SOX9 Elevation in the Prostate Promotes Proliferation and Cooperates with <i>PTEN</i> Loss to Drive Tumor Formation

Thomsen, Martin K.; Ambroisine, Laurence; Wynn, Sarah; Cheah, Kathryn S.E.; Foster, Christopher S.; Fisher, Gabrielle; Berney, Daniel M.; Møller, Henrik; Reuter, Victor E.; Scardino, Peter T.; Cuzick, Jack; Ragavan, Narasimhan; Singh, Paras B.; Martin, Francis L.; Butler, C. J.; Cooper, Christopher S.; Swain, Amanda

doi:10.1158/0008-5472.can-09-2370

Cited by 122 publications

(136 citation statements)

References 31 publications

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“…But the expression level of SOX9 in PCa tissues were higher than that in adjacent benign prostate tissues (IRS: PCa = 7.16 ± 0.228 vs. Benign = 5.96 ± 0.461, p = 0.041) significantly (Figure 2). The SOX7 and SOX9 expression occurred mainly in the nucleus, while SOX10 in the cytoplasm, which is similar to the results from the previous studies [10,12]. Representative pictures of immunohistochemistry staining of SOX7, SOX9 and SOX10 are shown in Figure 3.…”

Section: Resultssupporting

confidence: 88%

“…In 2007 and 2008, Wang et al [7,8] also demonstrated that SOX9 was expressed in PCa cells and was increased in relapsed hormonerefractory PCa. In 2010, Thomsen et al [12] identified SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it promotes tumor cell proliferation. All these previous studies were similar to the findings of our study.…”

Section: Discussionmentioning

confidence: 99%

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SOXs in human prostate cancer: implication as progression and prognosis factors

et al. 2012

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BackgroundSOX genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the involvement of SOXs in the progression and prognosis of human prostate cancer (PCa).MethodsThe gene expression changes of SOXs in human PCa tissues compared with non-cancerous prostate tissues was detected using gene expression microarray, and confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. The roles of these genes in castration resistance were investigated in LNCaP xenograft model of PCa.ResultsThe microarray analysis identified three genes (SOX7, SOX9 and SOX10) of SOX family that were significantly dis-regulated in common among four PCa specimens. Consistent with the results of the microarray, differential mRNA and protein levels of three selected genes were found in PCa tissues by QRT-PCR analysis and immunohistochemistry. Additionally, we found that the immunohistochemical staining scores of SOX7 in PCa tissues with higher serum PSA level (P = 0.02) and metastasis (P = 0.03) were significantly lower than those with lower serum PSA level and without metastasis; the increased SOX9 protein expression was frequently found in PCa tissues with higher Gleason score (P = 0.02) and higher clinical stage (P < 0.0001); the down-regulation of SOX10 tend to be found in PCa tissues with higher serum PSA levels (P = 0.03) and advanced pathological stage (P = 0.01). Moreover, both univariate and multivariate analyses showed that the down-regulation of SOX7 and the up-regulation of SOX9 were independent predictors of shorter biochemical recurrence-free survival. Furthermore, we discovered that SOX7 was significantly down-regulated and SOX9 was significantly up-regulated during the progression to castration resistance.ConclusionsOur data offer the convince evidence that the dis-regulation of SOX7, SOX9 and SOX10 may be associated with the aggressive progression of PCa. SOX7 and SOX9 may be potential markers for prognosis in PCa patients. Interestingly, the down-regulation of SOX7 and the up-regulation of SOX9 may be important mechanisms for castration-resistant progression of PCa.

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Section: Resultssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

SOXs in human prostate cancer: implication as progression and prognosis factors

et al. 2012

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“…Mouse models with specific loss of Pten in combination with other genes have unravelled prostate cancer modulators, such as TRP53, SMAD4 and JNK. 4,6,9,3,[27][28][29] We show here that JunB limits tumour progression of Pten-deficient prostate neoplasia as the loss of Junb, even in few cells, is sufficient to promote invasiveness.…”

Section: Discussionmentioning

confidence: 59%

Loss of JUNB/AP-1 promotes invasive prostate cancer

et al. 2014

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Prostate cancer is a frequent cause of male death in the Western world. Relatively few genetic alterations have been identified, likely owing to disease heterogeneity. Here, we show that the transcription factor JUNB/AP-1 limits prostate cancer progression. JUNB expression is increased in low-grade prostate cancer compared with normal human prostate, but downregulated in highgrade samples and further decreased in all metastatic samples. To model the hypothesis that this downregulation is functionally significant, we genetically inactivated Junb in the prostate epithelium of mice. When combined with Pten (phosphatase and tensin homologue) loss, double-mutant mice were prone to invasive cancer development. Importantly, invasive tumours also developed when Junb and Pten were inactivated in a small cell population of the adult anterior prostate by topical Cre recombinase delivery. The resulting tumours displayed strong histological similarity with human prostate cancer. Loss of JunB expression led to increased proliferation and decreased senescence, likely owing to decreased p16Ink4a and p21 CIP1 in epithelial cells. Furthermore, the tumour stroma was altered with increased osteopontin and S100 calcium-binding protein A8/9 expression, which correlated with poor prognoses in patients. These data demonstrate that JUNB/AP-1 cooperates with PTEN signalling as barriers to invasive prostate cancer, whose concomitant genetic or epigenetic suppression induce malignant progression.

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“…Sox9 sustains the survival of neurofibromatosis tumor cell lines (Miller et al, 2009). Sox9 is expressed in the prostate epithelia and promotes prostate tumor cell proliferation and cooperates with Pten loss to drive tumor formation (Thomsen et al, 2010 floxdel/floxdel chondrocytes. Thus, the chondrocytespecific anti-apoptotic mechanism includes PI3K-Akt pathways that are activated by Sox9 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…It is also possible that increased apoptosis in the terminal mature chondrocytes of 11Prom-Cre mice might reflect an acceleration of the whole process of terminal maturation, including their removal via apoptosis. Because Sox9 does not appear to increase phosphoAkt levels in the prostate (Thomsen et al, 2010), the mechanisms by which Sox9 sustains cell survival might differ between tissues.…”

Section: Discussionmentioning

confidence: 99%

Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways

et al. 2011

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SUMMARYDuring endochondral bone formation, Sox9 expression starts in mesenchymal progenitors, continues in the round and flat chondrocyte stages at high levels, and ceases just prior to the hypertrophic chondrocyte stage. Sox9 is important in mesenchymal progenitors for their differentiation into chondrocytes, but its functions post-differentiation have not been determined. To investigate Sox9 function in chondrocytes, we deleted mouse Sox9 at two different steps after chondrocyte differentiation. Sox9 inactivation in round chondrocytes resulted in a loss of Col2a1 expression and in apoptosis. Sox9 inactivation in flat chondrocytes caused immediate terminal maturation without hypertrophy and with excessive apoptosis. Inactivation of Sox9 in the last few cell layers resulted in the absence of Col10a1 expression, suggesting that continued expression of Sox9 just prior to hypertrophy is necessary for chondrocyte hypertrophy. SOX9 knockdown also caused apoptosis of human chondrosarcoma SW1353 cells. These phenotypes were associated with reduced Akt phosphorylation. Forced phosphorylation of Akt by Pten inactivation partially restored Col10a1 expression and cell survival in Sox9 floxdel/floxdel mouse chondrocytes, suggesting that phosphorylated Akt mediates chondrocyte survival and hypertrophy induced by Sox9. When the molecular mechanism of Sox9-induced Akt phosphorylation was examined, we found that expression of the PI3K subunit Pik3ca (p110) was decreased in Sox9 floxdel/floxdel mouse chondrocytes. Sox9 binds to the promoter and enhances the transcriptional activities of Pik3ca. Thus, continued expression of Sox9 in differentiated chondrocytes is essential for subsequent hypertrophy and sustains chondrocyte-specific survival mechanisms by binding to the Pik3ca promoter, inducing Akt phosphorylation.

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SOX9 Elevation in the Prostate Promotes Proliferation and Cooperates with PTEN Loss to Drive Tumor Formation

Cited by 122 publications

References 31 publications

SOXs in human prostate cancer: implication as progression and prognosis factors

SOXs in human prostate cancer: implication as progression and prognosis factors

Loss of JUNB/AP-1 promotes invasive prostate cancer

Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways

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