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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 downregulation contributed to HCC progression in vivo(A). Representative images of tumor-bearing mice (left) and images of the tumors from all of the mice in each group (right). (B). Tumor volumes were measured on the indicated days. (C). Mean tumor weights. (D). IHC staining showing that miR-432 downregulation increased the percentages of Ki-67 positive cells, whereas miR-432 overexpression inhibited the percentages of Ki-67 positive cells. Each bar represents the mean ± SD of three independent experiments. * P < 0.05.
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Figure 4: MiR-432 downregulation contributed to HCC progression in vivo(A). Representative images of tumor-bearing mice (left) and images of the tumors from all of the mice in each group (right). (B). Tumor volumes were measured on the indicated days. (C). Mean tumor weights. (D). IHC staining showing that miR-432 downregulation increased the percentages of Ki-67 positive cells, whereas miR-432 overexpression inhibited the percentages of Ki-67 positive cells. Each bar represents the mean ± SD of three independent experiments. * P < 0.05.

Mentions: To investigate whether miR-432 inhibits HCC progression in vivo, we used a xenografted tumor model to examine the biological effect of miR-432. As shown in Figure 4A-4C, the tumors formed by miR-432-silenced cells were larger in both size and weight than the tumors formed by control cells. Conversely, the tumors formed by miR-432-transduced-HCC cells were smaller and lighter than the control tumors. Furthermore, IHC analysis revealed that miR-432-silenced tumors showed higher percentages of Ki-67-positive cells, whereas miR-432-overexpressing tumors displayed lower percentages of Ki-67 positive cells than the control tumors (Figure 4D). Collectively, these results demonstrate that miR-432 finctions as a tumor suppressor in HCC in vivo.


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 downregulation contributed to HCC progression in vivo(A). Representative images of tumor-bearing mice (left) and images of the tumors from all of the mice in each group (right). (B). Tumor volumes were measured on the indicated days. (C). Mean tumor weights. (D). IHC staining showing that miR-432 downregulation increased the percentages of Ki-67 positive cells, whereas miR-432 overexpression inhibited the percentages of Ki-67 positive cells. Each bar represents the mean ± SD 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 4: MiR-432 downregulation contributed to HCC progression in vivo(A). Representative images of tumor-bearing mice (left) and images of the tumors from all of the mice in each group (right). (B). Tumor volumes were measured on the indicated days. (C). Mean tumor weights. (D). IHC staining showing that miR-432 downregulation increased the percentages of Ki-67 positive cells, whereas miR-432 overexpression inhibited the percentages of Ki-67 positive cells. Each bar represents the mean ± SD of three independent experiments. * P < 0.05.
Mentions: To investigate whether miR-432 inhibits HCC progression in vivo, we used a xenografted tumor model to examine the biological effect of miR-432. As shown in Figure 4A-4C, the tumors formed by miR-432-silenced cells were larger in both size and weight than the tumors formed by control cells. Conversely, the tumors formed by miR-432-transduced-HCC cells were smaller and lighter than the control tumors. Furthermore, IHC analysis revealed that miR-432-silenced tumors showed higher percentages of Ki-67-positive cells, whereas miR-432-overexpressing tumors displayed lower percentages of Ki-67 positive cells than the control tumors (Figure 4D). Collectively, these results demonstrate that miR-432 finctions as a tumor suppressor in HCC in vivo.

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