miR-9 functions as a tumor suppressor in ovarian serous carcinoma by targeting TLN1

Tang, Haosha; Yao, Liangqing; Tao, Xiang; Yu, Yi; Chen, Mo; Zhang, Rong; Xu, Congjian

doi:10.3892/ijmm.2013.1400

Cited by 60 publications

(50 citation statements)

References 33 publications

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“…Overexpression of talin occurs in several solid tumors, including PCa, 4 oral squamous cell carcinoma 5 and ovarian serous carcinoma, 6 with overexpression correlating with higher tumor grade and metastasis. 4-6 In these studies, phosphorylation of talin was not examined; therefore overexpression and phosphorylation may not be mutually exclusive mechanisms for β1 integrin activation.…”

Section: Discussionmentioning

confidence: 99%

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Talin1 phosphorylation activates β1 integrins: a novel mechanism to promote prostate cancer bone metastasis

et al. 2014

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Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind integrins and are essential for integrin activation. We previously showed that β1 integrins are activated in metastatic prostate cancer (PCa) cells, increasing PCa metastasis to lymph nodes and bone. However, how β1 integrins are activated in PCa cells is unknown. In this study, we identified a novel mechanism of β1 integrin activation. Using knockdown experiments, we first demonstrated talin1, but not talin2, is important in β1 integrin activation. We next showed that talin1 S425 phosphorylation, but not total talin1 expression, correlates with metastatic potential of PCa cells. Expressing a non-phosphorylatable mutant, talin1S425A, in talin1-silenced PC3-MM2 and C4-2B4 PCa cells, decreased activation of β1 integrins, integrin-mediated adhesion, motility, and increased the sensitivity of the cells to anoikis. In contrast, re-expression of the phosphorylation-mimicking mutant talin1S425D led to increased β1 integrin activation and generated biologic effects opposite to talin1S425A expression. In the highly metastatic PC3-MM2 cells, expression of a non-phosphorylatable mutant, talin1S425A, in talin1-silenced PC3-MM2 cells, abolished their ability to colonize in the bone following intracardiac injection, while re-expression of phosphorylation-mimicking mutant talin1S425D restored their ability to metastasize to bone. Immunohistochemical staining demonstrated that talin S425 phosphorylation is significantly increased in human bone metastases when compared to normal tissues, primary tumors, or lymph node metastases. We further showed that p35 expression, an activator of Cdk5, and Cdk5 activity were increased in metastatic tumor cells, and that Cdk5 kinase activity is responsible for talin1 phosphorylation and subsequent β1 integrin activation. Together, our study reveals Cdk5-mediated phosphorylation of talin1 leading to β1 integrin activation is a novel mechanism that increases metastatic potential of PCa cells.

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Section: Discussionmentioning

confidence: 99%

“…2 While numerous alterations in both tumor cells and the tumor microenvironment are required for metastasis of solid tumors, 3 recent studies have implicated aberrant expression of talin in promoting such critical steps in metastasis as adhesion, migration, invasion, cellular survival and proliferation. 4-6 …”

Section: Introductionmentioning

confidence: 99%

Talin1 phosphorylation activates β1 integrins: a novel mechanism to promote prostate cancer bone metastasis

et al. 2014

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“…Guo et al (2009) reported that miR-9 inhibited ovarian cancer cell growth by regulating nuclear factor kappa B1 (NF-κB1) expression. However, Tang et al (2013) reported that miR-9 might act through the suppression of the talin 1/FAK/Akt pathway. miR-9 has also been demonstrated to improve the chemotherapeutic efficacy against ovarian cancer, as targeted inhibition of miR-9 sensitizes ovarian xenograft tumors to cisplatin and PARP inhibitor (Sun et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of microRNA-9 in osteosarcoma tumorigenesis and tumor progression

Wang

et al. 2016

Genet. Mol. Res.

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ABSTRACT. MicroRNA-9 (miR-9) has a well-established role in various tumors; the clinical significance and potential mechanism of miR-9 in human osteosarcoma (OS) has not been elucidated. The aim of this study was to investigate the mechanism and role of miR-9 expression in osteosarcoma cells. miR-9 expression in the OS cell line MG-63 and OS tissues was compared to that in a human osteoblastic cell line (hFOB 1.19) and adjacent normal tissues, respectively, by reverse transcriptase-polymerase chain reaction. miR-9 expression was downregulated by introducing small interfering RNA against miR-9 (si-miR-9) into the cells, and the proliferative, migratory, and invasive capacities of si-miR-9-transfected MG-63 cells were compared to those of control MG-63 cells. miR-9 was significantly upregulated in OS tissues and cell lines compared to the corresponding non-cancerous bone tissues (P < 0.05) and human osteoblastic cell line (P < 0.05), respectively. Upregulated miR-9 expression was also associated with increased cell proliferation (P < 0.05), migration (P < 0.05), and invasion (P < 0.05), and decreased apoptotic ability (P < 0.05). These results suggest that miR-9 may play a pivotal role in tumorigenesis and tumor progression in osteosarcoma.

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“…Taken together, these data suggest that miR-9 mediates the suppression of Akt/FOXO1 axis by curcumin in ovarian cancer cells. Indeed, the inactivation of Akt signaling by miR-9 is also described in a previous study (Tang et al, 2013).…”

Section: Discussionmentioning

confidence: 93%

“…A recent study has shown that miR-9 has the potential of improving chemotherapeutic efficacy in ovarian cancer, as targeted inhibition of miR-9 sensitizes ovarian xenograft tumors to cisplatin and PARP inhibitor . Tang et al (2013) reported that miR-9 inhibits ovarian cancer cell proliferation, migration, and invasion through suppression of talin 1/FAK/Akt pathway. These studies combined with the finding that curcumin can alter miRNA expression profiles in cancer cells (Sun et al, 2008) suggest the possibility that miR-9 may be involved in the anticancer effects of curcumin against ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

Zhao¹,

Zhang²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Curcumin, a phenolic compound extracted from the rhizomes of Curcuma longa, has shown cytotoxic effects against a variety of cancers. The aim of this study was to identify potential microRNA (miRNA) mediators of the anticancer effects of curcumin in ovarian cancer cells. Materials and Methods: SKOV3 ovarian cancer cells were treated with curcumin (10-60 μM) and miR-9 expression, cell proliferation, and apoptosis were assessed. The effects of miR-9 depletion on curcumin-mediated growth suppression were also examined. Phosphorylation of Akt and forkhead box protein O1 (FOXO1) was measured in cells with miR-9 overexpression or curcumin treatment. Results: Curcumin caused a significant and dose-dependent increase of miR-9 expression in SKOV3 cells, while significantly impeding cell proliferation and stimulating apoptosis. Depletion of miR-9 significantly (p<0.05) attenuated the growth-suppressive effects of curcumin on SKOV3 cells, coupled with reduced percentages of apoptotic cells. In contrast, overexpression of miR-9 significantly enhanced the cleavage of caspase-3 and poly(ADP-ribose) polymerase and promoted apoptotic death in SKOV3 cells. Western blot analysis showed that both miR-9 overexpression and curcumin similarly caused a significant (p<0.05) decline in the phosphorylation of Akt and FOXO1, compared to untreated cells. Conclusions: The present study provided evidence that curcumin exerts its cytotoxic effects against SKOV3 ovarian cancer cells largely through upregulation of miR-9 and subsequent modulation of Akt/FOXO1 axis. Further studies are needed to identify direct targets of miR-9 that mediate the anticancer effects of curcumin in ovarian cancer cells.

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miR-9 functions as a tumor suppressor in ovarian serous carcinoma by targeting TLN1

Cited by 60 publications

References 33 publications

Talin1 phosphorylation activates β1 integrins: a novel mechanism to promote prostate cancer bone metastasis

Talin1 phosphorylation activates β1 integrins: a novel mechanism to promote prostate cancer bone metastasis

Pivotal role of microRNA-9 in osteosarcoma tumorigenesis and tumor progression

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

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