Inhibition of RUNX2 Transcriptional Activity Blocks the Proliferation, Migration and Invasion of Epithelial Ovarian Carcinoma Cells

Wang, Zhiqiang; Keita, Mamadou; Bachvarova, Magdalena; Gobeil, Stéphane; Morin, Chantale; Plante, Marie; Grégoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Trinh, Xuan Bich; Bachvarov, Dimcho

doi:10.1371/journal.pone.0074384

Cited by 34 publications

(39 citation statements)

References 76 publications

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“…33 Several reports have demonstrated that BMP7 transcriptionally induces Runt-related transcription factor 2 ( RUNX2 ) expression. 34, 35 Intriguingly, Wang et al 36 reported that in ovarian cancer cells RUNX2 gene silencing provides a sharp downregulation of NUPR1 , suggesting the existence of an interaction between these two transcription factors. Indeed, in our preliminary microarray analyses conducted using ≥1.5-fold selection criteria, we found that RUNX2 was downregulated in Hep3B cells upon NUPR1 suppression.…”

Section: Resultsmentioning

confidence: 99%

NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance

et al. 2016

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Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits are modest, and as its mechanisms of action remain elusive, a better understanding of its anticancer effects is needed. Based on our previous study results, we investigated here the implication of the nuclear protein 1 (NUPR1) in HCC and its role in sorafenib treatment. NUPR1 is a stress-inducible protein that is overexpressed in various malignancies, but its role in HCC is not yet fully understood. We found that NUPR1 expression was significantly higher in primary human HCC samples than in the normal liver. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibited the cell growth, migration and invasion of HCC cells, both in vitro and in vivo. Moreover, NUPR1 silencing influenced the expression of RELB and IER3 genes. Unsurprisingly, RELB and IER3 knockdown also inhibited HCC cell viability, growth and migration. Using gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-κB and ERK as downregulated gene nodes, and several HCC-related oncogenes were also suppressed. We identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1-regulated gene and demonstrated that RUNX2 gene silencing inhibits HCC cell viability, growth, migration and increased cell sensitivity to sorafenib. We propose that the NUPR1/RELB/IER3/RUNX2 pathway has a pivotal role in hepatocarcinogenesis. The identification of the NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management.

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Section: Resultsmentioning

confidence: 99%

NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance

et al. 2016

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“…Silencing of the RUNX2 is also confirmed to inhibit SGC7901 cell proliferation and promote apoptosis in gastric cancer [25]. Wang et al revealed that RUNX2 suppression of RUNX2 could inhibit epithelial ovarian carcinoma cell proliferation, migration and invasion [26]. Consistent with these findings, our results showed that knockdown of RUNX2 knockdown inhibited TE-1 and EC109 cell viability, repressed TE-1 cell migration and invasion, and induced TE-1 cell apoptosis in vitro and suppressed tumor formation in vivo.…”

Section: Discussionmentioning

confidence: 99%

RUNX2 Plays An Oncogenic Role in Esophageal Carcinoma by Activating the PI3K/AKT and ERK Signaling Pathways

Lü

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Esophageal carcinoma is a frequently occurring cancer at upper gastrointestinal tract. We aimed to evaluate the roles and possible mechanism of Runt Related Transcription Factor 2 (RUNX2) in the development of esophageal cancer. Methods: The expression of RUNX2 in esophageal carcinoma tissues and cells was investigated by qRT-PCR. Effects of RUNX2 on cell viability, apoptosis, migration and invasion were assessed using MTT assay, flow cytometry assay/western blot analysis, and Transwell assays, respectively. Afterwards, effects of RUNX2 on of the activation of the PI3K/AKT and ERK pathways were explored by Western blot analysis. In addition, a PI3K/AKT pathway inhibitor LY294002 and an ERK inhibitor U0126 were applied to further verify the regulatory relationship between RUNX2 and the PI3K/AKT and ERK signaling pathways. Besides, the RUNX2 function on tumor formation in vivo was investigated by tumor xenograft experiment. Results: The result showed that RUNX2 was highly expressed in esophageal carcinoma tissues and cells. Knockdown of RUNX2 significantly inhibited TE-1 and EC-109 cell viability, repressed TE-1 cell migration and invasion, and increased TE-1 cell apoptosis. RUNX2 overexpression showed the opposite effects on HET-1A cells. Moreover, RUNX2-mediated TE-1 cell viability, migration and invasion were associated with the activation of the PI3K/AKT and ERK pathways. Besides, knockdown of RUNX2 markedly suppressed tumor formation in vivo. Conclusion: Our results indicate that RUNX2 may play an oncogenic role in esophageal carcinoma by activating the PI3K/ AKT and ERK pathways. RUNX2 may serve as a potent target for the treatment of esophageal carcinoma.

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“…Factors that are crucial during embryogenesis are often hijacked during cancer progression, and RUNX2 is not an exception. RUNX2 is increasingly recognized in cancer biology for its oncogenic properties and a large number of articles link the deregulation of RUNX2 expression with progression and metastasization of different types of epithelial tumors (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Regulation of RUNX2 may occur at multiple levels and through multiple signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

Sancisi¹,

Gandolfi²,

Ambrosetti

et al. 2015

Cancer Research

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Aberrant reactivation of embryonic pathways occurs commonly in cancer. The transcription factor RUNX2 plays a fundamental role during embryogenesis and is aberrantly reactivated during progression and metastasization of different types of human tumors. In this study, we attempted to dissect the molecular mechanisms governing RUNX2 expression and its aberrant reactivation. We identified a new regulatory enhancer element, located within the RUNX2 gene, which is responsible for the activation of the RUNX2 promoter and for the regulation of its expression in cancer cells. Furthermore, we have shown that treatment with the anticancer compounds histone deacetylase inhibitor (HDACi) results in a profound inhibition of RUNX2 expression, which is determined by the disruption of the transcription-activating complex on the identified enhancer. These data envisage a possible targeting strategy to counteract the oncongenic function of RUNX2 in cancer cells and provide evidence that the cytotoxic activity of HDACi in cancer is not only dependent on the reactivation of silenced oncosuppressors but also on the repression of oncogenic factors that are necessary for survival and progression.Cancer Res; 75(9); 1868-82. Ó2015 AACR.

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Inhibition of RUNX2 Transcriptional Activity Blocks the Proliferation, Migration and Invasion of Epithelial Ovarian Carcinoma Cells

Cited by 34 publications

References 76 publications

NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance

NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance

RUNX2 Plays An Oncogenic Role in Esophageal Carcinoma by Activating the PI3K/AKT and ERK Signaling Pathways

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

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