Sox9 and Hif-2α regulate TUBB3 gene expression and affect ovarian cancer aggressiveness

Raspaglio, Giuseppina; Petrillo, Marco; Martinelli, Elisa; Puma, Domenica Donatella Li; Mariani, Marisa; Donato, Marta De; Filippetti, Flavia; Mozzetti, Simona; Prislei, Silvia; Zannoni, Gian Franco; Scambia, Giovanni; Ferlini, Cristiano

doi:10.1016/j.gene.2014.03.037

Cited by 70 publications

(65 citation statements)

References 27 publications

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“…Finally, we found that the inhibition of SOX9 with siRNA enhanced the cytotoxic effect of doxorubicin/cisplatin in chordoma cells, which is consistent with a previous report that the knockdown of SOX9 sensitized ovarian cancer cells to paclitaxel and cisplatin (53). This data suggests that a combination therapy of SOX9 inhibition and chemotherapy drugs could be considered for clinical trials as a potent treatment for chordoma patients.…”

Section: Discussionsupporting

confidence: 92%

Expression and Therapeutic Potential of SOX9 in Chordoma

Chen

Garbutt

Spentzos

et al. 2017

Clinical Cancer Research

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Purpose Conventional chemotherapeutic agents are ineffective in the treatment of chordoma. We investigated the functional roles and therapeutic relevance of the sex-determining region Y (SRY)-box 9 (SOX9) in chordoma. Experimental Design SOX9 expression was examined by immunohistochemistry (IHC) using 50 chordoma tissue samples. SOX9 expression in chordoma cell lines was examined by Western blot and immunofluorescence assays. We used synthetic human SOX9 siRNA to inhibit the expression of SOX9. Cell proliferation ability and cytotoxicity of inhibiting SOX9 were assessed by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and clonogenic assays. The effect of SOX9 knockdown on chordoma cell motility was evaluated by a wound healing assay and a transwell invasion chamber assay. Knockdown of SOX9 induced apoptosis, cell cycle arrest as well as decreased expression of cancer stem cell markers were determined by Western blot and flow cytometric assays. The effect of the combination of SOX9 siRNA and the chemotherapeutic drug doxorubicin/cisplatin on chordoma cells was assessed by a MTT assay. Results Tissue microarray (TMA) and IHC analysis showed that SOX9 is broadly expressed in chordomas and that higher expression levels of SOX9 correlated with a poor prognosis. RNA interference (RNAi)-mediated knockdown of SOX9 inhibited chordoma cell growth, decreased cell motility, and induced apoptosis as well as cell cycle arrest. Moreover, the combination of SOX9 inhibition and chemotherapeutic drugs had an enhanced anti-cancer effect on chordoma cells. Conclusions Our results demonstrate that SOX9 plays a crucial role in chordoma. Targeting SOX9 provides a new rationale for treatment of chordoma.

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Section: Discussionsupporting

confidence: 92%

Expression and Therapeutic Potential of SOX9 in Chordoma

Chen

Garbutt

Spentzos

et al. 2017

Clinical Cancer Research

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“…This molecule has been linked to both overexpression of ErbB2 [158, 159], which we found upregulated in margin Kd (p = 0.0031) and loss of PTEN [160, 161], which was also significantly downregulated in the margin Kd in our microarray data (p = 2.86 x 10 −5 ). TUBB3 is associated with aggressive tumorigenesis in hypoxic environments [162], where it has been linked with chemoresistance, particularly taxanes [163–165]. This may be relevant to KD where there is evidence of a similarly hypoxic environment [63, 166, 167].…”

Section: Resultsmentioning

confidence: 99%

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

et al. 2017

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Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFβ-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

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“…Transcription factors responded to diverse cellular stresses to regulate expression of their target genes, thereby inducing cell cycle control, apoptosis and senescence [23][24][25][26][27][28]. E2F family of transcription factors regulates various cellular functions related to cell cycle and apoptosis and is strongly up-regulated in human hepatocellular carcinoma, thus possibly contributing to hepatocarcinogenesis [24].…”

Section: Hypoxia As Well As the Endoplasmic Reticulum Stress Are Impomentioning

confidence: 99%

“…Recently it was shown that knockdown of endothelial PAS domain protein 1, which is also known as hypoxia-inducible transcription factor-2α (HIF-2α), as well as HIF-1α in pulmonary vascular endothelial cells decreased cell proliferation under normoxic as well as hypoxic conditions and that HIF-2α and SOX9 regulate TUBB3 gene expression and affect ovarian cancer aggressiveness [26,41]. Moreover, the expression of ePaS1 gene was significantly correlated with tumor size, invasion, and necrosis as well as with VeGf gene expression, which supported the correlation of EPAS1 up-regulation with tumor angiogenesis [42].…”

Section: Hypoxia As Well As the Endoplasmic Reticulum Stress Are Impomentioning

confidence: 99%

“…Thus, transcription factor HOXC6 may contribute to suppression of proliferation rate of glioma cells without ERN1 signaling enzyme function. Moreover, the decreased expression level of aTf3 and ePaS1 genes in ERN1 knockdown glioma cells may also contribute to suppression of proliferation, because these transcription factors play an important role in the control of tumor growth [25,26,[37][38][39]42]. At the same time, blockade of ERN1 signaling enzyme function enhances the hypoxic regulation of aTf3 and ePaS1 gene expressions, but prospective studies are still needed to clarify the significance of these results.…”

Section: Fig 1 Effect Of Hypoxia On the Expression Of Hoxc6 (Homeobmentioning

confidence: 99%

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