microRNAs: New ways to block tumor angiogenesis?
Authors: Sara Toffanin, Daniela Sia, Augusto Villanueva
Journal: Journal of Hepatology (2012)

MicroRNA-214 downregulation contributes to tumor angiogenesis by inducing secretion of the hepatoma-derived growth factor in human hepatomaJournal of HepatologyVol. 57Issue 3PreviewUnusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Although microRNA-214 (miR-214) is upregulated in other human cancers, it is downregulated in HCC. We elucidated the biological and clinical significance of miR-214 downregulation in HCC. Full-Text PDF One of the molecular hallmarks of hepatocellular carcinoma (HCC) is its high vascularization, and as such, one of the most appealing putative targets for anticancer therapies. HCC growth largely depends on its ability to form new vessels (angiogenesis), which guarantee supplying malignant cells with the oxygen and nutrients needed for unrestricted proliferation [[1]Zhu A.X. Duda D.G. Sahani D.V. Jain R.K. HCC and angiogenesis: possible targets and future directions.Nat Rev Clin Oncol. 2011; 8: 292-301Crossref PubMed Scopus (422) Google Scholar]. The activation of angiogenesis will ultimately lead to the invasion of tumor cells into the new vessels and their metastatic spread. Several molecules, mainly VEGF family members, produced by tumor cells and cells within the microenvironment, orchestrate the recruitment, activation, and organization of endothelial cells into a complex architectural structure that constitutes the tumor vascular system. This process requires several steps and molecular mediators. However, even when the understanding of tumoral angiogenesis has dramatically increased and numerous drugs are currently available in the clinical setting [[2]Villanueva A. Llovet J.M. Targeted therapies for hepatocellular carcinoma.Gastroenterology. 2011; 140: 1410-1426Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar], the mechanisms involved in this process have not been completely understood. In this issue of the Journal of Hepatology, Tsung-Chieh et al. provide new evidence linking microRNA (miRNA) expression and angiogenesis in HCC [[3]Shih T.C. Tien Y.J. Wen C.J. Yeh T.S. Yu M.C. Huang C.H. et al.MicroRNA-214 downregulation contributes to tumor angiogenesis via inducing secretion of hepatoma-derived growth factor in human hepatoma.J Hepatol. 2012; 57: 584-591Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]. miRNAs, crucial regulators of gene expression at the post-transcriptional level, have been shown to participate in many biological events at both physiological and pathological levels. They are involved in HCC pathogenesis, and their expression profiles have been used to identify HCC subclasses [[4]Toffanin S. Hoshida Y. Lachenmayer A. Villanueva A. Cabellos L. Minguez B. et al.MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a.Gastroenterology. 2011; 140 (1618–28.e16)Abstract Full Text Full Text PDF Scopus (198) Google Scholar]. A potential role of miRNA in angiogenesis has already been suggested. A previous study showed that miR-107 inhibited HIF-1β expression following hypoxia-induced activation of p53 [[5]Yamakuchi M. Lotterman C.D. Bao C. Hruban R.H. Karim B. Mendell J.T. et al.P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis.Proc Natl Acad Sci U S A. 2010; 107: 6334-6339Crossref PubMed Scopus (357) Google Scholar] and its overexpression in colon cancer cells inhibited angiogenesis and tumor growth in mice. Other examples are miR-15b and miR-16, which have been shown to control the expression of VEGF, a key pro-angiogenic factor particularly involved in tumor angiogenesis [[6]Cimmino A. Calin G.A. Fabbri M. Iorio M.V. Ferracin M. Shimizu M. et al.MiR-15 and miR-16 induce apoptosis by targeting BCL2.Proc Natl Acad Sci U S A. 2005; 102: 13944-13949Crossref PubMed Scopus (3047) Google Scholar]. In HCC, downregulation of miR-29b and miR-125b has been related to increased angiogenesis through regulation of matrix metalloproteinase 2 (MMP2) and placenta-growth factor (PGF), respectively [7Alpini G. Glaser S.S. Zhang J.P. Francis H. Han Y. Gong J. et al.Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer.J Hepatol. 2011; 55: 1339-1345Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 8Fang J.H. Zhou H.C. Zeng C. Yang J. Liu Y. Huang X. et al.MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression.Hepatology. 2011; 54: 1729-1740Crossref PubMed Scopus (256) Google Scholar]. The study by Tsung-Chieh et al. found a crosstalk between miR-214 and the hepatoma-derived growth factor (HDGF), a promoter of tumor angiogenesis. Also, ectopic expression of miR-214 suppressed tumor growth in a xenograft model of HCC as well as microvascularity density in tumors and surrounding liver tissues via HDGF secretion [[3]Shih T.C. Tien Y.J. Wen C.J. Yeh T.S. Yu M.C. Huang C.H. et al.MicroRNA-214 downregulation contributes to tumor angiogenesis via inducing secretion of hepatoma-derived growth factor in human hepatoma.J Hepatol. 2012; 57: 584-591Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]. However, the role of miR-214 in tumorigenesis is still controversial. Overexpression of miR-214 has been reported in several tumors including lung and gastric cancers while its downregulation has been shown in cervical cancer and intrahepatic cholangiocarcinoma [9Penna E. Orso F. Cimino D. Tenaglia E. Lembo A. Quaglino E. et al.MicroRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C.EMBO J. 2011; 30: 1990-2007Crossref PubMed Scopus (223) Google Scholar, 10Ueda T. Volinia S. Okumura H. Shimizu M. Taccioli C. Rossi S. et al.Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis.Lancet Oncol. 2010; 11: 136-146Abstract Full Text Full Text PDF PubMed Scopus (738) Google Scholar]. Inhibition of miR-214 resulted in enhanced proliferation, migration, and aggressiveness in an experimental model of intrahepatic cholangiocarcinoma due to upregulation of Twist, an important mediator of epithelial–mesenchymal transition (EMT). These discrepancies may be partially explained by the functional tissue-specificity of miR-214. This context-dependency has been shown for other miRNAs such as miR-29a that functions as a tumor suppressor in chronic lymphocytic leukemia and lung cancer and as an oncogene in breast cancer [[11]Gebeshuber C.A. Zatloukal K. Martinez J. MiR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis.EMBO Rep. 2009; 10: 400-405Crossref PubMed Scopus (348) Google Scholar]. The Food and Drug Administration (FDA) has approved different anti-angiogenetic agents for the treatment of human malignancies, including monoclonal antibodies (e.g. bevacizumab) and tyrosine kinase inhibitors (e.g. sunitinib, sorafenib) [[1]Zhu A.X. Duda D.G. Sahani D.V. Jain R.K. HCC and angiogenesis: possible targets and future directions.Nat Rev Clin Oncol. 2011; 8: 292-301Crossref PubMed Scopus (422) Google Scholar]. In HCC, sorafenib is the only systemic agent approved for patients at advanced stages [[12]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (9241) Google Scholar], and it has an anti-angiogenic activity derived from its ability to block VEGFR2 and PDGFR2. Other anti-angiogenics (e.g. linifanib, cediranib) are in clinical trials, although their approval might be jeopardized by toxicity, a true bottleneck for systemic drugs in patients with underlying liver damage. For example, a phase III trial evaluating sunitinib, an anti-angiogenic drug approved in renal cancer, was prematurely stopped due to adverse effects and futility [[13]Villanueva A. Llovet J.M. Second-line therapies in hepatocellular carcinoma: emergence of resistance to sorafenib.Clin Cancer Res. 2012; 18: 1824-1826Crossref PubMed Scopus (86) Google Scholar]. Also, a phase II trial study with cediranib in advanced HCC patients was discontinued because of the appearance of grade 3 toxicities in almost all patients (93%) [[14]Alberts SR, Fitch TR, Kim GP, Morlan BW, Dakhil SR, Gross HM, et al. Cediranib (AZD2171) in patients with advanced hepatocellular carcinoma: a phase II North Central Cancer Treatment Group Clinical Trial. Am J Clin Oncol 2011.Google Scholar]. Unfortunately, a significant number of patients treated with anti-angiogenic therapies end up developing resistance, with molecular mechanisms not yet entirely understood. Several hypotheses have been proposed, including revascularization due to VEGF-independent mechanisms [[15]Rubenstein J.L. Kim J. Ozawa T. Zhang M. Westphal M. Deen D.F. et al.Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption.Neoplasia. 2000; 2: 306-314Abstract Full Text PDF PubMed Scopus (441) Google Scholar]. As the evidence supporting an active role of miRNAs in angiogenesis is increasing, we need to speculate about how to translate this knowledge into improvement in HCC management. Targeting the miR-214/HDGF axis could provide additional anti-angiogenic benefits or show rescue potential in those patients resistant to VEGF-based therapies. Notably, in the study by Tsung-Chieh et al., the authors did not find any correlation between miRNA-214 and VEGF, suggesting that miR-214 could regulate angiogenesis independently of VEGF. Strategies modulating the expression of specific miRNAs have been developed and are under investigation. Recent data from a phase II clinical trial evaluating the safety and efficacy of Miravirsen, the first miRNA-targeted drug entering clinical trials in patients with hepatitis C (HCV), showed targeted-specific inhibition of miR-122 (a miRNA essential for HCV replication) and an acceptable tolerability profile [[16]Janssen H.L. Reesink H.W. Zeuzem S. Lawitz E. Rodriguez-Torres M. Chen A. et al.A randomized, double-blind, placebo (PLB) controlled safety and anti-viral proof of concept study of miravirsen (MIR), an oligonucleotide targeting miR-122, in treatment naive patients with genotype 1 (GT1) chronic HCV infection.Hepatology. 2011; 54 ([abstract LB-6]): 1430AGoogle Scholar]. However, there are no clinical trials currently testing miRNA-based reagents in patients with HCC. At the preclinical level, a previous study showed that restoring the expression of miR-26 using gene-therapy had dramatic effects in terms of tumor growth inhibition in a mouse model of HCC, without remarkable toxicity [[17]Kota J. Chivukula R.R. O’Donnell K.A. Wentzel E.A. Montgomery C.L. Hwang H.W. et al.Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model.Cell. 2009; 137: 1005-1017Abstract Full Text Full Text PDF PubMed Scopus (1509) Google Scholar]. These findings certainly show that modulating miRNA expression could be a promising strategy, even though further evidence is still needed. The second aspect that will require further evaluation relates to the lack of validated biomarkers for appropriate selection of ideal candidates to receive anti-angiogenic therapies or to anticipate resistance to VEGF-based inhibitors. In this context, the use of miRNA as prognostic biomarkers is promising, as demonstrated by the study from Ji et al., in which the expression of miR-26 was an independent predictor of survival in HCC resected patients, and identified those with a better response to interferon therapy [[18]Ji J. Shi J. Budhu A. Yu Z Forgues M. Roessler S. et al.MicroRNA expression, survival, and response to interferon in liver cancer.N Engl J Med. 2009; 361: 1437-1447Crossref PubMed Scopus (732) Google Scholar]. In conclusion, miRNAs have emerged as a novel source of potential anti-angiogenic therapies in HCC. Issues related to toxicity and off-target effects need to be considered, being still unclear whether they will end up having a role in the management of this disease. Certainly, miRNA-based anti-angiogenics could become an alternative to those patients that progress after VEGF antagonism. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.