutic and diagnostic applications of lanthanides. Mini Rev Med Chem 11:678–694

    Article  CAS  PubMed  Google Scholar 

  • Zhang C, Wen J, Li Z et al (2013) Efficacy and safety of lanthanum carbonate on chronic kidney disease-mineral and bone disorder in dialysis patients: a systematic review. BMC Nephrol 14:226

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (30960405, 81160193), the Natural Science Foundation of Jiangxi Province (2010GZY0348, 20121DH80026), the Program of Jiangxi Education Department (GJJ11310) and the Program of Wujiang Science and Technology (WWWK201408). Many thanks to Dr. Keegan for his efforts making the manuscript much better.

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Correspondence to Fei Guo.

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Lingfang Yu and Jieqi Xiong have contributed equally to this article.

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Yu, L., Xiong, J., Guo, L. et al. The effects of lanthanum chloride on proliferation and apoptosis of cervical cancer cells: involvement of let-7a and miR-34a microRNAs. Biometals 28, 879–890 (2015). https://doi.org/10.1007/s10534-015-9872-6

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  • DOI: https://doi.org/10.1007/s10534-015-9872-6

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