Transforming growth factor-β1 upregulates the expression of CXC chemokine receptor 4 (CXCR4) in human breast cancer MCF-7 cells

Zhao, Xiaoping; Huang, Yongyao; Huang, Yu; Lei, Ping; Peng, Jilin; Wang, Sha; Wang, Min; Li, Wen-han; Zhu, Hong-Jian; Shen, Guanxin

doi:10.1038/aps.2009.204

Cited by 52 publications

(19 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, studies have confirmed that there is cross-talk between the TGFb and CXCL12 pathways. Evidence indicates that TGFb induces CXCR4 in tumor cells (34), enhancing the response to CXCL12 to promote invasion and metastasis (35). We also revealed that DPP-4 suppression induces TGFb/Smad signaling, but the TGFb-induced CXCR4 cascade was not relevant for DPP-4-induced EMT and metastasis because the KR-induced CXCL12/CXCR4/mTOR axis and EMT were not suppressed by the TGFb-neutralizing antibody.…”

Section: Discussionmentioning

confidence: 69%

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

et al. 2019

View full text Add to dashboard Cite

Dipeptidyl peptidase (DPP)-4 is a multifunctional glycoprotein involved in various biological and pathologic processes. DPP-4 has been widely recognized as a therapeutic target for type 2 diabetes mellitus but is also implicated in the development of human malignancies. Here, we show that inhibition of DPP-4 accelerates breast cancer metastasis via induction of CXCL12/CXCR4, which activates mTOR to promote epithelial-mesenchymal transition (EMT). In cultured cells, DPP-4 knockdown induced EMT and cell migration. Treatment with the DPP-4 inhibitor KR62436 (KR) promoted primary tumor growth and lung metastasis in a 4T1 tumor allograft mouse model; DPP-4 knockdown in 4T1 cells displayed similar phenotypes in vivo and in vitro. KR treatment enhanced the levels of CXCL12/CXCR4 and phosphorylated mTOR, which were associated with the induction of EMT in metastatic cancer cells. KR-induced EMT in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 or the mTOR inhibitor rapamycin, and AMD3100 suppressed KR-induced metastasis in vivo. Our findings suggest that DPP-4 plays a significant role in cancer biology and that inhibition of DPP-4 promotes cancer metastasis via induction of the CXCL12/CXCR4/mTOR/EMT axis.Significance: These findings reveal that inhibition of DPP-4 increases the metastatic potential of breast cancer. This is especially important given the potential use of DPP-4 inhibition as a therapeutic strategy for type 2 diabetes.

show abstract

Section: Discussionmentioning

confidence: 69%

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In response to TGFβ1, rheumatoid synovial T cells also express high levels of CXCR4 and become responsive to SDF‐1α . In addition, Zhao and colleagues showed that MCF‐7 breast cancer cells significantly increased CXCR4 expression after TGFβ1 treatment. Our group has previously shown that TGFβ and its signaling protein, Smad3, are upregulated at sites of arterial injury .…”

Section: Discussionmentioning

confidence: 99%

Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia

et al. 2016

View full text Add to dashboard Cite

CXCR4 is a stem/progenitor cell surface receptor specific for the cytokine stromal cell‐derived factor‐1 (SDF‐1α). There is evidence that bone marrow‐derived CXCR4‐expressing cells contribute to intimal hyperplasia (IH) by homing to the arterial subintima which is enriched with SDF‐1α. We have previously found that transforming growth factor‐β (TGFβ) and its signaling protein Smad3 are both upregulated following arterial injury and that TGFβ/Smad3 enhances the expression of CXCR4 in vascular smooth muscle cells (SMCs). It remains unknown, however, whether locally induced CXCR4 expression in SM22 expressing vascular SMCs plays a role in neointima formation. Here, we investigated whether elevated TGFβ/Smad3 signaling leads to the induction of CXCR4 expression locally in the injured arterial wall, thereby contributing to IH. We found prominent CXCR4 upregulation (mRNA, 60‐fold; protein, 4‐fold) in TGFβ‐treated, Smad3‐expressing SMCs. Chromatin immunoprecipitation assays revealed a specific association of the transcription factor Smad3 with the CXCR4 promoter. TGFβ/Smad3 treatment also markedly enhanced SDF‐1α‐induced ERK1/2 phosphorylation as well as SMC migration in a CXCR4‐dependent manner. Adenoviral expression of Smad3 in balloon‐injured rat carotid arteries increased local CXCR4 levels and enhanced IH, whereas SMC‐specific depletion of CXCR4 in the wire‐injured mouse femoral arterial wall produced a 60% reduction in IH. Our results provide the first evidence that upregulation of TGFβ/Smad3 in injured arteries induces local SMC CXCR4 expression and cell migration, and consequently IH. The Smad3/CXCR4 pathway may provide a potential target for therapeutic interventions to prevent restenosis. Stem Cells 2016;34:2744–2757

show abstract

“…These results suggest that increased receptor numbers, at least in part, contribute to breast cancer metastasis. It has been reported that upregulation of CXCR4 receptors is induced by several oncogenic events such as hypoxia (40), HER2 overexpression (41), EGFR variant-mediated invasion (42) and TGFβ1 signaling (43), suggesting that CXCR4 mediates many oncogenic signals that lead to breast cancer metastasis. CXCL12, the CXCR4 ligand, attracts tumor cells expressing CXCR4 to organs such as the lymph node and bone marrow that produce CXCL12, thereby mediating metastasis.…”

Section: Discussionmentioning

confidence: 99%

Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer

et al. 2014

View full text Add to dashboard Cite

The chemokine receptor CXCR4 and signal transducer and activator of transcription 3 (STAT3) play an important role in breast cancer malignancy and metastasis. However, it remains unknown whether STAT3 can be activated by CXCR4 in human breast cancer. The expression levels of CXCR4, STAT3 and p-STAT3 in 208 breast cancer tissues and 26 tumor-adjacent tissues were examined by immunohistochemistry. Flow cytometry, western blot analysis and immunoprecipitation were used to study activation of STAT3 by CXCL12-CXCR4 signaling in human breast cancer cell lines. The expression levels of CXCR4, STAT3 and p-STAT3 were higher in the breast cancer samples than these levels in the tumor-adjacent samples. The combined expression of CXCR4 and p-STAT3 was correlated with TNM stage, tumor size, lymph node metastasis and histological grade of breast cancer. In the breast cancer cells, CXCL12 treatment increased the expression of p-STAT3. The CXCR4 antagonist AMD3100 and the Janus kinase 2 (JAK2) antagonist AG490 inhibited the CXCL12-induced increase in the phosphorylation of STAT3. Furthermore, CXCL12 promoted direct binding of JAK2 to CXCR4. Our findings suggest that activation of the JAK2/STAT3 pathway via CXCL12-CXCR4 signaling plays an important role in breast cancer malignancy and metastasis. Targeting the CXCL12-CXCR4/JAK2/STAT3 signaling pathway may be a potential therapeutic strategy for the treatment of breast cancer.

show abstract

Transforming growth factor-β1 upregulates the expression of CXC chemokine receptor 4 (CXCR4) in human breast cancer MCF-7 cells

Cited by 52 publications

References 33 publications

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia

Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer

Contact Info

Product

Resources

About