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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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HBx expression correlates with IGF2BP2 expression. (a) With the downregulation of miR-216b expression in 50 tumor tissues, the HBx expression and IGF2BP2 expression are increased. (Protein expression was evaluated by IPP6.0). (b) The HBx and IGF2BP2 expression are upregulated the same time in HCC tumor tissues than in adjacent liver tissues (A, adjacent liver; T, tumor tissue). (c) IGF2BP2 expression is significant higher in HCC tumor tissues with high HBx expression (A1, adjacent liver 1; T1, tumor tissue 1) than in adjacent liver in IHC assay. (d) The overexpression of HBx could obviously downregulate the expression of miR-216b in HepG2 cells (P<0.01). (e) When miR-216b expression is upregulated, the HBx upregulating effects on IGF2BP2 expression and the following pathways are offset. (f) When miR-216b expression is downregulated, the siHBx downregulating effects on IGF2BP2 expression and the following pathways are offset
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fig4: HBx expression correlates with IGF2BP2 expression. (a) With the downregulation of miR-216b expression in 50 tumor tissues, the HBx expression and IGF2BP2 expression are increased. (Protein expression was evaluated by IPP6.0). (b) The HBx and IGF2BP2 expression are upregulated the same time in HCC tumor tissues than in adjacent liver tissues (A, adjacent liver; T, tumor tissue). (c) IGF2BP2 expression is significant higher in HCC tumor tissues with high HBx expression (A1, adjacent liver 1; T1, tumor tissue 1) than in adjacent liver in IHC assay. (d) The overexpression of HBx could obviously downregulate the expression of miR-216b in HepG2 cells (P<0.01). (e) When miR-216b expression is upregulated, the HBx upregulating effects on IGF2BP2 expression and the following pathways are offset. (f) When miR-216b expression is downregulated, the siHBx downregulating effects on IGF2BP2 expression and the following pathways are offset

Mentions: We found that miR-216b expression was strongly associated with HBV infection. HBx has an important role in the pathogenesis of HBV-related HCC. RT-PCR and western blotting showed that expression levels of HBx and IGF2BP2 were upregulated in 50 HCC tissues that showed downregulated miR-216b expression (Figure 4a). Moreover, western blotting and IHC showed that expression levels of HBx and IGF2BP2 in tumor tissues were much higher than those in the adjacent liver tissues (Figures 4b and c). Next, we measured miR-216b levels and IGF2BP2 protein levels in HepG2, HepG2.215 and HepG2-HBx cells (Supplementary Figures D and E). Our results suggested that HBx regulated the expression levels of miR-216b and IGF2BP2. HBx inhibited miR-216b expression in HepG2 cells (Figure 4d), and stimulated IGF2BP2 expression and activated the downstream pathways (Figure 4e). When miR-216b expression was downregulated, siHBx downregulating effects on IGF2BP2 expression and the following pathways are offset (Figure 4f).


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)

HBx expression correlates with IGF2BP2 expression. (a) With the downregulation of miR-216b expression in 50 tumor tissues, the HBx expression and IGF2BP2 expression are increased. (Protein expression was evaluated by IPP6.0). (b) The HBx and IGF2BP2 expression are upregulated the same time in HCC tumor tissues than in adjacent liver tissues (A, adjacent liver; T, tumor tissue). (c) IGF2BP2 expression is significant higher in HCC tumor tissues with high HBx expression (A1, adjacent liver 1; T1, tumor tissue 1) than in adjacent liver in IHC assay. (d) The overexpression of HBx could obviously downregulate the expression of miR-216b in HepG2 cells (P<0.01). (e) When miR-216b expression is upregulated, the HBx upregulating effects on IGF2BP2 expression and the following pathways are offset. (f) When miR-216b expression is downregulated, the siHBx downregulating effects on IGF2BP2 expression and the following pathways are offset
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: HBx expression correlates with IGF2BP2 expression. (a) With the downregulation of miR-216b expression in 50 tumor tissues, the HBx expression and IGF2BP2 expression are increased. (Protein expression was evaluated by IPP6.0). (b) The HBx and IGF2BP2 expression are upregulated the same time in HCC tumor tissues than in adjacent liver tissues (A, adjacent liver; T, tumor tissue). (c) IGF2BP2 expression is significant higher in HCC tumor tissues with high HBx expression (A1, adjacent liver 1; T1, tumor tissue 1) than in adjacent liver in IHC assay. (d) The overexpression of HBx could obviously downregulate the expression of miR-216b in HepG2 cells (P<0.01). (e) When miR-216b expression is upregulated, the HBx upregulating effects on IGF2BP2 expression and the following pathways are offset. (f) When miR-216b expression is downregulated, the siHBx downregulating effects on IGF2BP2 expression and the following pathways are offset
Mentions: We found that miR-216b expression was strongly associated with HBV infection. HBx has an important role in the pathogenesis of HBV-related HCC. RT-PCR and western blotting showed that expression levels of HBx and IGF2BP2 were upregulated in 50 HCC tissues that showed downregulated miR-216b expression (Figure 4a). Moreover, western blotting and IHC showed that expression levels of HBx and IGF2BP2 in tumor tissues were much higher than those in the adjacent liver tissues (Figures 4b and c). Next, we measured miR-216b levels and IGF2BP2 protein levels in HepG2, HepG2.215 and HepG2-HBx cells (Supplementary Figures D and E). Our results suggested that HBx regulated the expression levels of miR-216b and IGF2BP2. HBx inhibited miR-216b expression in HepG2 cells (Figure 4d), and stimulated IGF2BP2 expression and activated the downstream pathways (Figure 4e). When miR-216b expression was downregulated, siHBx downregulating effects on IGF2BP2 expression and the following pathways are offset (Figure 4f).

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