MicroRNA miR-34a is recognized as a master regulator of tumor suppression. The strategy of miR-34a replacement has been investigated in clinical trials as the first attempt of miRNA application in cancer treatment. However, emerging outcomes promote the re-evaluation of existing knowledge and urge the need for better understanding the complex biological role of miR-34a. The targets of miR-34a encompass numerous regulators of cancer cell proliferation, survival and resistance to therapy. MiR-34a expression is transcriptionally controlled by p53, a crucial tumor suppressor pathway, often disrupted in cancer. Moreover, miR-34a abundance is fine-tuned by context-dependent feedback loops. The function and effects of exogenously delivered or re-expressed miR-34a on the background of defective p53 therefore remain prominent issues in miR-34a based therapy. In this work, we review p53-independent mechanisms regulating the expression of miR-34a. Aside from molecules directly interacting with MIR34A promoter, processes affecting epigenetic regulation and miRNA maturation are discussed. Multiple mechanisms operate in the context of cancer-associated phenomena, such as aberrant oncogene signaling, EMT or inflammation. Since p53-dependent tumor-suppressive mechanisms are disturbed in a substantial proportion of malignancies, we summarize the effects of miR-34a modulation in cell and animal models in the clinically relevant context of disrupted or insufficient p53 function.

Center of Biomolecular and Cellular Engineering International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Division of Experimental Urology Department of Urology Medical University of Innsbruck Innsbruck Austria

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Cell Death Dis. 2018 Jul 16;9(8):783. doi: 10.1038/s41419-018-0833-1. PubMed

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Svoronos AA, Engelman DM, Slack FJ. OncomiR or tumor suppressor? The duplicity of MicroRNAs in cancer. Cancer Res 2016; 76: 3666–3670. PubMed PMC

Wang L, Yu J, Xu J, Zheng C, Li X, Du J. The analysis of microRNA-34 family expression in human cancer studies comparing cancer tissues with corresponding pericarcinous tissues. Gene 2014; 554: 1–8. PubMed

Ohtsuka M, Ling H, Doki Y, Mori M, Calin GA. MicroRNA processing and human cancer. J Clin Med 2015; 4: 1651–1667. PubMed PMC

Bader AG. miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet 2012; 3: 120. PubMed PMC

Beg MS, Brenner AJ, Sachdev J, Borad M, Kang YK, Stoudemire J et al. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Invest New Drugs 2017; 35: 180–188. PubMed PMC

Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci USA 2007; 104: 15472–15477. PubMed PMC

Liang Y, Ridzon D, Wong L, Chen C. Characterization of microRNA expression profiles in normal human tissues. BMC Genomics 2007; 8: 166. PubMed PMC

Qiao P, Li G, Bi W, Yang L, Yao L, Wu D. microRNA-34a inhibits epithelial mesenchymal transition in human cholangiocarcinoma by targeting Smad4 through transforming growth factor-beta/Smad pathway. BMC Cancer 2015; 15: 469. PubMed PMC

Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V et al. Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids 2014; 3: e194. PubMed PMC

Rokavec M, Li H, Jiang L, Hermeking H. The p53/miR-34 axis in development and disease. J Mol Cell Biol 2014; 6: 214–230. PubMed

Rokavec M, Öner MG, Li H, Jackstadt R, Jiang L, Lodygin D et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 2014; 124: 1853–1867. PubMed PMC

Siemens H, Jackstadt R, Hunten S, Kaller M, Menssen A, Gotz U et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 2011; 10: 4256–4271. PubMed

Yamakuchi M, Ferlito M, Lowenstein CJ. miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA 2008; 105: 13421–13426. PubMed PMC

Chang T-C, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 2007; 26: 745–752. PubMed PMC

Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 2007; 26: 731–743. PubMed

Wong MY, Yu Y, Walsh WR, Yang JL. microRNA-34 family and treatment of cancers with mutant or wild-type p53 (Review). Int J Oncol 2011; 38: 1189–1195. PubMed

Concepcion CP, Han YC, Mu P, Bonetti C, Yao E, D'Andrea A et al. Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet 2012; 8: e1002797. PubMed PMC

Luan S, Sun L, Huang F. MicroRNA-34a: a novel tumor suppressor in p53-mutant glioma cell line U251. Arch Med Res 2010; 41: 67–74. PubMed

Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010; 2: a001008. PubMed PMC

Corney DC, Hwang CI, Matoso A, Vogt M, Flesken-Nikitin A, Godwin AK et al. Frequent downregulation of miR-34 family in human ovarian cancers. Clin Cancer Res 2010; 16: 1119–1128. PubMed PMC

Di Martino MT, Leone E, Amodio N, Foresta U, Lionetti M, Pitari MR et al. Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence. Clin Cancer Res 2012; 18: 6260–6270. PubMed PMC

Dijkstra MK, van Lom K, Tielemans D, Elstrodt F, Langerak AW, van 't Veer MB et al. 17p13/TP53 deletion in B-CLL patients is associated with microRNA-34a downregulation. Leukemia 2009; 23: 625–627. PubMed

Mraz M, Malinova K, Kotaskova J, Pavlova S, Tichy B, Malcikova J et al. miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 2009; 23: 1159–1163. PubMed

Zenz T, Mohr J, Eldering E, Kater AP, Buhler A, Kienle D et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood 2009; 113: 3801–3808. PubMed

Li XJ, Ren ZJ, Tang JH. MicroRNA-34a: a potential therapeutic target in human cancer. Cell Death Dis 2014; 5: e1327. PubMed PMC

Guennewig B, Roos M, Dogar AM, Gebert LF, Zagalak JA, Vongrad V et al. Synthetic pre-microRNAs reveal dual-strand activity of miR-34a on TNF-alpha. RNA 2014; 20: 61–75. PubMed PMC

Chou CH, Chang NW, Shrestha S, Hsu SD, Lin YL, Lee WH et al. miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res 2016; 44: D239–D247. PubMed PMC

Agostini M, Knight RA. miR-34: from bench to bedside. Oncotarget 2014; 5: 872–881. PubMed PMC

Ito Y, Inoue A, Seers T, Hato Y, Igarashi A, Toyama T et al. Identification of targets of tumor suppressor microRNA-34a using a reporter library system. Proc Natl Acad Sci USA 2017; 114: 3927–3932. PubMed PMC

Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435: 834–838. PubMed

Wang X, Li J, Dong K, Lin F, Long M, Ouyang Y et al. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal 2015; 27: 443–452. PubMed

Imani S, Zhang X, Hosseinifard H, Fu S, Fu J. The diagnostic role of microRNA-34a in breast cancer: a systematic review and meta-analysis. Oncotarget 2017; 8: 23177–23187. PubMed PMC

Bagchi A, Mills AA. The quest for the 1p36 tumor suppressor. Cancer Res 2008; 68: 2551–2556. PubMed PMC

Feinberg-Gorenshtein G, Avigad S, Jeison M, Halevy-Berco G, Mardoukh J, Luria D et al. Reduced levels of miR-34a in neuroblastoma are not caused by mutations in the TP53 binding site. Genes Chromosomes Cancer 2009; 48: 539–543. PubMed

Welch C, Chen Y, Stallings RL. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene 2007; 26: 5017–5022. PubMed

Junttila MR, Evan GI. p53—a Jack of all trades but master of none. Nat Rev Cancer 2009; 9: 821–829. PubMed

Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A et al. 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 2007; 6: 1586–1593. PubMed

Navarro F, Lieberman J. miR-34 and p53: new insights into a complex functional relationship. PLoS ONE 2015; 10: e0132767. PubMed PMC

Mandke P, Wyatt N, Fraser J, Bates B, Berberich SJ, Markey MP. MicroRNA-34a modulates MDM4 expression via a target site in the open reading frame. PLoS ONE 2012; 7: e42034. PubMed PMC

Okada N, Lin CP, Ribeiro MC, Biton A, Lai G, He X et al. A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes Dev 2014; 28: 438–450. PubMed PMC

Zhao J, Lammers P, Torrance CJ, Bader AG. TP53-independent function of miR-34a via HDAC1 and p21(CIP1/WAF1.). Mol Ther 2013; 21: 1678–1686. PubMed PMC

Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol 2007; 17: 1298–1307. PubMed

He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y et al. A microRNA component of the p53 tumour suppressor network. Nature 2007; 447: 1130–1134. PubMed PMC

Wang X, Dong K, Gao P, Long M, Lin F, Weng Y et al. microRNA-34a sensitizes lung cancer cell lines to DDP treatment independent of p53 status. Cancer Biother Radiopharm 2013; 28: 45–50. PubMed

Vinall RL, Ripoll AZ, Wang S, Pan CX, deVere White RW. MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status. Int J Cancer 2012; 130: 2526–2538. PubMed PMC

He C, Xiong J, Xu X, Lu W, Liu L, Xiao D et al. Functional elucidation of MiR-34 in osteosarcoma cells and primary tumor samples. Biochem Biophys Res Commun 2009; 388: 35–40. PubMed

Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011; 17: 211–215. PubMed PMC

Cortez MA, Ivan C, Valdecanas D, Wang X, Peltier HJ, Ye Y et al. PDL1 Regulation by p53 via miR-34. J Natl Cancer Inst 2016; 108 https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djv303. PubMed PMC

Nalls D, Tang SN, Rodova M, Srivastava RK, Shankar S. Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS ONE 2011; 6: e24099. PubMed PMC

Hiyoshi Y, Schetter AJ, Okayama H, Inamura K, Anami K, Nguyen GH et al. Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer. PLoS ONE 2015; 10: e0124899. PubMed PMC

Paris R, Henry RE, Stephens SJ, McBryde M, Espinosa JM. Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation. Cell Cycle 2008; 7: 2427–2433. PubMed PMC

Takeda Y, Venkitaraman AR. Micro(mi) RNA-34a targets protein phosphatase (PP)1gamma to regulate DNA damage tolerance. Cell Cycle 2015; 14: 3830–3841. PubMed PMC

Song R, Walentek P, Sponer N, Klimke A, Lee JS, Dixon G et al. miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110. Nature 2014; 510: 115–120. PubMed PMC

Wu J, Bao J, Kim M, Yuan S, Tang C, Zheng H et al. Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis. Proc Natl Acad Sci USA 2014; 111: E2851–E2857. PubMed PMC

Cheng CY, Hwang CI, Corney DC, Flesken-Nikitin A, Jiang L, Oner GM et al. miR-34 cooperates with p53 in suppression of prostate cancer by joint regulation of stem cell compartment. Cell Rep 2014; 6: 1000–1007. PubMed PMC

Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 2004; 432: 235–240. PubMed

Gurtner A, Falcone E, Garibaldi F, Piaggio G. Dysregulation of microRNA biogenesis in cancer: the impact of mutant p53 on Drosha complex activity. J Exp Clin Cancer Res 2016; 35: 45. PubMed PMC

Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A. Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell 2010; 39: 373–384. PubMed PMC

Mori M, Triboulet R, Mohseni M, Schlegelmilch K, Shrestha K, Camargo FD et al. Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell 2014; 156: 893–906. PubMed PMC

Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 2010; 467: 986–990. PubMed PMC

Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K. Modulation of microRNA processing by p53. Nature 2009; 460: 529–533. PubMed

Garibaldi F, Falcone E, Trisciuoglio D, Colombo T, Lisek K, Walerych D et al. Mutant p53 inhibits miRNA biogenesis by interfering with the microprocessor complex. Oncogene 2016; 35: 3760–3770. PubMed

Kawai S, Amano A. BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex. J Cell Biol 2012; 197: 201–208. PubMed PMC

Herbert KJ, Cook AL, Snow ET. SIRT1 modulates miRNA processing defects in p53-mutated human keratinocytes. J Dermatol Sci 2014; 74: 142–149. PubMed

Zhao L, Mao Y, Zhao Y, He Y. DDX3X promotes the biogenesis of a subset of miRNAs and the potential roles they played in cancer development. Sci Rep 2016; 6: 32739. PubMed PMC

Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012; 13: 484–492. PubMed

Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet 2013; 14: 204–220. PubMed

Baer C, Claus R, Frenzel LP, Zucknick M, Park YJ, Gu L et al. Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia. Cancer Res 2012; 72: 3775–3785. PubMed

Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Körner H et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle (Georgetown, Tex) 2008; 7: 2591–2600. PubMed

Vogt M, Munding J, Gruner M, Liffers ST, Verdoodt B, Hauk J et al. 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 Arch 2011; 458: 313–322. PubMed

Siemens H, Neumann J, Jackstadt R, Mansmann U, Horst D, Kirchner T et al. Detection of miR-34a promoter methylation in combination with elevated expression of c-Met and beta-catenin predicts distant metastasis of colon cancer. Clin Cancer Res 2013; 19: 710–720. PubMed

Meng F, Glaser SS, Francis H, Yang F, Han Y, Stokes A et al. Epigenetic regulation of miR-34a expression in alcoholic liver injury. Am J Pathol 2012; 181: 804–817. PubMed PMC

Craig VJ, Cogliatti SB, Imig J, Renner C, Neuenschwander S, Rehrauer H et al. Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1. Blood 2011; 117: 6227–6236. PubMed PMC

Dotsch V, Bernassola F, Coutandin D, Candi E, Melino G. p63 and p73, the ancestors of p53. Cold Spring Harb Perspect Biol 2010; 2: a004887. PubMed PMC

Agostini M, Tucci P, Killick R, Candi E, Sayan BS, Rivetti di Val Cervo P et al. Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets. Proc Natl Acad Sci USA 2011; 108: 21093–21098. PubMed PMC

Ahn Y-H, Gibbons DL, Chakravarti D, Creighton CJ, Rizvi ZH, Adams HP et al. ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression. J Clin Invest 2012; 122: 3170–3183. PubMed PMC

Antonini D, Russo MT, De Rosa L, Gorrese M, Del Vecchio L, Missero C. Transcriptional repression of miR-34 family contributes to p63-mediated cell cycle progression in epidermal cells. J Invest Dermatol 2010; 130: 1249–1257. PubMed

Ng WL, Chen G, Wang M, Wang H, Story M, Shay JW et al. OCT4 as a target of miR-34a stimulates p63 but inhibits p53 to promote human cell transformation. Cell Death Dis 2014; 5: e1024. PubMed PMC

Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2011; 140: 883–899. PubMed PMC

Gao F, Liang B, Reddy ST, Farias-Eisner R, Su X. Role of inflammation-associated microenvironment in tumorigenesis and metastasis. Curr Cancer Drug Targets 2014; 14: 30–45. PubMed

Jiang P, Liu R, Zheng Y, Liu X, Chang L, Xiong S et al. MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages. Exp Cell Res 2012; 318: 1175–1184. PubMed

Fan W, Fang R, Wu X, Liu J, Feng M, Dai G et al. Shear-sensitive microRNA-34a modulates flow-dependent regulation of endothelial inflammation. J Cell Sci 2015; 128: 70–80. PubMed

Mathe E, Nguyen GH, Funamizu N, He P, Moake M, Croce CM et al. Inflammation regulates microRNA expression in cooperation with p53 and nitric oxide. Int J Cancer 2012; 131: 760–765. PubMed PMC

Li J, Wang K, Chen X, Meng H, Song M, Wang Y et al. Transcriptional activation of microRNA-34a by NF-kappa B in human esophageal cancer cells. BMC Mol Biol 2012; 13: 4. PubMed PMC

Shin J, Xie D, Zhong XP. MicroRNA-34a enhances T cell activation by targeting diacylglycerol kinase zeta. PLoS ONE 2013; 8: e77983. PubMed PMC

Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S et al. TGF-beta-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 2012; 22: 291–303. PubMed PMC

Hanrahan K, O'Neill A, Prencipe M, Bugler J, Murphy L, Fabre A et al. The role of epithelial-mesenchymal transition drivers ZEB1 and ZEB2 in mediating docetaxel-resistant prostate cancer. Mol Oncol 2017; 11: 251–265. PubMed PMC

Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29: 4741–4751. PubMed PMC

Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S et al. An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell 2011; 22: 1686–1698. PubMed PMC

Dong P, Xiong Y, Watari H, Hanley SJ, Konno Y, Ihira K et al. MiR-137 and miR-34a directly target Snail and inhibit EMT, invasion and sphere-forming ability of ovarian cancer cells. J Exp Clin Cancer Res 2016; 35: 132. PubMed PMC

Du R, Sun W, Xia L, Zhao A, Yu Y, Zhao L et al. Hypoxia-induced down-regulation of microRNA-34a promotes EMT by targeting the Notch signaling pathway in tubular epithelial cells. PLoS ONE 2012; 7: e30771. PubMed PMC

Lu X, Chen Z, Liang H, Li Z, Zou X, Luo H et al. Thyroid hormone inhibits TGFbeta1 induced renal tubular epithelial to mesenchymal transition by increasing miR34a expression. Cell Signal 2013; 25: 1949–1954. PubMed

Hahn S, Jackstadt R, Siemens H, Hunten S, Hermeking H. SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition. EMBO J 2013; 32: 3079–3095. PubMed PMC

Knouf EC, Garg K, Arroyo JD, Correa Y, Sarkar D, Parkin RK et al. An integrative genomic approach identifies p73 and p63 as activators of miR-200 microRNA family transcription. Nucleic Acids Res 2012; 40: 499–510. PubMed PMC

Iqbal N, Mei J, Liu J, Skapek SX. miR-34a is essential for p19(Arf)-driven cell cycle arrest. Cell Cycle 2014; 13: 792–800. PubMed PMC

Christoffersen NR, Shalgi R, Frankel LB, Leucci E, Lees M, Klausen M et al. p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ 2009; 17: 236–245. PubMed

Xu X, Chen W, Miao R, Zhou Y, Wang Z, Zhang L et al. miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway. Oncotarget 2015; 6: 3988–4004. PubMed PMC

Cho CY, Huang JS, Shiah SG, Chung SY, Lay JD, Yang YY et al. Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells. RNA 2016; 22: 303–315. PubMed PMC

Dogar AM, Towbin H, Hall J. Suppression of latent transforming growth factor (TGF)-beta1 restores growth inhibitory TGF-beta signaling through microRNAs. J Biol Chem 2011; 286: 16447–16458. PubMed PMC

Cetinkaya C, Hultquist A, Su Y, Wu S, Bahram F, Pahlman S et al. Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells. Mol Cancer Ther 2007; 6: 2634–2641. PubMed

Peurala H, Greco D, Heikkinen T, Kaur S, Bartkova J, Jamshidi M et al. MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer. PLoS ONE 2011; 6: e26122. PubMed PMC

Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 2008; 40: 43–50. PubMed PMC

Kasinski AL, Slack FJ. miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res 2012; 72: 5576–5587. PubMed PMC

Stahlhut C, Slack FJ. Combinatorial action of MicroRNAs let-7 and miR-34 effectively synergizes with erlotinib to suppress non-small cell lung cancer cell proliferation. Cell Cycle 2015; 14: 2171–2180. PubMed PMC

Zhou JY, Chen X, Zhao J, Bao Z, Zhang P, Liu ZF. MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET. Cancer Lett 2014; 351: 265–271. PubMed

Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 2010; 1805: 105–117. PubMed PMC

Mirchandani D, Zheng J, Miller GJ, Ghosh AK, Shibata DK, Cote RJ et al. Heterogeneity in intratumor distribution of p53 mutations in human prostate cancer. Am J Pathol 1995; 147: 92–101. PubMed PMC

Robbins M, Judge A, Ambegia E, Choi C, Yaworski E, Palmer L et al. Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation. Hum Gene Ther 2008; 19: 991–999. PubMed

Rao DS, O'Connell RM, Chaudhuri AA, Garcia-Flores Y, Geiger TL, Baltimore D. MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1. Immunity 2010; 33: 48–59. PubMed PMC

Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S et al. MicroRNA-34a regulates cardiac ageing and function. Nature 2013; 495: 107–110. PubMed

Shetty SK, Tiwari N, Marudamuthu AS, Puthusseri B, Bhandary YP, Fu J et al. p53 and miR-34a feedback promotes lung epithelial injury and pulmonary fibrosis. Am J Pathol 2017; 187: 1016–1034. PubMed PMC

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