CXCL1/CXCR2 Paracrine Axis Contributes to Lung Metastasis in Osteosarcoma

Chao, Chia‐Chia; Lee, Chiang‐Wen; Chang, Tsung Ming; Chen, Po-Chun; Liu, Ju-Fang

doi:10.3390/cancers12020459

Cited by 23 publications

(29 citation statements)

References 47 publications

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“…Several transcription factor-binding sites have been identified in the 5-regulatory region [ 4 , 35 ]. NF-κB is a vital transcriptional factor that mediates VCAM-1 transcriptional activity and cancer metastasis [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…The migration-prone MG-63(M2), MG-63(M5), and MG-63(M10) cells were established from original MG-63 cells, as according to the methods described in our previous reports [ 4 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…The SimpleChIP ® Enzymatic Chromatin IP kit (Cell Signaling, MA, USA) was used to conduct ChIP assays. The purified DNA pellet was subjected to PCR testing, as detailed in our previous publication [ 4 ].…”

Section: Methodsmentioning

confidence: 99%

“…However, despite such treatment, only 60–70% of patients without clinically evident metastasis at first diagnosis remain alive after 3 years [ 2 ]. Major challenges that reduce overall survival of patients with osteosarcoma include the development of chemoresistance and progression to lung metastasis [ 3 , 4 , 5 ]. Since the lung is the most frequent organ affected by metastasis in osteosarcoma [ 2 ], the development of therapeutic strategies for delaying or inhibiting lung metastasis progression remains critical for improving patient survival outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…VCAM-1 is highly expressed in metastatic cancer cells [ 7 ]. In osteosarcoma, levels of VCAM-1 expression correlate with disease stage and tumor progression [ 4 ], with higher levels of VCAM-1 expression enabling connective tissue growth factor to stimulate the migration of osteosarcoma cells and promote metastasis [ 8 ]. Thus, inhibiting VCAM-1 expression may be an effective strategy for treating osteosarcoma metastasis.…”

Section: Introductionmentioning

confidence: 99%

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CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

Liu

Lee

Lin

et al. 2020

IJMS

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Osteosarcoma is the most common primary tumor of the skeletal system and is well-known to have an aggressive clinical outcome and high metastatic potential. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a vital role in the development of several cancers. However, the effect of CXCL13 in the motility of osteosarcoma cells remains uncertain. Here, we found that CXCL13 increases the migration and invasion potential of three osteosarcoma cell lines. In addition, CXCL13 expression was upregulated in migration-prone MG-63 cells. Vascular cell adhesion molecule 1 (VCAM-1) siRNA and antibody demonstrated that CXCL13 promotes migration via increasing VCAM-1 production. We also show that CXCR5 receptor controls CXCL13-mediated VCAM-1 expression and cell migration. Our study identified that CXCL13/CXCR5 axis facilitate VCAM-1 production and cell migration in human osteosarcoma via the phospholipase C beta (PLCβ), protein kinase C α (PKCα), c-Src, and nuclear factor-κB (NF-κB) signaling pathways. CXCL13 and CXCR5 appear to be a novel therapeutic target in metastatic osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

“…The migration-prone MG-63(M2), MG-63(M5), and MG-63(M10) cells were established from original MG-63 cells, as according to the methods described in our previous reports [ 4 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

Liu

Lee

Lin

et al. 2020

IJMS

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Destabilization of macrophage migration inhibitory factor by 4‐IPP reduces NF‐κB/P‐TEFb complex‐mediated c‐Myb transcription to suppress osteosarcoma tumourigenesis

Zheng

Feng

Tao

et al. 2022

Clinical & Translational Med

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Background As an inflammatory factor and oncogenic driver protein, the pleiotropic cytokine macrophage migration inhibitory factor (MIF) plays a crucial role in the osteosarcoma microenvironment. Although 4‐iodo‐6‐phenylpyrimidine (4‐IPP) can inactivate MIF biological functions, its anti‐osteosarcoma effect and molecular mechanisms have not been investigated. In this study, we identified the MIF inhibitor 4‐IPP as a specific double‐effector drug for osteosarcoma with both anti‐tumour and anti‐osteoclastogenic functions. Methods The anti‐cancer effects of 4‐IPP were evaluated by wound healing assay, cell cycle analysis, colony formation assay, CCK‐8 assay, apoptosis analysis, and Transwell migration/invasion assays. Through the application of a luciferase reporter, chromatin immunoprecipitation assays, and immunofluorescence and coimmunoprecipitation analyses, the transcriptional regulation of the NF‐κB/P‐TEFb complex on c‐Myb‐ and STUB1‐mediated proteasome‐dependent MIF protein degradation was confirmed. The effect of 4‐IPP on tumour growth and metastasis was assessed using an HOS‐derived tail vein metastasis model and subcutaneous and orthotopic xenograft tumour models. Results In vitro, 4‐IPP significantly reduced the proliferation and metastasis of osteosarcoma cells by suppressing the NF‐κB pathway. 4‐IPP hindered the binding between MIF and CD74 as well as p65. Moreover, 4‐IPP inhibited MIF to interrupt the formation of downstream NF‐κB/P‐TEFb complexes, leading to the down‐regulation of c‐Myb transcription. Interestingly, the implementation of 4‐IPP can mediate small molecule‐induced MIF protein proteasomal degradation via the STUB1 E3 ligand. However, 4‐IPP still interrupted MIF‐mediated communication between osteosarcoma cells and osteoclasts, thus promoting osteoclastogenesis. Remarkably, 4‐IPP strongly reduced HOS‐derived xenograft osteosarcoma tumourigenesis and metastasis in an in vivo mouse model. Conclusions Our findings demonstrate that the small molecule 4‐IPP targeting the MIF protein exerts an anti‐osteosarcoma effect by simultaneously inactivating the biological functions of MIF and promoting its proteasomal degradation. Direct destabilization of the MIF protein with 4‐IPP may be a promising therapeutic strategy for treating osteosarcoma.

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Tumor metastasis: Mechanistic insights and therapeutic interventions

Liu

Yang

et al. 2021

MedComm

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Cancer metastasis is responsible for the vast majority of cancer‐related deaths worldwide. In contrast to numerous discoveries that reveal the detailed mechanisms leading to the formation of the primary tumor, the biological underpinnings of the metastatic disease remain poorly understood. Cancer metastasis is a complex process in which cancer cells escape from the primary tumor, settle, and grow at other parts of the body. Epithelial‐mesenchymal transition and anoikis resistance of tumor cells are the main forces to promote metastasis, and multiple components in the tumor microenvironment and their complicated crosstalk with cancer cells are closely involved in distant metastasis. In addition to the three cornerstones of tumor treatment, surgery, chemotherapy, and radiotherapy, novel treatment approaches including targeted therapy and immunotherapy have been established in patients with metastatic cancer. Although the cancer survival rate has been greatly improved over the years, it is still far from satisfactory. In this review, we provided an overview of the metastasis process, summarized the cellular and molecular mechanisms involved in the dissemination and distant metastasis of cancer cells, and reviewed the important advances in interventions for cancer metastasis.

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CXCL1/CXCR2 Paracrine Axis Contributes to Lung Metastasis in Osteosarcoma

Cited by 23 publications

References 47 publications

CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

Destabilization of macrophage migration inhibitory factor by 4‐IPP reduces NF‐κB/P‐TEFb complex‐mediated c‐Myb transcription to suppress osteosarcoma tumourigenesis

Tumor metastasis: Mechanistic insights and therapeutic interventions

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