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A novel role for microRNA-129-5p in inhibiting ovarian cancer cell proliferation and survival via direct suppression of transcriptional co-activators YAP and TAZ.

Tan G, Cao X, Dai Q, Zhang B, Huang J, Xiong S, Zhang Yy, Chen W, Yang J, Li H - Oncotarget (2015)

Bottom Line: Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells.Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms.Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Interventional Radiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

ABSTRACT
Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells. Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms. The involvement of microRNA in cancer progression has recently been reported, though whether they have a role in activating YAP and TAZ in human cancer cells remains unclear. Here, we report a microRNA, miR-129-5p, directly represses YAP and TAZ expression, leading to the inactivation of TEA domain (TEAD) transcription, and the downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A. Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival. Hence, we demonstrate a novel mechanism for YAP and TAZ activation in cancers, indicating not only a potentially pivotal role for miR-129-5p in the progression of ovarian cancer, but also offering new therapeutic strategies to circumvent the disease.

No MeSH data available.


Related in: MedlinePlus

miR-129-5p suppresses tumorigenicity of ovarian cancer cells in vivo(A and B) Xenograft model in nude mice. Images of tumors from all mice in each group. (C) Tumor volumes were measured on the indicated days and presented as the mean ± SD. (D) Tumor weights of each group. (E) Proliferation index determined by counting the proportion of Ki67-positive cells. (F) Apoptotic index measured by the percentage of TUNEL-positive cells. Scale bars: 50 μm. Each bar represents the mean ± SD of three independent experiments. *p < 0.05.
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Figure 5: miR-129-5p suppresses tumorigenicity of ovarian cancer cells in vivo(A and B) Xenograft model in nude mice. Images of tumors from all mice in each group. (C) Tumor volumes were measured on the indicated days and presented as the mean ± SD. (D) Tumor weights of each group. (E) Proliferation index determined by counting the proportion of Ki67-positive cells. (F) Apoptotic index measured by the percentage of TUNEL-positive cells. Scale bars: 50 μm. Each bar represents the mean ± SD of three independent experiments. *p < 0.05.

Mentions: We then examined the tumor suppressive role of miR-129-5p in ovarian cancer progression using an in vivo tumor model. Importantly, intratumoral injection with miR-129-5p mimic dramatically inhibited tumor growth, while injecting a mimic control had no effect on tumor development (Figure 5A, and 5D). Conversely, the tumors injected with antagomiR-129-5p were significantly larger, in both size and weight, than the control tumors (Figure 5B–5D). The expression of miR-129-5p is marked upregulated in the miR-125-5p/tumors but decreased in the antagomiR-125-5p/tumors compared control tumors, respectively (Supplementary Figure 4A). Furthermore, western blotting analysis showed that overexpressing miR-129-5p reduced, while silencing miR-129-5p increased YAP and TAZ in xenograft tumors, further supporting the notion that miR-129-5p regulated the tumor growth via YAP and TAZ (Supplementary Figure 4B). Meanwhile, our staining assays revealed that miR-129-5p-overexpressing tumors exhibited decreased Ki67-positive cells and increased TUNEL-positive cells, whereas miR-129-5p-silenced tumors presented a higher Ki67 proliferation index and decreased TUNEL-positive apoptotic cells (Figure 5E and 5F). Here, our results suggest that miR-129-5p suppresses the tumorigenicity of ovarian cancer cells in vivo.


A novel role for microRNA-129-5p in inhibiting ovarian cancer cell proliferation and survival via direct suppression of transcriptional co-activators YAP and TAZ.

Tan G, Cao X, Dai Q, Zhang B, Huang J, Xiong S, Zhang Yy, Chen W, Yang J, Li H - Oncotarget (2015)

miR-129-5p suppresses tumorigenicity of ovarian cancer cells in vivo(A and B) Xenograft model in nude mice. Images of tumors from all mice in each group. (C) Tumor volumes were measured on the indicated days and presented as the mean ± SD. (D) Tumor weights of each group. (E) Proliferation index determined by counting the proportion of Ki67-positive cells. (F) Apoptotic index measured by the percentage of TUNEL-positive cells. Scale bars: 50 μm. 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=PMC4496175&req=5

Figure 5: miR-129-5p suppresses tumorigenicity of ovarian cancer cells in vivo(A and B) Xenograft model in nude mice. Images of tumors from all mice in each group. (C) Tumor volumes were measured on the indicated days and presented as the mean ± SD. (D) Tumor weights of each group. (E) Proliferation index determined by counting the proportion of Ki67-positive cells. (F) Apoptotic index measured by the percentage of TUNEL-positive cells. Scale bars: 50 μm. Each bar represents the mean ± SD of three independent experiments. *p < 0.05.
Mentions: We then examined the tumor suppressive role of miR-129-5p in ovarian cancer progression using an in vivo tumor model. Importantly, intratumoral injection with miR-129-5p mimic dramatically inhibited tumor growth, while injecting a mimic control had no effect on tumor development (Figure 5A, and 5D). Conversely, the tumors injected with antagomiR-129-5p were significantly larger, in both size and weight, than the control tumors (Figure 5B–5D). The expression of miR-129-5p is marked upregulated in the miR-125-5p/tumors but decreased in the antagomiR-125-5p/tumors compared control tumors, respectively (Supplementary Figure 4A). Furthermore, western blotting analysis showed that overexpressing miR-129-5p reduced, while silencing miR-129-5p increased YAP and TAZ in xenograft tumors, further supporting the notion that miR-129-5p regulated the tumor growth via YAP and TAZ (Supplementary Figure 4B). Meanwhile, our staining assays revealed that miR-129-5p-overexpressing tumors exhibited decreased Ki67-positive cells and increased TUNEL-positive cells, whereas miR-129-5p-silenced tumors presented a higher Ki67 proliferation index and decreased TUNEL-positive apoptotic cells (Figure 5E and 5F). Here, our results suggest that miR-129-5p suppresses the tumorigenicity of ovarian cancer cells in vivo.

Bottom Line: Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells.Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms.Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Interventional Radiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

ABSTRACT
Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells. Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms. The involvement of microRNA in cancer progression has recently been reported, though whether they have a role in activating YAP and TAZ in human cancer cells remains unclear. Here, we report a microRNA, miR-129-5p, directly represses YAP and TAZ expression, leading to the inactivation of TEA domain (TEAD) transcription, and the downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A. Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival. Hence, we demonstrate a novel mechanism for YAP and TAZ activation in cancers, indicating not only a potentially pivotal role for miR-129-5p in the progression of ovarian cancer, but also offering new therapeutic strategies to circumvent the disease.

No MeSH data available.


Related in: MedlinePlus