Elevated expression of SOX9 is related with the progression of gastric carcinoma

Zhou, Chengjun; Guo, Jianqiang; Zhu, Kongxi; Pan, Cheng-Ran; Xu, Weihua; Wang, Hongjuan; Liu, Bin

doi:10.1002/dc.21348

Cited by 34 publications

(33 citation statements)

References 20 publications

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“…In the present study, it was revealed that SOX9 knockdown led to suppressed cell proliferation and increased cell apoptosis, indicating that SOX9 is a tumor promoter in AEG. This finding is consistent with the role of SOX9 in other types of tumor (20)(21)(22). It has previously been reported that SOX9 mediates the effect of certain antitumor drugs; SOX9 expression was markedly inhibited in mice tumors by combination treatment with ABT-263 and 5-FU (24).…”

Section: Discussionsupporting

confidence: 91%

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Inï¿½vitro study on the role of SOX9 in trastuzumab resistance of adenocarcinoma of the esophagogastric junction

et al. 2018

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Abstract. Trastuzumab is recommended for the treatment of human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagogastric junction (AEG) in combination with chemotherapy; however, drug resistance has severely affected its clinical application. The present study aimed to investigate the effect of sex determining region Y-box 9 (SOX9), a prognostic marker in adjuvant oncological settings, on AEG cell proliferation and apoptosis in the presence or absence of trastuzumab. Furthermore, the molecular mechanism underlying the role of SOX9 in trastuzumab resistance was explored. ESO26 cells were treated with various concentrations of trastuzumab, and trastuzumab induced SOX9 expression in a concentration-dependent manner, as determined by reverse transcription-quantitative polymerase chain reaction and western blotting analyses. Transfection of ESO26 cells with SOX9 small interfering RNA was conducted to knock down SOX9 expression, and the results of MTT and flow cytome try assays demonstrated that SOX9 knockdown sensitized ESO26 cells to trastuzumab by inhibiting cell proliferation and enhancing cell apoptosis. In addition, it was observed that the trastuzumab-induced phosphorylation of AKT was suppressed by SOX9 knockdown. In conclusion, the present study demonstrated that SOX9 participated in trastuzumab resistance by affecting cell proliferation and apoptosis, and indicated that SOX9 may exert its effect on trastuzumab resistance via activation of the phosphatidylinositol-3-kinase/AKT signaling pathway. This study identified a novel mechanism underlying trastuzumab resistance in vitro and may be useful in improving the efficacy of trastuzumab treatment. IntroductionAdenocarcinoma of the esophagogastric junction (AEG) is a lethal malignancy originating from the distal esophagus and the esophagogastric junction (1,2). The incidence of AEG has increased rapidly worldwide during the past two decades (3-6). The prognosis of AEG is poor due to distant metastasis at the time of diagnosis and the limited treatment options (7,8). Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), has emerged as an effective therapeutic option for AEG when combined with chemotherapy (9).In a phase III, open-label, international, randomized controlled trial, Bang et al (9) observed that patients treated with trastuzumab plus chemotherapy had longer median follow-up and median overall survival times compared with patients treated with chemotherapy alone. The authors suggested that trastuzumab in combination with chemotherapy may be a new standard option for the first-line treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer (9). International National Comprehensive Cancer Network Guidelines recommend the detection of HER2 in patients with AEG in order to guide the selection of further clinical treatment options (10). However, trastuzumab treatment is invalid for nearly half of HER2-positive patients (9), and the mechanisms of drug resistance are curre...

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Section: Discussionsupporting

confidence: 91%

“…The importance of SOX9 in tumorigenesis has been identified, and the dysregulation of SOX9 has been implicated in several cancers, including prostate cancer, lung adenocarcinoma and gastric carcinoma (20)(21)(22). Overexpression of SOX9 has been demonstrated to increase tumor growth, invasion and angiogenesis (14,23).…”

Section: Discussionmentioning

confidence: 99%

Inï¿½vitro study on the role of SOX9 in trastuzumab resistance of adenocarcinoma of the esophagogastric junction

et al. 2018

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“…Previously, increased mortality associated with elevated SOX9 has been observed in numerous cancers, including separate cohorts of colon and rectal cancer (Lü et al , 2008; Zhou et al , 2011; Matheu et al , 2012; Mazur et al , 2012). Many studies report mechanistic roles for SOX9 in cancer promotion, specifically in apoptotic resistance, neoplastic transformation and proliferation in glioma, colorectal and prostate cancer (Bastide et al , 2007; Matheu et al , 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In cancer, SOX9 regulates proliferation, differentiation and metastasis (Bastide et al , 2007; Matheu et al , 2012). Clinical studies in breast, gastric biliary tract and CRC indicate poorer prognosis with tumour SOX9 overexpression (Lü et al , 2008; Zhou et al , 2011; Matheu et al , 2012; Mazur et al , 2012). Hence, considering the mechanistic evidence for the roles of HEY1, HES1 and SOX9 in cancer pathogenesis and the preclinical data implicating Notch signalling chemotherapy responsiveness, we set out to characterise the expression of these NTFs in CRC and to explore a potential role in chemotherapy resistance.…”

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confidence: 99%

Notch-induced transcription factors are predictive of survival and 5-fluorouracil response in colorectal cancer patients

et al. 2013

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Background:The purpose of this study was to evaluate the expression of Notch-induced transcription factors (NTFs) HEY1, HES1 and SOX9 in colorectal cancer (CRC) patients to determine their clinicopathologic and prognostic significance.Methods:Levels of HEY1, HES1 and SOX9 protein were measured by immunohistochemistry in a nonmalignant and malignant tissue microarray of 441 CRC patients, and the findings correlated with pathologic, molecular and clinical variables.Results:The NTFs HEY1, HES1 and SOX9 were overexpressed in tumours relative to colonic mucosa (OR=3.44, P<0.0001; OR=7.40, P<0.0001; OR=4.08 P<0.0001, respectively). HEY1 overexpression was a negative prognostic factor for all CRC patients (HR=1.29, P=0.023) and strongly correlated with perineural and vascular invasion and lymph node (LN) metastasis. In 5-fluorouracil (5-FU)-treated patients, the tumour overexpression of SOX9 correlated with markedly poorer survival (HR=8.72, P=0.034), but had no predictive effect in untreated patients (HR=0.70, P=0.29). When HEY1, HES1 and SOX9 expression were combined to predict survival with chemotherapy, in treated patients there was an additive increase in the risk of death with each NTF overexpressed (HR=2.09, P=0.01), but no prognostic import in the untreated patient group (HR=0.74, P=0.19).Conclusion:The present study is the first to discover that HEY1 overexpression correlates with poorer outcome in CRC, and NTF expression is predictive of CRC patient survival with 5-FU chemotherapy. If confirmed in future studies, testing of NTF expression has the potential to enter routine pathological practice for the selection of patients to undergo chemotherapy alone or in combination with Notch inhibitors.

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“…SOX9 expression is upregulated by PGD2, and ectopic SOX9 expression has been shown to suppress growth of ovarian cancer and melanoma cells in vitro and/or in vivo [32]. However, both aberrant SOX9 expression in carcinoma tissues and elevated SOX9 expression are correlated to disease progression and poor prognosis for hepatocellular carcinoma, gastric cancer and prostate cancer [33-35]. SOX9 protein levels are elevated in invasive human uroepithelial carcinoma tissues, which are induced by the activation of epidermal growth factor receptor [34].…”

Section: Introductionmentioning

confidence: 99%

H-rev107 regulates prostaglandin D2 synthase-mediated suppression of cellular invasion in testicular cancer cells

Shyu

Wang

et al. 2013

J Biomed Sci

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BackgroundH-rev107 is a member of the HREV107 type II tumor suppressor gene family which includes H-REV107, RIG1, and HRASLS. H-REV107 has been shown to express at high levels in differentiated tissues of post-meiotic testicular germ cells. Prostaglandin D2 (PGD2) is conjectured to induce SRY-related high-mobility group box 9 (SOX9) expression and subsequent Sertoli cell differentiation. To date, the function of H-rev107 in differentiated testicular cells has not been well defined.ResultsIn the study, we found that H-rev107 was co-localized with prostaglandin D2 synthase (PTGDS) and enhanced the activity of PTGDS, resulting in increase of PGD2 production in testis cells. Furthermore, when H-rev107 was expressed in human NT2/D1 testicular cancer cells, cell migration and invasion were inhibited. Also, silencing of PTGDS would reduce H-rev107-mediated increase in PGD2, cAMP, and SOX9. Silencing of PTGDS or SOX9 also alleviated H-rev107-mediated suppression of cell migration and invasion.ConclusionsThese results revealed that H-rev107, through PTGDS, suppressed cell migration and invasion. Our data suggest that the PGD2-cAMP-SOX9 signal pathway might play an important role in H-rev107-mediated cancer cell invasion in testes.

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Elevated expression of SOX9 is related with the progression of gastric carcinoma

Cited by 34 publications

References 20 publications

Inï¿½vitro study on the role of SOX9 in trastuzumab resistance of adenocarcinoma of the esophagogastric junction

Inï¿½vitro study on the role of SOX9 in trastuzumab resistance of adenocarcinoma of the esophagogastric junction

Notch-induced transcription factors are predictive of survival and 5-fluorouracil response in colorectal cancer patients

H-rev107 regulates prostaglandin D2 synthase-mediated suppression of cellular invasion in testicular cancer cells

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