WNT5A promotes migration and invasion of human osteosarcoma cells via SRC/ERK/MMP‐14 pathway

Wang, Xingwen; Zhao, Xin; Yi, Zhigang; Ma, Bing; Wang, Hong; Pu, Yanchuan; Wang, Jing; Wang, Shuanke

doi:10.1002/cbin.10936

Cited by 21 publications

(18 citation statements)

References 35 publications

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“…Here we found that DCLK1 overexpression induced the phosphorylation of ERK MAPK pathway (Figure 4(a)), but not JNK or p38 MAPK pathways, in T47D cells. Previous studies demonstrated that activation of ERK MAPK pathway can promote the expression of MT1-MMP, which is a key protease and plays an important role in pro-migration proteolysis and is thereby involved in many cancer metastases [20–22]. We observed that DCLK1 overexpression caused an upregulation of MT1-MMP, which was likely due to activation of ERK MAPK pathway (Figure 4(a)).…”

Section: Resultssupporting

confidence: 55%

DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells

Liu

Wen

Zhou

et al. 2019

BioMed Research International

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Background. Doublecortin-like kinase 1 (DCLK1) has been universally identified as a cancer stem cell (CSC) marker and is found to be overexpressed in many types of cancers including breast cancer. However, there is little data regarding the functional role of DCLK1 in breast cancer metastasis. In the present study, we sought to investigate whether and how DCLK1 plays a metastatic-promoting role in human breast cancer cells. Methods. We used Crispr/Cas9 technology to knock out DCLK1 in breast cancer cell line BT474, which basically possesses DCLK1 at a higher level, and stably overexpressed DCLK1 in another breast cancer cell line, T47D, that basically expresses DCLK1 at a lower level. We further analyzed the alterations of metastatic characteristics and the underlying mechanisms in these cells. Results. It was shown that, compared with the corresponding control cells, DCLK1 overexpression led to an increase in metastatic behaviors including enhanced migration and invasion of T47D cells. By contrast, forced depletion of DCLK1 drastically inhibited these metastatic characteristics in BT474 cells. Mechanistically, the epithelial-mesenchymal transition (EMT) program, which is critical for cancer metastasis, was prominently activated in DCLK1-overexpressing cancer cells, evidenced by a decrease in an epithelial marker ZO-1 and an enhancement in several mesenchymal markers including ZEB1 and Vimentin. In addition, DCLK1 overexpression induced the ERK MAPK pathway, which resultantly enhanced the expression of MT1-MMP that is also involved in cancer metastasis. Knockout of DCLK1 could reverse these events, further supporting a metastatic-promoting role for DCLK1. Conclusions. Collectively, our data suggested that DCLK1 overexpression may be responsible for the increased metastatic features in breast cancer cells. Targeting DCLK1 may become a therapeutic option for breast cancer metastasis.

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Section: Resultssupporting

confidence: 55%

DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells

Liu

Wen

Zhou

et al. 2019

BioMed Research International

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“… 65 Only one study noted increased mRNA of WNT7b in human OS cell lines, 61 while another reported that the prototypical non-canonical Wnt ligand Wnt5a promotes the migration and invasion of a human OS cell line in vitro. 66 …”

Section: Discussionmentioning

confidence: 99%

Wnt signaling and Loxl2 promote aggressive osteosarcoma

et al. 2020

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Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. Using genetically modified mouse models (GEMMs), we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2. c-Fos/AP-1 directly regulates the expression of the Wnt ligands Wnt7b and Wnt9a in OS cells through promoter binding, and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2. Concordantly, inhibition of Wnt ligand secretion by inactivating the Wnt-less (Wls) gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS. Wls-deficient osteosarcomas proliferate less, are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers. Importantly, Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models. Finally, OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies. Congruently, a strong correlation between c-FOS, LOXL2 and WNT7B/WNT9A expression is observed in human OS samples, and c-FOS/LOXL2 co-expression correlates with OS aggressiveness and decreased patient survival. Therefore, therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric, recurrent, and metastatic OS.

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“…Integrins, MMP-2, MMP-9, MT1-MMP and other molecules are known to be involved in the migration and invasion in osteosarcoma cells. In addition, it has been reported that MMP-2, MMP-9 and MT1-MMP may be modulated via the PI3K/Akt and Erk1/2 signaling pathways [25][26][27][28]. The extracellular matrix (ECM) serves as a barrier for the metastasis of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The tetraspanin CD81 mediates the growth and metastases of human osteosarcoma

et al. 2019

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Purpose CD81 is a member of the tetraspanin family of membrane proteins. Recently, it has been shown that CD81 may be involved in cancer cell proliferation and metastasis. As yet, however, there have been few reports on the expression and role of CD81 in osteosarcoma. Methods The expression of CD81 was investigated in human osteoblast cell line hFOB1.19 and in human osteosarcoma cell lines Saos2, MG63 and 143B. The expression of CD81 was inhibited in osteosarcoma cells using siRNA after which cell proliferation, migration and invasion were assessed. We also used Western blotting to investigate the phosphorylation status of Akt, Erk, JNK and p38, and measured the expression of MMP-2, MMP-9 and MT1-MMP. In addition, we used a CRISPR/Cas9 system to stably knock out CD81 expression in 143B cells, transplanted the cells into mice, and assessed tumor formation and lung metastasis in these mice compared to those in the control group. Results We found that CD81 was expressed in the human osteoblast cell line and in all osteosarcoma cell lines tested. The osteosarcoma cell line 143B exhibited a particularly high level of expression. In addition, we found that osteosarcoma cell proliferation, migration and invasion were decreased after CD81 inhibition, and that the phosphorylation of Akt and Erk was suppressed. Also, the expression levels of MMP-2, MMP-9 and MT1-MMP were found to be suppressed, with MMP-9 showing the greatest suppression. In vivo, we found that mice transplanted with CD81 knockout 143B cells exhibited significantly less tumor formation and lung metastasis than mice in the control group. Conclusion Based on our findings we conclude that inhibition of CD81 suppresses intracellular signaling and reduces tumorigenesis and lung metastasis in osteosarcoma cells.

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WNT5A promotes migration and invasion of human osteosarcoma cells via SRC/ERK/MMP‐14 pathway

Cited by 21 publications

References 35 publications

DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells

DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells

Wnt signaling and Loxl2 promote aggressive osteosarcoma

The tetraspanin CD81 mediates the growth and metastases of human osteosarcoma

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