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MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer.

Kim HS, Lee KS, Bae HJ, Eun JW, Shen Q, Park SJ, Shin WC, Yang HD, Park M, Park WS, Kang YK, Nam SW - Oncotarget (2015)

Bottom Line: MiR-31 expression was down-regulated in a large cohort of hepatocellular carcinoma (HCC) patients, and low expression of miR-31 was significantly associated with poor prognosis of HCC patients.We also found that ectopic expression of miR-31 mimics reduced metastatic potential of HCC cells by selectively regulating epithelial-mesenchymal transition (EMT) regulatory proteins such as N-cadherin, E-cadherin, vimentin and fibronectin.HCC tissues derived from chemical-induced rat liver cancer models validated that miR-31 expression is significantly down-regulated, and that those cell cycle- and EMT-regulatory proteins are deregulated in rat liver cancer.

View Article: PubMed Central - PubMed

Affiliation: Lab of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

ABSTRACT
MicroRNA-31 (miR-31) is among the most frequently altered microRNAs in human cancers and altered expression of miR-31 has been detected in a large variety of tumor types, but the functional role of miR-31 still hold both tumor suppressive and oncogenic roles in different tumor types. MiR-31 expression was down-regulated in a large cohort of hepatocellular carcinoma (HCC) patients, and low expression of miR-31 was significantly associated with poor prognosis of HCC patients. Ectopic expression of miR-31 mimics suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. Additional study evidenced miR-31 directly to suppress HDAC2 and CDK2 expression by inhibiting mRNA translation in HCC cells. We also found that ectopic expression of miR-31 mimics reduced metastatic potential of HCC cells by selectively regulating epithelial-mesenchymal transition (EMT) regulatory proteins such as N-cadherin, E-cadherin, vimentin and fibronectin. HCC tissues derived from chemical-induced rat liver cancer models validated that miR-31 expression is significantly down-regulated, and that those cell cycle- and EMT-regulatory proteins are deregulated in rat liver cancer. Overall, we suggest that miR-31 functions as a tumor suppressor by selectively regulating cell cycle and EMT regulatory proteins in human hepatocarcinogenesis providing a novel target for the molecular treatment of liver malignancies.

No MeSH data available.


Related in: MedlinePlus

MiR-31 is down-regulated in hepatocellular carcinoma(A) Recapitulated miRNA expression levels of the large cohort of HCC patients. The miRNA microarray data were obtained from NCBI, GEO database (Accession No: GSE21362 and GSE39678). The miRNA expression of HCC patients were illustrated by scatter plots. The median expression is indicated by horizontal line. The microRNA expression levels are shown on the y axis (log2 intensity, *P<0.05; **P<0.005; ***P<0.001, Student's t test) (TG1; Edmonson grade I, TG2; Edmonson grade II, TG3; Edmonson grade III) (B) Kaplan-Meier survival curve of the GSE31384 dataset. The five year survival rate was significantly decreased in patient with low level of miR-31 expression in the tumor tissues (Log-rank P = 0.0015*) (C) The qRT-PCR analysis for 9 paired HCC tissues. MiR-31 was significantly down-regulated compared to corresponding non-tumor tissue. The expression of miR-31 was normalized to U6 snRNA (*P<0.05; **P<0.005, Student's t test) (D) The qRT-PCR analysis of miR-31 for hepatocellular carcinoma cell lines (n=7) and liver normal cell lines (n=2) (**P<0.005; ***P<0.001, Student's t test).
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Figure 1: MiR-31 is down-regulated in hepatocellular carcinoma(A) Recapitulated miRNA expression levels of the large cohort of HCC patients. The miRNA microarray data were obtained from NCBI, GEO database (Accession No: GSE21362 and GSE39678). The miRNA expression of HCC patients were illustrated by scatter plots. The median expression is indicated by horizontal line. The microRNA expression levels are shown on the y axis (log2 intensity, *P<0.05; **P<0.005; ***P<0.001, Student's t test) (TG1; Edmonson grade I, TG2; Edmonson grade II, TG3; Edmonson grade III) (B) Kaplan-Meier survival curve of the GSE31384 dataset. The five year survival rate was significantly decreased in patient with low level of miR-31 expression in the tumor tissues (Log-rank P = 0.0015*) (C) The qRT-PCR analysis for 9 paired HCC tissues. MiR-31 was significantly down-regulated compared to corresponding non-tumor tissue. The expression of miR-31 was normalized to U6 snRNA (*P<0.05; **P<0.005, Student's t test) (D) The qRT-PCR analysis of miR-31 for hepatocellular carcinoma cell lines (n=7) and liver normal cell lines (n=2) (**P<0.005; ***P<0.001, Student's t test).

Mentions: MiR-31 is among the most frequently altered miRNAs in human cancers and altered expression of miR-31 has been detected in a large variety of tumor types. For example, miR-31 down-regulation has been detected in several other malignancies, such as bladder, esophageal, ovarian, and prostate cancer as well as in glioma, leukemia, melanoma, and mesothelioma. However, increased expression of miR-31 has also been detected for example in colorectal, lung and pancreatic cancer, head and neck squamous cell carcinoma, and osteosarcoma [14]. For liver cancer, the only one study reported that miR-31 was over-expressed, but no correlation with clinicopathlogical features was found [15]. Thus, functional role of miR-31 in liver cancer is elusive and to be uncovered. Therefore, to validate the expression of miR-31 in liver cancer, we observed miR-31 expression in the large cohorts of HCC patients available from the National Center for Biotechnology Information (NCBI) and Gene Expression Omnibus (GEO) database (accession numbers GSE21362 and GSE39678), and the data were presented as scatter plots. Unlikely with previous observation in liver cancer study, miR-31 expression was significantly down-regulated in these two different HCC cohorts (Fig. 1A). Interestingly, in a subset of HCCs defined by Edmondson grade I (TG1, n = 5), grade II (TG2, n = 5), grade III (TG3, n = 6), miR-31 was gradually down-regulated in the progression of liver cancer (Fig. 1A, GSE39678). In addition, Kaplan-Meier survival curves of patients with HCC indicated that the 5-year overall survival (OS) rates of HCC patients with low miR-31 expression was significantly lower than that of HCC patients with high miR-31 expression (Fig. 1B). Next, to verify the suppression of miR-31 in HCC patients, miR-31 expressions of 9 randomly selected HCC tissues paired with adjacent non-cancerous liver tissues were investigated by quantitative real-time PCR (qRT-PCR). From this, all 9 HCC tissues exhibited significantly down-regulation of miR-31 in HCC (Fig.1C). Additionally, endogenous expression of miR-31 was investigated by qRT-PCR in nine different liver cell lines, including immortalized normal hepatic cell lines (Fig. 1D). The human liver cancer cell lines (Hep3B, Huh7, PLC/PRF/5, SK-Hep-1, SNU-182 and SNU-449) exhibited relatively low miR-31 expression levels compared to that of non-cancer cell lines (MIHA and L-O2). These results suggest that the expression of miR-31 is suppressed in HCC and its low expression associates with biological process of tumorigenesis and poor prognostic signs of HCC patients.


MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer.

Kim HS, Lee KS, Bae HJ, Eun JW, Shen Q, Park SJ, Shin WC, Yang HD, Park M, Park WS, Kang YK, Nam SW - Oncotarget (2015)

MiR-31 is down-regulated in hepatocellular carcinoma(A) Recapitulated miRNA expression levels of the large cohort of HCC patients. The miRNA microarray data were obtained from NCBI, GEO database (Accession No: GSE21362 and GSE39678). The miRNA expression of HCC patients were illustrated by scatter plots. The median expression is indicated by horizontal line. The microRNA expression levels are shown on the y axis (log2 intensity, *P<0.05; **P<0.005; ***P<0.001, Student's t test) (TG1; Edmonson grade I, TG2; Edmonson grade II, TG3; Edmonson grade III) (B) Kaplan-Meier survival curve of the GSE31384 dataset. The five year survival rate was significantly decreased in patient with low level of miR-31 expression in the tumor tissues (Log-rank P = 0.0015*) (C) The qRT-PCR analysis for 9 paired HCC tissues. MiR-31 was significantly down-regulated compared to corresponding non-tumor tissue. The expression of miR-31 was normalized to U6 snRNA (*P<0.05; **P<0.005, Student's t test) (D) The qRT-PCR analysis of miR-31 for hepatocellular carcinoma cell lines (n=7) and liver normal cell lines (n=2) (**P<0.005; ***P<0.001, Student's t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: MiR-31 is down-regulated in hepatocellular carcinoma(A) Recapitulated miRNA expression levels of the large cohort of HCC patients. The miRNA microarray data were obtained from NCBI, GEO database (Accession No: GSE21362 and GSE39678). The miRNA expression of HCC patients were illustrated by scatter plots. The median expression is indicated by horizontal line. The microRNA expression levels are shown on the y axis (log2 intensity, *P<0.05; **P<0.005; ***P<0.001, Student's t test) (TG1; Edmonson grade I, TG2; Edmonson grade II, TG3; Edmonson grade III) (B) Kaplan-Meier survival curve of the GSE31384 dataset. The five year survival rate was significantly decreased in patient with low level of miR-31 expression in the tumor tissues (Log-rank P = 0.0015*) (C) The qRT-PCR analysis for 9 paired HCC tissues. MiR-31 was significantly down-regulated compared to corresponding non-tumor tissue. The expression of miR-31 was normalized to U6 snRNA (*P<0.05; **P<0.005, Student's t test) (D) The qRT-PCR analysis of miR-31 for hepatocellular carcinoma cell lines (n=7) and liver normal cell lines (n=2) (**P<0.005; ***P<0.001, Student's t test).
Mentions: MiR-31 is among the most frequently altered miRNAs in human cancers and altered expression of miR-31 has been detected in a large variety of tumor types. For example, miR-31 down-regulation has been detected in several other malignancies, such as bladder, esophageal, ovarian, and prostate cancer as well as in glioma, leukemia, melanoma, and mesothelioma. However, increased expression of miR-31 has also been detected for example in colorectal, lung and pancreatic cancer, head and neck squamous cell carcinoma, and osteosarcoma [14]. For liver cancer, the only one study reported that miR-31 was over-expressed, but no correlation with clinicopathlogical features was found [15]. Thus, functional role of miR-31 in liver cancer is elusive and to be uncovered. Therefore, to validate the expression of miR-31 in liver cancer, we observed miR-31 expression in the large cohorts of HCC patients available from the National Center for Biotechnology Information (NCBI) and Gene Expression Omnibus (GEO) database (accession numbers GSE21362 and GSE39678), and the data were presented as scatter plots. Unlikely with previous observation in liver cancer study, miR-31 expression was significantly down-regulated in these two different HCC cohorts (Fig. 1A). Interestingly, in a subset of HCCs defined by Edmondson grade I (TG1, n = 5), grade II (TG2, n = 5), grade III (TG3, n = 6), miR-31 was gradually down-regulated in the progression of liver cancer (Fig. 1A, GSE39678). In addition, Kaplan-Meier survival curves of patients with HCC indicated that the 5-year overall survival (OS) rates of HCC patients with low miR-31 expression was significantly lower than that of HCC patients with high miR-31 expression (Fig. 1B). Next, to verify the suppression of miR-31 in HCC patients, miR-31 expressions of 9 randomly selected HCC tissues paired with adjacent non-cancerous liver tissues were investigated by quantitative real-time PCR (qRT-PCR). From this, all 9 HCC tissues exhibited significantly down-regulation of miR-31 in HCC (Fig.1C). Additionally, endogenous expression of miR-31 was investigated by qRT-PCR in nine different liver cell lines, including immortalized normal hepatic cell lines (Fig. 1D). The human liver cancer cell lines (Hep3B, Huh7, PLC/PRF/5, SK-Hep-1, SNU-182 and SNU-449) exhibited relatively low miR-31 expression levels compared to that of non-cancer cell lines (MIHA and L-O2). These results suggest that the expression of miR-31 is suppressed in HCC and its low expression associates with biological process of tumorigenesis and poor prognostic signs of HCC patients.

Bottom Line: MiR-31 expression was down-regulated in a large cohort of hepatocellular carcinoma (HCC) patients, and low expression of miR-31 was significantly associated with poor prognosis of HCC patients.We also found that ectopic expression of miR-31 mimics reduced metastatic potential of HCC cells by selectively regulating epithelial-mesenchymal transition (EMT) regulatory proteins such as N-cadherin, E-cadherin, vimentin and fibronectin.HCC tissues derived from chemical-induced rat liver cancer models validated that miR-31 expression is significantly down-regulated, and that those cell cycle- and EMT-regulatory proteins are deregulated in rat liver cancer.

View Article: PubMed Central - PubMed

Affiliation: Lab of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

ABSTRACT
MicroRNA-31 (miR-31) is among the most frequently altered microRNAs in human cancers and altered expression of miR-31 has been detected in a large variety of tumor types, but the functional role of miR-31 still hold both tumor suppressive and oncogenic roles in different tumor types. MiR-31 expression was down-regulated in a large cohort of hepatocellular carcinoma (HCC) patients, and low expression of miR-31 was significantly associated with poor prognosis of HCC patients. Ectopic expression of miR-31 mimics suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. Additional study evidenced miR-31 directly to suppress HDAC2 and CDK2 expression by inhibiting mRNA translation in HCC cells. We also found that ectopic expression of miR-31 mimics reduced metastatic potential of HCC cells by selectively regulating epithelial-mesenchymal transition (EMT) regulatory proteins such as N-cadherin, E-cadherin, vimentin and fibronectin. HCC tissues derived from chemical-induced rat liver cancer models validated that miR-31 expression is significantly down-regulated, and that those cell cycle- and EMT-regulatory proteins are deregulated in rat liver cancer. Overall, we suggest that miR-31 functions as a tumor suppressor by selectively regulating cell cycle and EMT regulatory proteins in human hepatocarcinogenesis providing a novel target for the molecular treatment of liver malignancies.

No MeSH data available.


Related in: MedlinePlus