Targeting BMI1 + Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma

Chen, Demeng; Wu, Man-Si; Yang, Li; Chang, Insoon; Yuan, Quan; Ekimyan-Salvo, Mari; Deng, Peng; Yu, Bo; Yu, Yongxin; Dong, Jiaqiang; Szymanski, John M.; Sivakumar, R; Li, Jiong; Wang, Cun‐Yu

doi:10.1016/j.stem.2017.02.003

Cited by 224 publications

(242 citation statements)

References 43 publications

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“…Bmi1-positive lingual epithelia could serve as CSCs and were considered to be the origin of tongue cancer [37]. Furthermore, overexpression of Bmi1 was reported to be associated with poor survival in OSCC patients [38][39][40], and targeting Bmi1 could inhibit tumor growth and overcome chemoresistance [21,41]. Collectively, these findings suggest that sustained upregulation of Bmi1 in oral epithelia after radiotherapy may lead to the development and poor outcome of s-OSCC.…”

Section: Discussionmentioning

confidence: 99%

The poor outcome of second primary oral squamous cell carcinoma is attributed to Bmi1 upregulation

Chen

et al. 2018

Cancer Medicine

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Radiotherapy for nasopharyngeal carcinoma has been reported to cause second primary oral squamous cell carcinoma (s‐OSCC). The prognosis and pathologic characteristic of s‐OSCC are largely unknown. Bmi1 was associated with the repair of radiation‐induced DNA damage, suggesting its possible involvement in the pathologic process of s‐OSCC. Herein, we compared the prognosis between s‐OSCC and primary OSCC (p‐OSCC) and explored the involvement of Bmi1 in s‐OSCC development. In this retrospective study, s‐OSCC and p‐OSCC patients were matched by propensity scores. Their outcomes were compared by univariate and multivariate analyses. The expression of Bmi1 in s‐OSCC and p‐OSCC was detected by immunohistochemistry (IHC). Radiation‐induced Bmi1 alteration in early‐stage was explored in a rat model and HaCaT cells. After matching, 116 pairs of patients with highly balanced characteristics were included. In univariate analysis, the overall survival (OS), disease‐specific survival (DSS), and local recurrence‐free survival (LRFS) were poorer in s‐OSCC than in p‐OSCC (P < 0.05), while their regional metastasis‐free survival (RMFS) was parallel (P = 0.112). Multivariate analysis further revealed that radiotherapy history was an independent risk factor for OS, DSS, and LRFS (P < 0.05). IHC results showed that the positive rate of Bmi1 was higher in s‐OSCC (P = 0.0027). In a rat model of radiotherapy‐induced mucositis, Bmi1 upregulation was observed 8 days after irradiation. Consistently, Bmi1 was upregulated in HaCaT cells 1 h after irradiation, and its upregulation was in accord with X‐ray exposure duration. In conclusion, the prognosis of s‐OSCC is poorer as compared to p‐OSCC, which may be attributed to Bmi1 upregulation.

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Section: Discussionmentioning

confidence: 99%

The poor outcome of second primary oral squamous cell carcinoma is attributed to Bmi1 upregulation

Chen

et al. 2018

Cancer Medicine

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“…These have been particularly valuable for studying specific aspects of cancer biology and treatment response (Agarwal et al., ; Dardenne et al., ). Also, spheroid cultures, an established procedure for culturing normal and cancer stem cells in vitro (Civenni et al., ), can be initiated from GEM models, thereby allowing for the selective isolation and propagation of tumor‐initiating cells with stem cell‐like features (Chen et al., ). This opens the possibility of investigating in an ex vivo setting the role of individual or combined genetic drivers on the expansion and maintenance of prostate cancer stem cells.…”

Section: Discussionmentioning

confidence: 99%

Overview of Genetically Engineered Mouse Models of Prostate Cancer and Their Applications in Drug Discovery

2018

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Prostate cancer (PCa) is the most common malignant visceral neoplasm in males in Western countries. Despite progress made in the early treatment of localized malignancies, there remains a need for therapies effective against advanced forms of the disease. Genetically engineered mouse (GEM) models are valuable tools for addressing this issue, particularly in defining the cellular and molecular mechanisms responsible for tumor initiation and progression. While cell and tissue culture systems are important models for this purpose as well, they cannot recapitulate the complex interactions within heterotypic cells and the tumor microenvironment that are crucial in the initiation and progression of prostate tumors. Limitations of GEM models include resistance to developing invasive and metastatic tumors that resemble the advanced stages of human PCa. Nonetheless, because genetic models provide valuable information on the human condition that would otherwise be impossible to obtain, they are increasingly employed to identify molecular targets and to examine the efficacy of cancer therapeutics. The aim of this overview is to provide a brief but comprehensive summary of GEM models for PCa, with particular emphasis on the strengths and weaknesses of this experimental approach. © 2018 by John Wiley & Sons, Inc.

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“…Moreover, our data show that this increased expression markedly promoted migration of cervical cancer cells, suggesting that GLDC is involved in metastasis promotion. Since GLDC functioned in driving tumorigenesis in cancer stem cells (CSCs) [9], and CSCs is critical for tumor metastasis [34][35][36], GLDC might be the connection between CSCs and metastasis. In one hand, metastasis could be triggered by CSCs via elevated activities of glycine metabolism enzymes including GLDC.…”

Section: Discussionmentioning

confidence: 99%

OGT-mediated O-GlcNAcylation on GLDC promotes metastasis in cervical cancer

Cai¹,

Jin²,

Zhu³

et al. 2018

Oncotarget

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Glycine decarboxylase (GLDC) is one of the glycine metabolic enzymes and was reported as a oncogene involved in tumorigenesis of non-small cell lung cancer. However, the function of GLDC in cervical cancer remains unclear. In this study, we determined the increased expression of GLDC in cervical cancer tissues and cell lines. The clinical pathological characters of GLDC revealed that increased GLDC expression was involved in cervical cancer metastasis. Further in vitro experiments confi rmed the promotion of GLDC on cervical cancer metastasis. Furthermore, we found that OGT interacted with GLDC and modifi ed GLDC with O-GlcNAcylation in cervical cancer cell lines. In addition, the O-GlcNAcylation of GLDC greatly enhanced its promotion on migration and invasion in vitro and in vivo. The clinical data further demonstrated the promotion of GLDC and OGT on cervical cancer metastasis, and showed that OGT worsened the prognosis of GLDC High patients. Collectively, this study identifi ed OGT-mediated O-GlcNAcylation on GLDC as an essential regulatory mechanism for promoting cervical cancer metastasis, and provided a therapeutic target for metastatic cervical cancer. www.impactjournals.com/oncotarget/

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Targeting BMI1 + Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma

Cited by 224 publications

References 43 publications

The poor outcome of second primary oral squamous cell carcinoma is attributed to Bmi1 upregulation

The poor outcome of second primary oral squamous cell carcinoma is attributed to Bmi1 upregulation

Overview of Genetically Engineered Mouse Models of Prostate Cancer and Their Applications in Drug Discovery

OGT-mediated O-GlcNAcylation on GLDC promotes metastasis in cervical cancer

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