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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

Clinical relevance of miR-432 downregulation and β-catenin nuclear accumulation, and the expression of LRP6, TRIM29 and Pygo2 in HCC(A). Expression of miR-432 and β-catenin nuclear accumulation(p84 served as loading control), LRP6, TRIM29 and Pygo2 protein, as measured by real-time PCR (top) and western blotting (bottom), respectively. α-Tubulin served as loading control. (B). Correlation between miR-432 and β-catenin LRP6, TRIM29 and Pygo2 expression was analyzed by SPSS software. Error bars represent the mean ± SD from of three independent experiments. *P < 0.05.
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Figure 6: Clinical relevance of miR-432 downregulation and β-catenin nuclear accumulation, and the expression of LRP6, TRIM29 and Pygo2 in HCC(A). Expression of miR-432 and β-catenin nuclear accumulation(p84 served as loading control), LRP6, TRIM29 and Pygo2 protein, as measured by real-time PCR (top) and western blotting (bottom), respectively. α-Tubulin served as loading control. (B). Correlation between miR-432 and β-catenin LRP6, TRIM29 and Pygo2 expression was analyzed by SPSS software. Error bars represent the mean ± SD from of three independent experiments. *P < 0.05.

Mentions: Finally, we examine whether miR-432-mediated suppression of LRP6, TRIM29, and Pygo2 and β-catenin nuclear accumulation in HCC are clinically relevant. Using 10 freshly collected clinical HCC samples, we found that miR-432 expression was inversely correlated with the expression of β-catenin(r = −0.688, P = 0.002), LRP6 (r = −0.872, P = 0.007), TRIM29 (r = −0.775, P = 0.004), Pygo2 (r = −0.663, P = 0.014) (Figure 6A and 6B). Collectively, these results support the notion that miR-432 downregulation promotes proliferation in HCC and activates the Wnt/β-catenin signaling pathway by repressing multiple important regulator this pathway.


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)

Clinical relevance of miR-432 downregulation and β-catenin nuclear accumulation, and the expression of LRP6, TRIM29 and Pygo2 in HCC(A). Expression of miR-432 and β-catenin nuclear accumulation(p84 served as loading control), LRP6, TRIM29 and Pygo2 protein, as measured by real-time PCR (top) and western blotting (bottom), respectively. α-Tubulin served as loading control. (B). Correlation between miR-432 and β-catenin LRP6, TRIM29 and Pygo2 expression was analyzed by SPSS software. Error bars represent the mean ± SD from of three independent experiments. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Clinical relevance of miR-432 downregulation and β-catenin nuclear accumulation, and the expression of LRP6, TRIM29 and Pygo2 in HCC(A). Expression of miR-432 and β-catenin nuclear accumulation(p84 served as loading control), LRP6, TRIM29 and Pygo2 protein, as measured by real-time PCR (top) and western blotting (bottom), respectively. α-Tubulin served as loading control. (B). Correlation between miR-432 and β-catenin LRP6, TRIM29 and Pygo2 expression was analyzed by SPSS software. Error bars represent the mean ± SD from of three independent experiments. *P < 0.05.
Mentions: Finally, we examine whether miR-432-mediated suppression of LRP6, TRIM29, and Pygo2 and β-catenin nuclear accumulation in HCC are clinically relevant. Using 10 freshly collected clinical HCC samples, we found that miR-432 expression was inversely correlated with the expression of β-catenin(r = −0.688, P = 0.002), LRP6 (r = −0.872, P = 0.007), TRIM29 (r = −0.775, P = 0.004), Pygo2 (r = −0.663, P = 0.014) (Figure 6A and 6B). Collectively, these results support the notion that miR-432 downregulation promotes proliferation in HCC and activates the Wnt/β-catenin signaling pathway by repressing multiple important regulator this pathway.

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