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Downregulation of miR-432 activates Wnt/β-catenin signaling and promotes human hepatocellular carcinoma proliferation.

Jiang N, Chen WJ, Zhang JW, Xu C, Zeng XC, Zhang T, Li Y, Wang GY - Oncotarget (2015)

Bottom Line: Sustained cell growth and proliferation, one of the hallmarks of cancer, is considered to responsible for cancer-related deaths by disorganizing the balance of growth promotion and growth limitation.Elucidating the molecular mechanism of this abnormality in hepatocellular carcinoma carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy.Furthermore, miR-432 directly targeted and suppressed multiple regulators of the Wnt/β-catenin signaling cascade, including LRP6, TRIM29 and Pygo2, which subsequently deactivated Wnt/β-catenin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.

ABSTRACT
Sustained cell growth and proliferation, one of the hallmarks of cancer, is considered to responsible for cancer-related deaths by disorganizing the balance of growth promotion and growth limitation. Aberrant activation of the Wnt/β-catenin signaling pathway leads to cell proliferation, growth and survival, and promotes the development of various human tumors, including hepatocellular carcinoma. Elucidating the molecular mechanism of this abnormality in hepatocellular carcinoma carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy. Herein, we report that the expression of miR-432 was markedly downregulated in hepatocellular carcinoma cell lines and tissues, and upregulation of miR-432 inhibited, whereas downregulation of miR-432 enhanced the proliferation and tumorigenicity of hepatocellular carcinoma cells both in vitro and in vivo. Furthermore, miR-432 directly targeted and suppressed multiple regulators of the Wnt/β-catenin signaling cascade, including LRP6, TRIM29 and Pygo2, which subsequently deactivated Wnt/β-catenin signaling pathway. Finally, miR-432 expression was inversely correlated with three targets in clinical hepatocellular carcinoma samples. These results demonstrated that miR-432 functions as a tumor-suppressive miRNA by suppressing Wnt/β-catenin signaling activation and may represent a therapeutic target for hepatocellular carcinoma.

No MeSH data available.


Related in: MedlinePlus

MiR-432 is downregulated in HCC cell lines and tissues(A). Expression profiling of miRNAs showing that miR-432 is downregulated in HCC tissues (T) compared with matched non-cancerous liver tissue (N) (n = 89, p<0.001; NCBI /GEO /GSE 36915). (B). Expression profiling of miR-432 from The Cancer Genome Altas (TCGA) datasets in liver hepatocellular carcinoma ((http://cancergenome.nih.gov/). (C). Real-time PCR analysis of miR-432 expression in normal human LO2 hepatocyte and in HCC cell lines (Hep3B, MHCC97L, Huh7, HCCC-9810, HepG2, BEL-7402, MHCC97H and QGY-7703). Transcript levels were normalized to U6 expression. (D). Real-time PCR analysis of miR-432 expression in primary HCC tissues (T) with matched adjacent non-tumor tissues (ANT) from eight individual patients. Transcript levels were normalized to U6 expression. Each bar represents the mean ± SD of three independent experiments. *P < 0.05.
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Figure 1: MiR-432 is downregulated in HCC cell lines and tissues(A). Expression profiling of miRNAs showing that miR-432 is downregulated in HCC tissues (T) compared with matched non-cancerous liver tissue (N) (n = 89, p<0.001; NCBI /GEO /GSE 36915). (B). Expression profiling of miR-432 from The Cancer Genome Altas (TCGA) datasets in liver hepatocellular carcinoma ((http://cancergenome.nih.gov/). (C). Real-time PCR analysis of miR-432 expression in normal human LO2 hepatocyte and in HCC cell lines (Hep3B, MHCC97L, Huh7, HCCC-9810, HepG2, BEL-7402, MHCC97H and QGY-7703). Transcript levels were normalized to U6 expression. (D). Real-time PCR analysis of miR-432 expression in primary HCC tissues (T) with matched adjacent non-tumor tissues (ANT) from eight individual patients. Transcript levels were normalized to U6 expression. Each bar represents the mean ± SD of three independent experiments. *P < 0.05.

Mentions: By analyzing a published microarray-based high-throughput assessment, miR-432 was identified to be significantly downregulated in HCC tissues compared with non-cancerous liver tissue (n = 89; P < 0.05; NCBI/GEO/GSE36915; Figure 1A). Consistent with this observation, we further analyzed the data from The Cancer Genome Atlas (TCGA) (http://cancergenome.nih.gov/, n=48 pairs) in liver hepatocellular carcinoma and matched non-cancerous liver tissue and found that miR-432 was significantly downregulated in tumor samples (Figure 1B). Strikingly, real-time PCR showed that miR-432 was downregulated in all 10 tumor tissue samples and in eight HCC cell lines (QGY-7703, Huh7, MHCC97L, Hep3B, HepG2, BEL-7402, MHCC97H, HCCC-9810)compared with adjacent non-cancerous tissues and normal human LO2 hepatocyte, respectively (Figure 1C and 1D). Collectively, these results indicated that miR-432 is downregulated in HCC.


Downregulation of miR-432 activates Wnt/β-catenin signaling and promotes human hepatocellular carcinoma proliferation.

Jiang N, Chen WJ, Zhang JW, Xu C, Zeng XC, Zhang T, Li Y, Wang GY - Oncotarget (2015)

MiR-432 is downregulated in HCC cell lines and tissues(A). Expression profiling of miRNAs showing that miR-432 is downregulated in HCC tissues (T) compared with matched non-cancerous liver tissue (N) (n = 89, p<0.001; NCBI /GEO /GSE 36915). (B). Expression profiling of miR-432 from The Cancer Genome Altas (TCGA) datasets in liver hepatocellular carcinoma ((http://cancergenome.nih.gov/). (C). Real-time PCR analysis of miR-432 expression in normal human LO2 hepatocyte and in HCC cell lines (Hep3B, MHCC97L, Huh7, HCCC-9810, HepG2, BEL-7402, MHCC97H and QGY-7703). Transcript levels were normalized to U6 expression. (D). Real-time PCR analysis of miR-432 expression in primary HCC tissues (T) with matched adjacent non-tumor tissues (ANT) from eight individual patients. Transcript levels were normalized to U6 expression. Each bar represents the mean ± SD of three independent experiments. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4480722&req=5

Figure 1: MiR-432 is downregulated in HCC cell lines and tissues(A). Expression profiling of miRNAs showing that miR-432 is downregulated in HCC tissues (T) compared with matched non-cancerous liver tissue (N) (n = 89, p<0.001; NCBI /GEO /GSE 36915). (B). Expression profiling of miR-432 from The Cancer Genome Altas (TCGA) datasets in liver hepatocellular carcinoma ((http://cancergenome.nih.gov/). (C). Real-time PCR analysis of miR-432 expression in normal human LO2 hepatocyte and in HCC cell lines (Hep3B, MHCC97L, Huh7, HCCC-9810, HepG2, BEL-7402, MHCC97H and QGY-7703). Transcript levels were normalized to U6 expression. (D). Real-time PCR analysis of miR-432 expression in primary HCC tissues (T) with matched adjacent non-tumor tissues (ANT) from eight individual patients. Transcript levels were normalized to U6 expression. Each bar represents the mean ± SD of three independent experiments. *P < 0.05.
Mentions: By analyzing a published microarray-based high-throughput assessment, miR-432 was identified to be significantly downregulated in HCC tissues compared with non-cancerous liver tissue (n = 89; P < 0.05; NCBI/GEO/GSE36915; Figure 1A). Consistent with this observation, we further analyzed the data from The Cancer Genome Atlas (TCGA) (http://cancergenome.nih.gov/, n=48 pairs) in liver hepatocellular carcinoma and matched non-cancerous liver tissue and found that miR-432 was significantly downregulated in tumor samples (Figure 1B). Strikingly, real-time PCR showed that miR-432 was downregulated in all 10 tumor tissue samples and in eight HCC cell lines (QGY-7703, Huh7, MHCC97L, Hep3B, HepG2, BEL-7402, MHCC97H, HCCC-9810)compared with adjacent non-cancerous tissues and normal human LO2 hepatocyte, respectively (Figure 1C and 1D). Collectively, these results indicated that miR-432 is downregulated in HCC.

Bottom Line: Sustained cell growth and proliferation, one of the hallmarks of cancer, is considered to responsible for cancer-related deaths by disorganizing the balance of growth promotion and growth limitation.Elucidating the molecular mechanism of this abnormality in hepatocellular carcinoma carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy.Furthermore, miR-432 directly targeted and suppressed multiple regulators of the Wnt/β-catenin signaling cascade, including LRP6, TRIM29 and Pygo2, which subsequently deactivated Wnt/β-catenin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.

ABSTRACT
Sustained cell growth and proliferation, one of the hallmarks of cancer, is considered to responsible for cancer-related deaths by disorganizing the balance of growth promotion and growth limitation. Aberrant activation of the Wnt/β-catenin signaling pathway leads to cell proliferation, growth and survival, and promotes the development of various human tumors, including hepatocellular carcinoma. Elucidating the molecular mechanism of this abnormality in hepatocellular carcinoma carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy. Herein, we report that the expression of miR-432 was markedly downregulated in hepatocellular carcinoma cell lines and tissues, and upregulation of miR-432 inhibited, whereas downregulation of miR-432 enhanced the proliferation and tumorigenicity of hepatocellular carcinoma cells both in vitro and in vivo. Furthermore, miR-432 directly targeted and suppressed multiple regulators of the Wnt/β-catenin signaling cascade, including LRP6, TRIM29 and Pygo2, which subsequently deactivated Wnt/β-catenin signaling pathway. Finally, miR-432 expression was inversely correlated with three targets in clinical hepatocellular carcinoma samples. These results demonstrated that miR-432 functions as a tumor-suppressive miRNA by suppressing Wnt/β-catenin signaling activation and may represent a therapeutic target for hepatocellular carcinoma.

No MeSH data available.


Related in: MedlinePlus