- Open Access
High expression of microRNA-130b correlates with poor prognosis of patients with hepatocellular carcinoma
© Wang et al.; licensee BioMed Central Ltd. 2014
- Received: 10 April 2014
- Accepted: 2 August 2014
- Published: 15 August 2014
Whether microRNA-130b(miR-130b) can serve as a prognostic biomarker of hepatocellular carcinoma (HCC) has not been investigated. In the present study, we investigated the feasibility of miR-130b as a novel prognostic biomarker for HCC.
We retrospectively investigated 97 patients diagnosed with HCC who underwent routine curative surgery between May 2007 and July 2012. miR-130b expression in HCC tissues and paired normal adjacent liver tissues was measured by reverse transcription and real-time PCR (RT-PCR). Survival curves were plotted using the Kaplan-Meier method and differences in survival rates were analyzed using the log-rank test.
miR-130b expression level was significantly higher in HCC tissues compared with normal adjacent liver tissues (P < 0.0001). The 5-year overall survival (OS) of high miR-130b expression group was significantly shorter than that of low miR-130b expression group (43.6% vs. 71.5%; P = 0.022). Moreover, the 5-year disease-free survival (DFS) of high miR-130b expression group was also significantly shorter than that of low miR-130b expression group (25.9% vs. 63.9%; P = 0.012). In a multivariate Cox model, we found that miR-130b expression was an independent prognostic factor for both 5-year OS (hazards ratio [HR] = 2.523, 95% confidence interval [CI] = 1.024-7.901, P = 0.011) and 5-year DFS (HR = 4.003, CI = 1.578-7.899, P = 0.005) in HCC.
The results indicated that high expression of microRNA-130b was correlated with significant characteristics of patients with HCC, and it might be useful as a novel prognostic biomarker for HCC.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_160
- Papillary Thyroid Carcinoma
- Independent Poor Prognostic Factor
- Normal Adjacent Liver Tissue
- Median Relative Expression Level
- Paired Normal Adjacent Liver Tissue
Hepatocellular carcinoma (HCC) is the third most common cause of mortality from cancer worldwide . In China, HCC is the second highest cancer killer since the 1990s, which alone accounts for 53% of all liver cancer deaths worldwide . More than 90% of HCC cases develop in chronically inflamed liver as a result of viral hepatitis, alcohol abuse and in increasing incidence in patients with non-alcoholic fatty liver disease . Although the clinical staging systems for HCC have been used in routine clinical decision making, there is still a need to refine and complement outcome predictions. Modifications of these staging systems by the addition of new biomarkers are likely to improve the prognostic assessment of HCC patients and could therefore fulfill a clinical need -.
MicroRNAs (miRNAs) are endogenously expressed, small interfering RNAs . They are transcribed as precursor molecules that are subsequently processed into the active ~21 nucleotide mature miRNAs. The mature miRNA binds to the 3’untranslated region of the target mRNA through imperfect base pairing, producing translational arrest and/or degradation of the mRNA. A growing number of both direct and indirect evidence suggests a relationship between differential miRNA expression and cancer ,. miR-130b has been found to be deregulated in some types of cancers, including being overexpressed in gastric cancer ,, glioma , and renal cell carcinoma(RCC) , while being downregulated in endometrial cancer  and papillary thyroid carcinoma . Previously, Liu et al. reported that the expression level of miR-130b was upregulated in HCC tissues. Furthermore, circulating miR-130b in serum was a biomarker with clinical value for HCC screening . However, whether miR-130b can serve as a prognostic biomarker of HCC has not been investigated. Therefore, in the present study, we investigated the feasibility of miR-130b as a novel prognostic biomarker for HCC.
Patients and tissue samples
Clinicopathological features and miR-130b expression in HCC
miR-130b expression level
Number of cases
Tumor size (cm)
Isolation of total RNA and real-time PCR analysis
MiR-130b expression level in HCC tissues and paired normal adjacent tissues was measured by reverse transcription and real-time PCR (RT-PCR). Total RNA was isolated from frozen samples using Trizol reagent (Invitrogen, CA, U.S.A.) according to the manufacturer’s protocol. The TaqMan microRNA assay and TaqMan universal PCR master mix were used to detect the expression of miR-130b, and the U6 gene was used as an internal control to normalize variances. Relative quantification of target miRNA expression was evaluated using the comparative cycle threshold (CT) method. Each sample was examined in triplicate and the raw data were presented as the relative quantity of target miRNA, normalized with respect to U6.
The Mann–Whitney test or Kruskal–Wallis was performed to determine the significance of miRNA levels. Survival curves were plotted using the Kaplan-Meier method and differences in survival rates were analyzed using the log-rank test. Prognostic relevance of each variable to overall survival (OS) and disease-free survival (DFS) were analyzed using the Cox regression model. Multivariate analysis of the prognostic factors was performed with Cox regression model. P < 0.05 was considered statistically significant. All statistical calculations were performed using SPSS 18.0 for Windows (SPSS Inc, IL, USA).
miR-130b was significantly upregulated in HCC tissues
Association between miR-130b expression and the clinicopathological features of HCC
For better understanding of the clinical relevance of miR-130b expression in HCC, we divided the 97 HCC patients into a high expression group (n =49) and a low expression group (n =48), according to the median expression level of miR-130b (1.90) in all HCC samples. And, the relationships of the miR-130b with various clinical features of HCC were analyzed and summarized in Table 1. The results revealed that a high level of miR-130b expression was correlated with serum a-fetoprotein (AFP) level (P = 0.04), HBsAg status (P =0.02), tumor size (P = 0.04), high histologic grade (P =0.005), and high TNM stage (p < 0.001). However, there were no significant correlations of miR-130b expression with other clinical features such as gender, age, vein invasion, and tumor number(all P > 0.05).
Prognostic values of miR-130b expression in HCC
Multivariate analysis of the associations of prognosis with various clinicopathologic parameters and miR-130b expression in HCC patients
A growing number of novel treatment strategies have been developed for HCC, including molecular targeted therapy, gene therapy, and immunotherapy. However, satisfactory therapeutic outcomes have not been achieved, and the survival rate of HCC is still low. A complete understanding of the molecular mechanisms underlying tumor initiation and progression is essential for novel prognostic and therapeutic approaches aimed at improving the outcome of patients with HCC. Over the last years, miRNAs are emerging as a new class of gene regulators involved in different malignancies.
The miR-130 family is formed by mature miR-130a and miR-130b that share the same seed sequence and are coded by two independent loci (miRBase Database). miR-130 has been found to linked to mesenchymal differentiation, immune cell function, and hypoxic response modulation . miR-130 has also been validated as a peroxisome proliferator–activated receptor γ (PPARγ) regulator because it suppresses the adipogenic process through the binding to two distinct highly conserved sites located in the coding sequence and 3’UTR of the corresponding mRNA ,. miR-130b has been found to be deregulated in some types of cancers, including being overexpressed in gastric cancer ,, glioma , and RCC , while being downregulated in endometrial cancer  and papillary thyroid carcinoma . For example, Zhao et al. demonstrated that the deregulated expression of miR-130b was associated with poor prognosis and aggressive phenotype of pancreatic cancer, and miR-130b played an important role in the regulation of pancreatic cancer malignant behavior including cell proliferation and invasion by directly targeting STAT3, indicating that miR-130b might be applied as a potential prognostic biomarker and inhibitor in pancreatic cancer . Previously, Liu et al. reported that the expression level of miR-130b was upregulated in HCC tissues. Furthermore, circulating miR-130b in serum was a biomarker with clinical value for HCC screening . However, whether miR-130b can serve as a prognostic biomarker of HCC has not been investigated. Therefore, we investigated the feasibility of miR-130b as a novel prognostic biomarker for HCC.
In the present study, our results showed that miR-130b expression was significantly higher in HCC tissues compared with normal adjacent liver tissues. The relationships of the miR-130b with various clinical features of HCC were analyzed. The results revealed that a high level of miR-130b expression was correlated with serum AFP level, HBsAg status, tumor size, high histologic grade, and high TNM stage, suggesting that miR-130b might be involved in the carcinogenesis and metastasis of HCC. Furthermore, the 5-year OS of high miR-130b expression group was significantly shorter than that of low miR-130b expression group. Moreover, the 5-year DFS of high miR-130b expression group was also significantly shorter than that of low miR-130b expression group. In a multivariate Cox model, we found that miR-130b expression was an independent poor prognostic factor for both 5-year OS and 5-year DFS, indicating that high miR-130b level might be a promising non-invasive biomarker for prognosis of patients with HCC.
In conclusion, we demonstrated that miR-130b was significantly upregulated in HCC and correlated with poorer patients’ prognosis and it might be useful as a prognostic biomarker for HCC.
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61 (2): 69-90. 10.3322/caac.20107.PubMedView ArticleGoogle Scholar
- Pisani P, Parkin DM, Bray F, Ferlay J: Erratum: Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer. 1999, 83: 18-29. 10.1002/(SICI)1097-0215(19990924)83:1<18::AID-IJC5>3.0.CO;2-M.Int J Cancer 1999, 83(6):870–873,PubMedView ArticleGoogle Scholar
- Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA: Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology. 2011, 54 (2): 463-471. 10.1002/hep.24397.PubMedPubMed CentralView ArticleGoogle Scholar
- Su ZX, Zhao J, Rong ZH, Geng WM, Wu YG, Qin CK: Upregulation of microRNA-25 associates with prognosis in hepatocellular carcinoma. Diagn Pathol. 2014, 9: 47-10.1186/1746-1596-9-47.PubMedPubMed CentralView ArticleGoogle Scholar
- Bao YX, Cao Q, Yang Y, Mao R, Xiao L, Zhang H, Zhao HR, Wen H: Expression and prognostic significance of Golgiglycoprotein73 (GP73) with Epithelial-mesenchymal transition (EMT) related molecules in Hepatocellular Carcinoma (HCC). Diagn Pathol. 2013, 8: 197-10.1186/1746-1596-8-197.PubMedPubMed CentralView ArticleGoogle Scholar
- Radwan NA, Ahmed NS: The diagnostic value of arginase-1 immunostaining in differentiating hepatocellular carcinoma from metastatic carcinoma and cholangiocarcinoma as compared to HepPar-1. Diagn Pathol. 2012, 7: 149-10.1186/1746-1596-7-149.PubMedPubMed CentralView ArticleGoogle Scholar
- Guo X, Xiong L, Zou L, Sun T, Zhang J, Li H, Peng R, Zhao J: L1 cell adhesion molecule overexpression in hepatocellular carcinoma associates with advanced tumor progression and poor patient survival. Diagn Pathol. 2012, 7: 96-10.1186/1746-1596-7-96.PubMedPubMed CentralView ArticleGoogle Scholar
- Schmilovitz-Weiss H, Tobar A, Halpern M, Levy I, Shabtai E, Ben-Ari Z: Tissue expression of squamous cellular carcinoma antigen and Ki67 in hepatocellular carcinoma-correlation with prognosis: a historical prospective study. Diagn Pathol. 2011, 6: 121-10.1186/1746-1596-6-121.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhou Y, Zhou N, Fang W, Huo J: Overexpressed HDGF as an independent prognostic factor is involved in poor prognosis in Chinese patients with liver cancer. Diagn Pathol. 2010, 5: 58-10.1186/1746-1596-5-58.PubMedPubMed CentralView ArticleGoogle Scholar
- Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116 (2): 281-297. 10.1016/S0092-8674(04)00045-5.PubMedView ArticleGoogle Scholar
- Fabbri M, Croce CM, Calin GA: MicroRNAs. Cancer J. 2008, 14 (1): 1-6. 10.1097/PPO.0b013e318164145e.PubMedView ArticleGoogle Scholar
- He L, Hannon GJ: MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004, 5 (7): 522-531. 10.1038/nrg1379.PubMedView ArticleGoogle Scholar
- Lai KW, Koh KX, Loh M, Tada K, Subramaniam MM, Lim XY, Vaithilingam A, Salto-Tellez M, Iacopetta B, Ito Y, Soong R: MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer. Eur J Cancer. 2010, 46 (8): 1456-1463. 10.1016/j.ejca.2010.01.036.PubMedView ArticleGoogle Scholar
- Yao Y, Suo AL, Li ZF, Liu LY, Tian T, Ni L, Zhang WG, Nan KJ, Song TS, Huang C: MicroRNA profiling of human gastric cancer. Mol Med Rep. 2009, 2 (6): 963-970.PubMedGoogle Scholar
- Malzkorn B, Wolter M, Liesenberg F, Grzendowski M, Stuhler K, Meyer HE, Reifenberger G: Identification and functional characterization of microRNAs involved in the malignant progression of gliomas. Brain Pathol. 2010, 20 (3): 539-550. 10.1111/j.1750-3639.2009.00328.x.PubMedView ArticleGoogle Scholar
- Wu X, Weng L, Li X, Guo C, Pal SK, Jin JM, Li Y, Nelson RA, Mu B, Onami SH, Wu JJ, Ruel NH, Wilczynski SP, Gao H, Covarrubias M, Figlin RA, Weiss LM, Wu H: Identification of a 4-microRNA signature for clear cell renal cell carcinoma metastasis and prognosis. PLoS One. 2012, 7 (5): e35661-10.1371/journal.pone.0035661.PubMedPubMed CentralView ArticleGoogle Scholar
- Dong P, Karaayvaz M, Jia N, Kaneuchi M, Hamada J, Watari H, Sudo S, Ju J, Sakuragi N: Mutant p53 gain-of-function induces epithelial-mesenchymal transition through modulation of the miR-130b-ZEB1 axis. Oncogene. 2013, 32 (27): 3286-3295. 10.1038/onc.2012.334.PubMedPubMed CentralView ArticleGoogle Scholar
- Yip L, Kelly L, Shuai Y, Armstrong MJ, Nikiforov YE, Carty SE, Nikiforova MN: MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma. Ann Surg Oncol. 2011, 18 (7): 2035-2041. 10.1245/s10434-011-1733-0.PubMedView ArticleGoogle Scholar
- Liu AM, Yao TJ, Wang W, Wong KF, Lee NP, Fan ST, Poon RT, Gao C, Luk JM: Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open. 2012, 2 (2): e000825-PubMedPubMed CentralView ArticleGoogle Scholar
- Lee EK, Lee MJ, Abdelmohsen K, Kim W, Kim MM, Srikantan S, Martindale JL, Hutchison ER, Kim HH, Marasa BS, Selimyan R, Egan JM, Smith SR, Fried SK, Gorospe M: miR-130 suppresses adipogenesis by inhibiting peroxisome proliferator-activated receptor gamma expression. Mol Cell Biol. 2011, 31 (4): 626-638. 10.1128/MCB.00894-10.PubMedPubMed CentralView ArticleGoogle Scholar
- Lehrke M, Pascual G, Glass CK, Lazar MA: Gaining weight: the Keystone Symposium on PPAR and LXR. Genes Dev. 2005, 19 (15): 1737-1742. 10.1101/gad.1341005.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhao G, Zhang JG, Shi Y, Qin Q, Liu Y, Wang B, Tian K, Deng SC, Li X, Zhu S, Gong Q, Niu Y, Wang CY: MiR-130b is a prognostic marker and inhibits cell proliferation and invasion in pancreatic cancer through targeting STAT3. PLoS One. 2013, 8 (9): e73803-10.1371/journal.pone.0073803.PubMedPubMed CentralView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.