Overexpression of SDF-1 activates the NF-κB pathway to induce epithelial to mesenchymal transition and cancer stem cell-like phenotypes of breast cancer cells

Kong, Lingxin; Guo, Shu; Liu, Chunfeng; Zhao, Yong; Feng, Chong; Liu, Yunshuang; Wang, Tao; Li, Caijuan

doi:10.3892/ijo.2016.3343

Cited by 42 publications

(28 citation statements)

References 40 publications

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“…Migration and CSL properties increase the risk of malignant tumor metastasis (28)(29)(30). Therefore, we investigated these phenomena along the NF-κB/Twist axis, using scratch assay and sphere formation to detect migration and self-renewal.…”

Section: Discussionmentioning

confidence: 99%

Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

et al. 2017

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Abstract. Persistent human papilloma virus (HPV) infection induces chronic inflammation resulting in human cervical cancer. However, the mechanisms underlying carcinogenesis via chronic inflammation remain largely unclear. We investigated the role of pro-inflammatory factors in epithelial-mesenchymal transition (EMT) and cancer stem cell-like (CSCL) characteristics of HeLa cells exposed to TNF-α with or without TGF-β. We then determined the role of NF-κB/Twist signal axis in the pathogenesis of cervical cancer. We found that HeLa cells exposed to TNF-α following chronic treatment with TGF-β exhibited EMT, self-renewal and high mobility. Knockdown of NF-κBp65 inhibited NF-κB and Twist1 expression, and EMT and CSCL properties of HeLa cells following co-treatment with TNF-α and TGF-β. Conversely, overexpression of NF-κBp65 potentiated the above effects. However, knockdown or overexpression of Twist1 had no effect on NF-κBp65 expression, but inhibited or promoted EMT and CSCL features. Notably, overexpression of Twist1 rescued NF-κBp65 knockdown. Our results demonstrate the role of NF-κB/Twist signaling axis in which HeLa cells treated with TNF-α following chronic exposure to TGF-β induce EMT and CSCL properties. The NF-κB/Twist signal axis may represent an effective therapeutic target in cervical cancer. IntroductionCervical cancer is a key factor associated with morbidity and mortality in women worldwide (1). Infection with human papilloma viruses (HPV) triggers carcinogenesis. Most of the precancerous lesions do not progress to invasive carcinoma, suggesting that HPV is not the only factor contributing to the development of cervical cancer (2,3). However, persistent HPV infection alters the pro-inflammatory cytokine profile, resulting in chronic inflammation and recurrence of cervical cancer (4). Cancer stem cells (CSCs) play a vital role in cancer initiation and metastasis (5). Metastasis results in treatment failure and death (6). Epithelial-mesenchymal transition (EMT) has been implicated as the key factor in CSCs transformation (7,8). EMT has been shown to induce reversion to a CSC-like phenotype, linking CSCs and EMT (9,10).NF-κB is a classic transcription factor activated by inflammatory stimuli, such as LPS (11), TNF-α (12) and IL-10 (13). Activated NF-κB induces extensive gene expression in immune response (TNF-α), angiogenesis (VEGF), invasion (MMP-9) and EMT (Twist) (14-17). Furthermore, NF-κB, a pleiotropic transcription factor, has been implicated in . In mammary epithelial cells, EMT is upregulated via overexpression of NF-κBp65 (17).The transcriptional factor TWIST mediates EMT and cancer metastasis (18,19). In uterine cancers, Twist overexpression promotes invasion and metastasis (20-23). However, the role of NF-κB/Twist axis in cervical cancer has not been investigated. In this study, we focused on the role of NF-κB/ Twist axis in vitro, by co-treatment of human cervical cancer cell line HeLa with TNF-α and TGF-β. Materials and methodsReagents. DMEM was obtained from Gibco, FBS from PAA, trypsin a...

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Section: Discussionmentioning

confidence: 99%

Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

et al. 2017

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“…Meanwhile, an increase of angiogenic factors, such as HIF-1 α , SDF-1, and VEGF, in turn causes activation of matrix metalloproteinase-9 and thus initiates recruitment and mobilization of BM-EPCs in the peripheral circulation [49]. Our results indicate that active c-Kit + ASCs may recruit myeloid cells by SDF-1 for angiogenesis, thereby stimulating EPCs to form vessels followed by the release of VEGF-A, which are crucial factors for the proliferation of breast cancer cells in the tumor microenvironment [50, 51]. …”

Section: Discussionmentioning

confidence: 97%

c-Kit-Positive Adipose Tissue-Derived Mesenchymal Stem Cells Promote the Growth and Angiogenesis of Breast Cancer

Cheng

2017

BioMed Research International

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Background Adipose tissue-derived mesenchymal stem cells (ASCs) improve the regenerative ability and retention of fat grafts for breast reconstruction in cancer patients following mastectomy. However, ASCs have also been shown to promote breast cancer cell growth and metastasis. For the safety of ASC application, we aimed to identify specific markers for the subpopulation of ASCs that enhance the growth of breast cancer. Methods ASCs and bone marrow-derived vascular endothelial progenitor cells (EPCs) were isolated from Balb/c mice. c-Kit-positive (c-Kit+) or c-Kit-negative (c-Kit−) ASCs were cocultured with 4T1 breast cancer cells. Orthotropic murine models of 4T1, EPCs + 4T1, and c-Kit+/-ASCs + 4T1/EPCs were established in Balb/c mice. Results In coculture, c-Kit+ ASCs enhanced the viability and proliferation of 4T1 cells and stimulated c-Kit expression and interleukin-3 (IL-3) release. In mouse models, c-Kit+ASCs + 4T1/EPCs coinjection increased the tumor volume and vessel formation. Moreover, IL-3, stromal cell-derived factor-1, and vascular endothelial growth factor A in the c-Kit+ASCs + 4T1/EPCs coinjection group were higher than those in the 4T1, EPCs + 4T1, and c-Kit−ASCs + 4T1/EPCs groups. Conclusions c-Kit+ ASCs may promote breast cancer growth and angiogenesis by a synergistic effect of c-Kit and IL-3. Our findings suggest that c-Kit+ subpopulations of ASCs should be eliminated in fat grafts for breast reconstruction of cancer patients following mastectomy.

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“…The potential mechanism may be that SDF-1 activates the NF-κB pathway by the interaction with CXCR4. The SDF-1/CRCR4-NF-κB pathway participates in the regulation of cell prliferation, apoptosis, and angiogenesis in cervical cancer [28,29]. The increased expression of VEGF and MMPS caused by SDF-1-CXCR4 interaction and many NF-κB-related biological macular-involved cell cycle, apoptosis, and chronic inflammation responses may mediate the initiation and progression of cervical cancer [30–32].…”

Section: Discussionmentioning

confidence: 99%

High Expression of Stromal Cell-Derived Factor 1 (SDF-1) and NF-κB Predicts Poor Prognosis in Cervical Cancer

Song

Zhang

et al. 2017

Med Sci Monit

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BackgroundSDF-1 and NF-κB are associated with the prognosis of a wide range of cancers, but their value in cervical cancer remains controversial. The aim of this study was to investigate the expression of SDF-1and NF-κB in cervical cancer and their significance in clinical prognosis.Material/MethodsThe expression of SDF-1and NF-κB in 105 formalin-fixed, paraffin-embedded cervical cancer tissues and the adjacent tissues was examined by immunohistochemistry (IHC). The results were semi-quantitatively scored and analyzed by chi-square test. The overall survival times (OS) were collected by follow-up and analyzed by Kaplan-Meier analysis.ResultsThe expression level of both SDF-1and NF-κB in cervical cancer are higher than that in the adjacent tissues (P<0.05). SDF-1 expression are correlated with tumor size and FIGO histology grade (P<0.05). NF-κB expression are correlated with tumor size and FIGO histology grade, and lymph node metastasis (LNM) status (P<0.05). The patients with a positive expression of SDF-1or NF-κB tended to have much shorter survival time than patients with negative expression. In addition, multivariate Cox regression analysis demonstrated that SDF-1 expression and lymph node metastasis are independent predictors of the OS in cervical cancer patients.ConclusionsThe expression of SDF-1 is significantly associated with tumor size and FIGO histology grade. The expression of NF-κB is significantly associated with tumor size, FIGO histology grade, and lymph node metastasis. The positive SDF-1or NF-κB expression is significantly correlated with poor prognosis. These may be valuable biomarkers for the prognosis and the potential therapeutic targets of cervical cancer.

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Overexpression of SDF-1 activates the NF-κB pathway to induce epithelial to mesenchymal transition and cancer stem cell-like phenotypes of breast cancer cells

Cited by 42 publications

References 40 publications

Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

c-Kit-Positive Adipose Tissue-Derived Mesenchymal Stem Cells Promote the Growth and Angiogenesis of Breast Cancer

High Expression of Stromal Cell-Derived Factor 1 (SDF-1) and NF-κB Predicts Poor Prognosis in Cervical Cancer

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