Abstract
The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly associated with tumor recurrence. So far, no tissue biomarker of recurrence has been confirmed in biopsy specimens. Previous studies have reported that aberrant expression of microRNA-34a (miR-34a) is involved in oncogenesis and progression of HCC. The aim of this study was to investigate the prognostic value of tissue miR-34a expression in patients with HCC treated with RFA. Patients with early-stage single-nodule HCC treated with RFA were included, and tissue expression of miR-34a were assessed by quantitative reverse-transcription polymerase chain reaction. Main clinical endpoints were overall and early recurrence. The Kaplan-Meier method was used to plot recurrence curves and univariable and multivariable Cox regression analyses were performed to assess independent predictive factors for recurrence. Of 120 patients, recurrence occurred in 67 patients (55.8 %) with a median follow-up of 31 months. Forty-one patients (34.2 %) recurred within 2 years after RFA. The median miR-34a level was 0.87 (range 0.06–21.54). Low miR-34a level was associated with larger tumor size (P = 0.033) and higher serum alpha-fetoprotein (AFP) level (P = 0.004). When analyzed with a Cox regression model, the two independent predictive factors for overall recurrence were high serum AFP level (hazard ratio [HR] = 1.21; 95 % confidence interval [CI] = 1.04–1.36; P = 0.039) and low miR-34a level (HR = 1.44; 95 % CI = 1.13–1.72; P = 0.011). The expression of miR-34a was also an independent predictive factor for early recurrence (HR = 1.49; 95 % CI = 1.15–1.79; P = 0.008). Taken together, this study suggests that the expression of miR-34a in HCC biopsy specimens has an independent predictive value of early recurrence after RFA.
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References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
Huang J, Yan L, Cheng Z, Wu H, Du L, Wang J, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg. 2010;252:903–12.
Llovet JM, Ducreux M, Lencioni R, Di Bisceglie AM, Galle PR, Dufour JF, et al. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.
Shiina S, Tateishi R, Arano T, Uchino K, Enooku K, Nakagawa H, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol. 2012;107:569–77.
Cho YK, Rhim H, Noh S. Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: a systematic review. J Gastroenterol Hepatol. 2011;26:1354–60.
Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–7.
Kumada T, Nakano S, Takeda I, Sugiyama K, Osada T, Kiriyama S, et al. Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology. 1997;25:87–92.
Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30:1434–40.
Roayaie S, Blume IN, Thung SN, Guido M, Fiel MI, Hiotis S, et al. A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma. Gastroenterology. 2009;137:850–5.
Ishizawa T, Hasegawa K, Aoki T, Takahashi M, Inoue Y, Sano K, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology. 2008;134:1908–16.
Hummel R, Hussey DJ, Haier J. MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer. 2010;46:298–311.
Bader AG. miR-34—a microRNA replacement therapy is headed to the clinic. Front Genet. 2012;3:120.
Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A. 2010;107:264–9.
Dang Y, Luo D, Rong M, Chen G. Underexpression of miR-34a in hepatocellular carcinoma and its contribution towards enhancement of proliferating inhibitory effects of agents targeting c-MET. PLoS One. 2013;8:e61054.
Tryndyak VP, Ross SA, Beland FA, Pogribny IP. Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet. Mol Carcinog. 2009;48:479–87.
Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y, et al. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett. 2009;275:44–53.
Lou W, Chen Q, Ma L, Liu J, Yang Z, Shen J, et al. Oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in experimental tumor model. J Mol Med (Berl). 2013;91:715–25.
Zhao J, Kelnar K, Bader AG. In-depth analysis shows synergy between erlotinib and miR-34a. PLoS One. 2014;9:e89105.
Kelnar K, Peltier HJ, Leatherbury N, Stoudemire J, Bader AG. Quantification of therapeutic miRNA mimics in whole blood from nonhuman primates. Anal Chem. 2014;86:1534–42.
Yang F, Li QJ, Gong ZB, Zhou L, You N, Wang S, et al. MicroRNA-34a targets Bcl-2 and sensitizes human hepatocellular carcinoma cells to sorafenib treatment. Technol Cancer Res Treat. 2014;13:77–86.
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This work was supported by a grant from the Postdoctoral Science Foundation of China (No. 20100471534).
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Cui, X., Wu, Y., Wang, Z. et al. MicroRNA-34a expression is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma. Tumor Biol. 36, 3887–3893 (2015). https://doi.org/10.1007/s13277-014-3031-5
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DOI: https://doi.org/10.1007/s13277-014-3031-5