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MiR-424-5p reversed epithelial-mesenchymal transition of anchorage-independent HCC cells by directly targeting ICAT and suppressed HCC progression.

Zhang Y, Li T, Guo P, Kang J, Wei Q, Jia X, Zhao W, Huai W, Qiu Y, Sun L, Han L - Sci Rep (2014)

Bottom Line: Microarray expression profiling revealed that expression of miR-424-5p was significantly decreased in anoikis-resistant HCC cells.Clinical investigation demonstrated that miR-424-5p was significantly downregulated in HCC tissues compared with that of the non-cancerous liver tissues, and this decreased expression of miR-424-5p was significantly correlated with higher pathological grades and more advanced TNM stages.Therefore, aberrant expression of miR-424-5p is critically involved in resistance to anoikis and EMT during the metastatic process of HCC, and its downregulation significantly contributes to liver cancer progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, China.

ABSTRACT
Resistance to anoikis and Epithelial-mesenchymal transition (EMT) are two processes critically involved in cancer metastasis. In this study, we demonstrated that after anchorage deprival, hepatocellular carcinoma (HCC) cells not only resisted anoikis, but also exhibited EMT process. Microarray expression profiling revealed that expression of miR-424-5p was significantly decreased in anoikis-resistant HCC cells. Ectopic overexpression of miR-424-5p was sufficient to reverse resistance to anoikis, block EMT process and inhibit malignant behaviors of HCC cells. Target analysis showed that a potent β-catenin inhibitor, ICAT/CTNNBIP1 was a direct target of miR-424-5p. Further study demonstrated that miR-424-5p reversed resistance to anoikis and EMT of HCCs by directly targeting ICAT and further maintaining the E-cadherin/β-catanin complex on the cellular membrance. In vivo study further demonstrated that miR-424-5p significantly inhibited the tumorigenicity of HCC cells in nude mice. Clinical investigation demonstrated that miR-424-5p was significantly downregulated in HCC tissues compared with that of the non-cancerous liver tissues, and this decreased expression of miR-424-5p was significantly correlated with higher pathological grades and more advanced TNM stages. Therefore, aberrant expression of miR-424-5p is critically involved in resistance to anoikis and EMT during the metastatic process of HCC, and its downregulation significantly contributes to liver cancer progression.

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Clinical investigation of miR-424-5p in the liver cancer tissues and sera samples from HCC patients.(a–b) The expression of miR-424-5p (a) and ICAT (b) in HCC tissues and corresponding non-cancerous liver tissues were determined by real-time PCR. (c–d) Correlation between the expression of miR-424-5p and ICAT in both cancer tissues(d) and non-cancerous tissues (d) were analyzed by Spearman correlation analysis. (e–f) Expression of miR-424-5p(e) and ICAT(f) in metastatic HCC tissues and non-metastatic HCC tissues were determined by real-time PCR. (g–h) Correlation between the expression of miR-424-5p (g) and ICAT (h) in metastatic HCC tissues and non-metastatic tissues were analyzed. (i) miR-424-5p expression in the sera from metastatic HCC patients, non-metastatic HCC patients and healthy controls were analyzed by real-time PCR. (j) In those patients whose sera and liver tissue specimen were both available, expression of miR-424-5p in both the sera and liver tissues were detected; and the correlation of miR-424-5p expression in sera and that in liver tissues were further analyzed. *P<0.05, **P<0.01,***P<0.001.
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f8: Clinical investigation of miR-424-5p in the liver cancer tissues and sera samples from HCC patients.(a–b) The expression of miR-424-5p (a) and ICAT (b) in HCC tissues and corresponding non-cancerous liver tissues were determined by real-time PCR. (c–d) Correlation between the expression of miR-424-5p and ICAT in both cancer tissues(d) and non-cancerous tissues (d) were analyzed by Spearman correlation analysis. (e–f) Expression of miR-424-5p(e) and ICAT(f) in metastatic HCC tissues and non-metastatic HCC tissues were determined by real-time PCR. (g–h) Correlation between the expression of miR-424-5p (g) and ICAT (h) in metastatic HCC tissues and non-metastatic tissues were analyzed. (i) miR-424-5p expression in the sera from metastatic HCC patients, non-metastatic HCC patients and healthy controls were analyzed by real-time PCR. (j) In those patients whose sera and liver tissue specimen were both available, expression of miR-424-5p in both the sera and liver tissues were detected; and the correlation of miR-424-5p expression in sera and that in liver tissues were further analyzed. *P<0.05, **P<0.01,***P<0.001.

Mentions: To investigate the role of miR-424-5p in HCC patients, we analyzed the association between miR-424-5p expression and clinical pathological features of hepatocacinoma patients. Our data showed that miR-424-5p expression was significantly reduced in the liver cancer tissues compared with that of the corresponding non-cancerous liver tissues (Fig. 8a); while the expression of ICAT was significantly upregulated in cancer tissue compared with that of the non-cancerous liver tissues (Fig. 8b). Spearman Correlation analysis showed that in both cancer tissues and non-cancerous liver tissues, expression of miR-424-5p was negatively correlated with expression of ICAT (Fig. 8c–d). Because EMT process is tightly linked with metastasis, expression of miR-424-5p and ICAT was also investigated in the HCC tissues from metastatic patients and non-metastatic patients. Our data showed that miR-424-5p was significantly downregulated while ICAT was significantly upregulated in the HCC tissues from metastatic patients compared with those from non-metastatic patients (Fig. 8e–f). Expression of miR-424-5p and ICAT was significantly negatively correlated in HCC tissues from both metastatic patients and non-metastatic patients (Fig. 8g–h). Statistical analysis showed that the more advanced HCC patients usually have lower miR-424-5p expression (Table 1). In addition, the expression of miR-424-5p was positively correlated with epithelial markers including E-cadherin and β-catenin while negatively correlated with ICAT expression (Table 2). These data further demonstrated that loss of miR-424-5p expression contributed to EMT related behaviors of HCC cells, probably through decreasing ICAT expression.


MiR-424-5p reversed epithelial-mesenchymal transition of anchorage-independent HCC cells by directly targeting ICAT and suppressed HCC progression.

Zhang Y, Li T, Guo P, Kang J, Wei Q, Jia X, Zhao W, Huai W, Qiu Y, Sun L, Han L - Sci Rep (2014)

Clinical investigation of miR-424-5p in the liver cancer tissues and sera samples from HCC patients.(a–b) The expression of miR-424-5p (a) and ICAT (b) in HCC tissues and corresponding non-cancerous liver tissues were determined by real-time PCR. (c–d) Correlation between the expression of miR-424-5p and ICAT in both cancer tissues(d) and non-cancerous tissues (d) were analyzed by Spearman correlation analysis. (e–f) Expression of miR-424-5p(e) and ICAT(f) in metastatic HCC tissues and non-metastatic HCC tissues were determined by real-time PCR. (g–h) Correlation between the expression of miR-424-5p (g) and ICAT (h) in metastatic HCC tissues and non-metastatic tissues were analyzed. (i) miR-424-5p expression in the sera from metastatic HCC patients, non-metastatic HCC patients and healthy controls were analyzed by real-time PCR. (j) In those patients whose sera and liver tissue specimen were both available, expression of miR-424-5p in both the sera and liver tissues were detected; and the correlation of miR-424-5p expression in sera and that in liver tissues were further analyzed. *P<0.05, **P<0.01,***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4150107&req=5

f8: Clinical investigation of miR-424-5p in the liver cancer tissues and sera samples from HCC patients.(a–b) The expression of miR-424-5p (a) and ICAT (b) in HCC tissues and corresponding non-cancerous liver tissues were determined by real-time PCR. (c–d) Correlation between the expression of miR-424-5p and ICAT in both cancer tissues(d) and non-cancerous tissues (d) were analyzed by Spearman correlation analysis. (e–f) Expression of miR-424-5p(e) and ICAT(f) in metastatic HCC tissues and non-metastatic HCC tissues were determined by real-time PCR. (g–h) Correlation between the expression of miR-424-5p (g) and ICAT (h) in metastatic HCC tissues and non-metastatic tissues were analyzed. (i) miR-424-5p expression in the sera from metastatic HCC patients, non-metastatic HCC patients and healthy controls were analyzed by real-time PCR. (j) In those patients whose sera and liver tissue specimen were both available, expression of miR-424-5p in both the sera and liver tissues were detected; and the correlation of miR-424-5p expression in sera and that in liver tissues were further analyzed. *P<0.05, **P<0.01,***P<0.001.
Mentions: To investigate the role of miR-424-5p in HCC patients, we analyzed the association between miR-424-5p expression and clinical pathological features of hepatocacinoma patients. Our data showed that miR-424-5p expression was significantly reduced in the liver cancer tissues compared with that of the corresponding non-cancerous liver tissues (Fig. 8a); while the expression of ICAT was significantly upregulated in cancer tissue compared with that of the non-cancerous liver tissues (Fig. 8b). Spearman Correlation analysis showed that in both cancer tissues and non-cancerous liver tissues, expression of miR-424-5p was negatively correlated with expression of ICAT (Fig. 8c–d). Because EMT process is tightly linked with metastasis, expression of miR-424-5p and ICAT was also investigated in the HCC tissues from metastatic patients and non-metastatic patients. Our data showed that miR-424-5p was significantly downregulated while ICAT was significantly upregulated in the HCC tissues from metastatic patients compared with those from non-metastatic patients (Fig. 8e–f). Expression of miR-424-5p and ICAT was significantly negatively correlated in HCC tissues from both metastatic patients and non-metastatic patients (Fig. 8g–h). Statistical analysis showed that the more advanced HCC patients usually have lower miR-424-5p expression (Table 1). In addition, the expression of miR-424-5p was positively correlated with epithelial markers including E-cadherin and β-catenin while negatively correlated with ICAT expression (Table 2). These data further demonstrated that loss of miR-424-5p expression contributed to EMT related behaviors of HCC cells, probably through decreasing ICAT expression.

Bottom Line: Microarray expression profiling revealed that expression of miR-424-5p was significantly decreased in anoikis-resistant HCC cells.Clinical investigation demonstrated that miR-424-5p was significantly downregulated in HCC tissues compared with that of the non-cancerous liver tissues, and this decreased expression of miR-424-5p was significantly correlated with higher pathological grades and more advanced TNM stages.Therefore, aberrant expression of miR-424-5p is critically involved in resistance to anoikis and EMT during the metastatic process of HCC, and its downregulation significantly contributes to liver cancer progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, China.

ABSTRACT
Resistance to anoikis and Epithelial-mesenchymal transition (EMT) are two processes critically involved in cancer metastasis. In this study, we demonstrated that after anchorage deprival, hepatocellular carcinoma (HCC) cells not only resisted anoikis, but also exhibited EMT process. Microarray expression profiling revealed that expression of miR-424-5p was significantly decreased in anoikis-resistant HCC cells. Ectopic overexpression of miR-424-5p was sufficient to reverse resistance to anoikis, block EMT process and inhibit malignant behaviors of HCC cells. Target analysis showed that a potent β-catenin inhibitor, ICAT/CTNNBIP1 was a direct target of miR-424-5p. Further study demonstrated that miR-424-5p reversed resistance to anoikis and EMT of HCCs by directly targeting ICAT and further maintaining the E-cadherin/β-catanin complex on the cellular membrance. In vivo study further demonstrated that miR-424-5p significantly inhibited the tumorigenicity of HCC cells in nude mice. Clinical investigation demonstrated that miR-424-5p was significantly downregulated in HCC tissues compared with that of the non-cancerous liver tissues, and this decreased expression of miR-424-5p was significantly correlated with higher pathological grades and more advanced TNM stages. Therefore, aberrant expression of miR-424-5p is critically involved in resistance to anoikis and EMT during the metastatic process of HCC, and its downregulation significantly contributes to liver cancer progression.

Show MeSH
Related in: MedlinePlus