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. 2015:2015:649750.
doi: 10.1155/2015/649750. Epub 2015 Feb 25.

Investigating the pretreatment miRNA expression patterns of advanced hepatocellular carcinoma patients in association with response to TACE treatment

Medhat S El-Halawany  1 , Heba M Ismail  2 , Ahmed A Zeeneldin  3 , Ammar Elfiky  2 , Marwa Tantawy  4 , Mohamed H Kobaisi  5 , Ikram Hamed  6 , Abdel Hady A Abdel Wahab  2
Affiliations

Investigating the pretreatment miRNA expression patterns of advanced hepatocellular carcinoma patients in association with response to TACE treatment

Medhat S El-Halawany et al. Biomed Res Int. 2015.

Abstract

Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis and limited treatment options. Transarterial chemoembolization (TACE) using chemotherapy agents-doxorubicin and cisplatin-is an accepted treatment option for locally advanced hepatocellular carcinoma. In the current study, we analyzed the expression pattern of a selected panel of 94 miRNAs in archival samples that were collected prior to treatment from 15 Egyptian patients diagnosed with advanced hepatocelleular carcinoma. We observed an overall increase in miRNA expression in HCC samples compared with normal subjects. Out of 94 examined miRNAs, 53 were significantly upregulated while 3 miRNAs were downregulated in HCC samples compared to normal liver samples. Comparing the pretreatment miRNA expression profiles in HCC patients and the patients response to TACE treatment resulted in the identification of a set of 12 miRNAs that are significantly upregulated in nonresponders group. This miRNA panel includes miR-10a-1, miR-23a-1, miR-24, miR-26a, miR-27a, miR-30c, miR-30e, miR-106b, miR-133b, miR-199a, miR-199-3p, and miR-200b. Furthermore, we observed that a panel of 10 miRNAs was significantly associated with patients' survival status at 1 year. These results highlight the potential implications of pretreatment miRNAs expression profiling in prediction of the patients' response to TACE treatment in liver cancer.

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Figures

Figure 1
Figure 1
Profiling of 94 miRNA expression patterns in advanced HCC Egyptian patients compared to normal subjects. Expression of 94 miRNAs was determined by real-time PCR in specimens of normal controls (n = 10) and HCC patients (n = 15). (a) Heatmap of expression profile of 94 miRNAs in HCC patients (P1–P15) and normal donors (N1–N6). (b) Volcano plot of relative gene expression fold of change of the 93 miRNA versus P value. Fold of change is represented in log2 ratio in the x-axis versus P value represented in log10 ratio in the y-axis.
Figure 2
Figure 2
Comparison of miRNA profiles significantly deregulated in our study with published HCC studies. Boxplots of mean miRNA expression after control-based normalization are shown in all panels. Black bars indicate the median. * P < 0.05, ** P < 0.01, and *** P < 0.001 are based on nonparametric Mann-Whitney tests comparing between miRNA expression levels in normal and tumours. (a) miRNA regulated in our study but not reported in other HCC studies. (b) miRNAs upregulated in our study and upregulated in other HCC studies. (c) miRNAs upregulated in our study and downregulated in other HCC studies.
Figure 3
Figure 3
Upregulation of 12 miRNAs panel is significantly associated with patients' poor response to TACE treatment. Expression of miRNAs was determined by real-time PCR in HCC patients. Expression profiles were normalized against normal controls. log2 fold of change of miRNA was compared in TACE treatments responders versus nonresponders. (a) Graph shows 12 miRNA that were significantly deregulated in response to treatment. (b) Heatmap of expression profile of 12 miRNAs in TACE responders (n = 5) versus TACE nonresponders (n = 10). (c) Hierarchical clustering (Pearson correlation, average linkage) of the 12 altered miRNAs in responders and nonresponders groups. Heatmap colors represent relative miRNA expression as indicated in the color key. * P < 0.05 and ** P < 0.01 are based on nonparametric Mann-Whitney tests comparing between miRNA expression levels in responders and nonresponders.
Figure 4
Figure 4
miRNA expression profile associated with patients' survival status at 1 year. Expression of miRNAs was determined by real-time PCR in HCC patients. Expression profiles were normalized against normal controls. Log2 fold of change of miRNA was compared in HCC patients at one year of survival. (a) Graph shows 10 miRNAs that were significantly deregulated in association with survival status of patients at one year. (b) Heatmap of expression profile of 10 miRNAs in (a). (c) Hierarchical clustering with the 10 altered miRNAs showed a clear separation between alive and dead groups.
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