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MiR-216b is involved in pathogenesis and progression of hepatocellular carcinoma through HBx-miR-216b-IGF2BP2 signaling pathway.

Liu FY, Zhou SJ, Deng YL, Zhang ZY, Zhang EL, Wu ZB, Huang ZY, Chen XP - Cell Death Dis (2015)

Bottom Line: Using real-time quantitative PCR to detect the expression in paired tissues from 150 patients with HCC, miR-216b was selected as its expression value in HCC patients was significantly lower compared with healthy volunteers.In 150 HCC, 37 (75%) tumors showed reduced miR-216b expression comparing with their adjacent liver tissues.The decreased expression of miR-216b was significantly correlated with tumor volume (P=0.044), HBV infection (P=0.026), HBV DNA quantitative (P=0.001) and vascular invasion (P=0.032).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Surgery, Wuhan Center Hospital, Wuhan, Hubei, China [2] Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China.

ABSTRACT
This study aims to investigate the expression status of miRNA-216b in familial hepatocellular carcinoma (HCC) and the correlation between miRNA-216b expression and pathogenesis, as well as the progression of HCC. The expression profile of miRNAs in plasma of peripheral blood between HCC patients with HCC family history and healthy volunteers without HCC family history was determined by microarray. Using real-time quantitative PCR to detect the expression in paired tissues from 150 patients with HCC, miR-216b was selected as its expression value in HCC patients was significantly lower compared with healthy volunteers. Next, miR-216b expression and the clinicopathological features of HCC were evaluated. The effect of miR-216b expression on tumor cells was investigated by regulating miR-216b expression in SMMC-7721 and HepG2 in vitro and in vivo. Finally, we explored mRNA targets of miR-216b. In 150 HCC, 37 (75%) tumors showed reduced miR-216b expression comparing with their adjacent liver tissues. The decreased expression of miR-216b was significantly correlated with tumor volume (P=0.044), HBV infection (P=0.026), HBV DNA quantitative (P=0.001) and vascular invasion (P=0.032). The 5-year disease-free survival and overall rates after liver resection in low expression and high expression groups of miR-216b are 62% and 54%, 25% and 20%, respectively. MiR-216b overexpression inhibited cell proliferation, migration and invasion, and miR-216b inhibition did the opposite. The expression of hepatitis B virus x protein (HBx) has tight correlation with downregulation of miR-216b. Furthermore, miR-216b downregulated the expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and exerted its tumor-suppressor function through inhibition of protein kinase B and extracellular signal-regulated kinase signaling downstream of IGF2. MiR-216b inhibits cell proliferation, migration and invasion of HCC by regulating IGF2BP2 and it is regulated by HBx.

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MiR-216b is downregulated in HCC tissues and plasma, direct correlation with prognosis of HCC patients. (a) miRNA array test of the expression levels of all kinds of miRNAs in plasma of HCC patients with HCC family history. (b) RT-PCR analysis of the expression levels of miR-216b between 10 pairs of HCC patients and healthy volunteer's plasma. The miR-216b expression levels in healthy volunteer plasma were much higher than in HCC patients' plasma. (c) RT-PCR analysis of the expression levels of miR-216b in 150 pairs of HCC patients' tissues and contrast the expression value between tumor and adjacent liver tissues. The expression of miR-216b in tumor tissues was significant higher than in adjacent liver. (d and e) After operation, the 5-year cumulative survival rate and disease-free survival rate of low miR-216b expression group is much lower than high expression group, and P<0.05
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fig1: MiR-216b is downregulated in HCC tissues and plasma, direct correlation with prognosis of HCC patients. (a) miRNA array test of the expression levels of all kinds of miRNAs in plasma of HCC patients with HCC family history. (b) RT-PCR analysis of the expression levels of miR-216b between 10 pairs of HCC patients and healthy volunteer's plasma. The miR-216b expression levels in healthy volunteer plasma were much higher than in HCC patients' plasma. (c) RT-PCR analysis of the expression levels of miR-216b in 150 pairs of HCC patients' tissues and contrast the expression value between tumor and adjacent liver tissues. The expression of miR-216b in tumor tissues was significant higher than in adjacent liver. (d and e) After operation, the 5-year cumulative survival rate and disease-free survival rate of low miR-216b expression group is much lower than high expression group, and P<0.05

Mentions: Agilent MiRNA Base 16.0 microarray showed 45 significant differential expression miRNAs between HCC patients and healthy volunteers, of which 26 miRNAs showed >20-fold difference in expression (Table 1). Of these 26 miRNAs, 12 have been reported previously in HCC or other tumors (Supplementary Table 2). Of the remaining 14 miRNAs, miR-216b showed 127.56-fold decreased expression in the plasma of patients with HCC compared with that of healthy controls (Supplementary Table 3 and Figure 1a). This result was validated by measuring miR-216b expression in 10 patients with HCC and 10 healthy volunteers by using real-time PCR (Figure 1b). In addition, miR-216b expression was measured in 150 HCC tissues and adjacent liver tissues. We found that miR-216b expression was significantly lower in tumor tissues than in adjacent liver tissues (P<0.05; Figure 1c).


MiR-216b is involved in pathogenesis and progression of hepatocellular carcinoma through HBx-miR-216b-IGF2BP2 signaling pathway.

Liu FY, Zhou SJ, Deng YL, Zhang ZY, Zhang EL, Wu ZB, Huang ZY, Chen XP - Cell Death Dis (2015)

MiR-216b is downregulated in HCC tissues and plasma, direct correlation with prognosis of HCC patients. (a) miRNA array test of the expression levels of all kinds of miRNAs in plasma of HCC patients with HCC family history. (b) RT-PCR analysis of the expression levels of miR-216b between 10 pairs of HCC patients and healthy volunteer's plasma. The miR-216b expression levels in healthy volunteer plasma were much higher than in HCC patients' plasma. (c) RT-PCR analysis of the expression levels of miR-216b in 150 pairs of HCC patients' tissues and contrast the expression value between tumor and adjacent liver tissues. The expression of miR-216b in tumor tissues was significant higher than in adjacent liver. (d and e) After operation, the 5-year cumulative survival rate and disease-free survival rate of low miR-216b expression group is much lower than high expression group, and P<0.05
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4385924&req=5

fig1: MiR-216b is downregulated in HCC tissues and plasma, direct correlation with prognosis of HCC patients. (a) miRNA array test of the expression levels of all kinds of miRNAs in plasma of HCC patients with HCC family history. (b) RT-PCR analysis of the expression levels of miR-216b between 10 pairs of HCC patients and healthy volunteer's plasma. The miR-216b expression levels in healthy volunteer plasma were much higher than in HCC patients' plasma. (c) RT-PCR analysis of the expression levels of miR-216b in 150 pairs of HCC patients' tissues and contrast the expression value between tumor and adjacent liver tissues. The expression of miR-216b in tumor tissues was significant higher than in adjacent liver. (d and e) After operation, the 5-year cumulative survival rate and disease-free survival rate of low miR-216b expression group is much lower than high expression group, and P<0.05
Mentions: Agilent MiRNA Base 16.0 microarray showed 45 significant differential expression miRNAs between HCC patients and healthy volunteers, of which 26 miRNAs showed >20-fold difference in expression (Table 1). Of these 26 miRNAs, 12 have been reported previously in HCC or other tumors (Supplementary Table 2). Of the remaining 14 miRNAs, miR-216b showed 127.56-fold decreased expression in the plasma of patients with HCC compared with that of healthy controls (Supplementary Table 3 and Figure 1a). This result was validated by measuring miR-216b expression in 10 patients with HCC and 10 healthy volunteers by using real-time PCR (Figure 1b). In addition, miR-216b expression was measured in 150 HCC tissues and adjacent liver tissues. We found that miR-216b expression was significantly lower in tumor tissues than in adjacent liver tissues (P<0.05; Figure 1c).

Bottom Line: Using real-time quantitative PCR to detect the expression in paired tissues from 150 patients with HCC, miR-216b was selected as its expression value in HCC patients was significantly lower compared with healthy volunteers.In 150 HCC, 37 (75%) tumors showed reduced miR-216b expression comparing with their adjacent liver tissues.The decreased expression of miR-216b was significantly correlated with tumor volume (P=0.044), HBV infection (P=0.026), HBV DNA quantitative (P=0.001) and vascular invasion (P=0.032).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Surgery, Wuhan Center Hospital, Wuhan, Hubei, China [2] Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China.

ABSTRACT
This study aims to investigate the expression status of miRNA-216b in familial hepatocellular carcinoma (HCC) and the correlation between miRNA-216b expression and pathogenesis, as well as the progression of HCC. The expression profile of miRNAs in plasma of peripheral blood between HCC patients with HCC family history and healthy volunteers without HCC family history was determined by microarray. Using real-time quantitative PCR to detect the expression in paired tissues from 150 patients with HCC, miR-216b was selected as its expression value in HCC patients was significantly lower compared with healthy volunteers. Next, miR-216b expression and the clinicopathological features of HCC were evaluated. The effect of miR-216b expression on tumor cells was investigated by regulating miR-216b expression in SMMC-7721 and HepG2 in vitro and in vivo. Finally, we explored mRNA targets of miR-216b. In 150 HCC, 37 (75%) tumors showed reduced miR-216b expression comparing with their adjacent liver tissues. The decreased expression of miR-216b was significantly correlated with tumor volume (P=0.044), HBV infection (P=0.026), HBV DNA quantitative (P=0.001) and vascular invasion (P=0.032). The 5-year disease-free survival and overall rates after liver resection in low expression and high expression groups of miR-216b are 62% and 54%, 25% and 20%, respectively. MiR-216b overexpression inhibited cell proliferation, migration and invasion, and miR-216b inhibition did the opposite. The expression of hepatitis B virus x protein (HBx) has tight correlation with downregulation of miR-216b. Furthermore, miR-216b downregulated the expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and exerted its tumor-suppressor function through inhibition of protein kinase B and extracellular signal-regulated kinase signaling downstream of IGF2. MiR-216b inhibits cell proliferation, migration and invasion of HCC by regulating IGF2BP2 and it is regulated by HBx.

Show MeSH
Related in: MedlinePlus