GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2

Li, Shan; Ma, Yanmin; Zheng, Pan; Zhang, Ping

doi:10.1186/s13046-018-0744-0

Cited by 131 publications

(111 citation statements)

References 41 publications

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“…OPC secreted proteins include Matn4, Lum, and Dcn, which have been previously reported to inhibit cell proliferation (Uckelmann et al, 2016;Vij, Roberts, Joyce, & Chakravarti, 2004;Xaus, Comalada, Cardó, Valledor, & Celada, 2001). Microglia secreted proteins include Ccl3, Ccl4, and Gdf15, with previously reported roles in promoting cell proliferation (Li, Ma, Zheng, & Zhang, 2018;Tsai et al, 2013). These proteins are among the candidate signals that mediate the effect of OPC and microglia on astrocyte development.…”

Section: Younger and Older Astrocytes Similarly Promote Astrocyte Mmentioning

confidence: 99%

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Khankan

Caneda

et al. 2019

Glia

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Astrocytes are critical for the development and function of the central nervous system. In developing brains, immature astrocytes undergo morphological, molecular, cellular, and functional changes as they mature. Although the mechanisms that regulate the maturation of other major cell types in the central nervous system such as neurons and oligodendrocytes have been extensively studied, little is known about the cellular and molecular mechanisms that control astrocyte maturation. Here, we identified molecular markers of astrocyte maturation and established an in vitro assay for studying the mechanisms of astrocyte maturation. Maturing astrocytes in vitro exhibit similar molecular changes and represent multiple molecular subtypes of astrocytes found in vivo. Using this system, we found that astrocyte‐to‐astrocyte contact strongly promotes astrocyte maturation. In addition, secreted signals from microglia, oligodendrocyte precursor cells, or endothelial cells affect a small subset of astrocyte genes but do not consistently change astrocyte maturation. To identify molecular mechanisms underlying astrocyte maturation, we treated maturing astrocytes with molecules that affect the function of tumor‐associated genes. We found that a positive feedback loop of heparin‐binding epidermal growth factor‐like growth factor (HBEGF) and epidermal growth factor receptor (EGFR) signaling regulates astrocytes maturation. Furthermore, HBEGF, EGFR, and tumor protein 53 (TP53) affect the expression of genes important for cilium development, the circadian clock, and synapse function. These results revealed cellular and molecular mechanisms underlying astrocytes maturation with implications for the understanding of glioblastoma.

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Section: Younger and Older Astrocytes Similarly Promote Astrocyte Mmentioning

confidence: 99%

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Khankan

Caneda

et al. 2019

Glia

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“…Growth differentiation factor 15 (GDF15) is a divergent member of the human transforming growth factor-β (TGF-β) superfamily and has been linked to the development of cancers, such as cervical cancer, multiple myeloma, and colon cancer (Corre et al, 2012;S. Li, Ma, Zheng, & Zhang, 2018;Mehta et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

c‐Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment

Ding

Hao

et al. 2019

Journal Cellular Physiology

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Inflammatory microenvironment is an important factor for promoting cancer invasion and metastasis, but the underlying molecular mechanisms remain unclear. Here, we mimicked an inflammatory microenvironment both in vitro and in vivo and investigated its effects on the invasion and metastasis of colon cancer. Moreover, colon cancer patient samples were also analyzed statistically. Conditioned medium from the differentiated macrophages induced invasion and migration of colon cancer cells in vitro, which could be reversed by the treatment of a neutralizing anti-growth differentiation factor 15 (GDF15) antibody, indicating GDF15 involvement in inflammation-induced invasiveness. Also, we observed similar effects of human recombinant GDF15 on colon cancer cells. Mechanistically, GDF15 activated c-Fos by separating it from Lamin A/C, increasing transcriptional activity of c-Fos and regulating EMT gene expressions. However, c-Fos knockdown using lentivirus shRNA plasmid inhibited GDF15-triggered invasion and migration in vitro. In vivo, inflammation caused by lipopolysaccharides obviously increased GDF15 secretion, and c-Fos knockdown reduced the lung metastasis of colon cancer cells in mice model. In addition, c-Fos expressions in patient samples were found to be associated with colon cancer metastasis and TNM stages. Taken together, GDF15 in inflammatory microenvironment induces colon cancer invasion and metastasis by regulating EMT genes by activating c-Fos, which might be a potential therapeutic target for metastatic colon cancer. K E Y W O R D S EMT, Erk1/2, Lamin A/C/c-Fos signaling axis, macrophages-derived cytokine Abbreviations: CM, conditioned medium; DAPI, diamidinophenylindole; EMSA, electrophoretic mobility shift assays; EMT, epithelial-mesenchymal transition; GDF15, growth differentiation factor 15; H&E, hematoxylin and eosin; IH C, immunohistochemistry; LPS, lipopolysaccharides; PMA, phorbol 12-myristate 13-acetate; RM, regular medium; TAMs, tumor-associated macrophages. *Youxiang Ding and Kun Hao contributed equally to this work. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.How to cite this article: Ding Y, Hao K, Li Z, et al. c-Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment.

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“…GDF15 may be involved in the proliferation, migration, invasion, and angiogenesis of tumors, with with recent research finding GDF15 promoted EMT and invasion of breast cancers [43], and supported the maintenance of breast cancer stem-like cells [44]. Furthermore, GDF15 promoted the proliferation of cervical cancer cells by interaction with ErB2 to activate PI3K/AKT and MAPK/ERK pathways [28], and enhanced the migration of pancreatic cancer cells via an AKT pathway [29]. Similarly, our study found that increased pAKT levels in MDA-MB-231 co-culture were responsible for tumor cell migration-promoting effects.…”

Section: Visfatin-primed Adscs Promote Tumor Stemness and Emt Throughmentioning

confidence: 78%

“…This reversed the enhancement of migration and invasion of MDA-MB-231 by co-culture ( Figure 3D). Since GDF15 has been reported to activate the AKT pathway [28,29], we examined the expression of phosphor-AKT (pAKT) of MDA-MB-231 and found its induction within two hours after GDF15 treatment ( Figure 3E). We checked the level of pAKT in MDA-MB-231 after co-culture and found it was higher in co-culture with vADSCs than with uADSCs ( Figure 3F).…”

Section: Growth Differentiation Factor 15 (Gdf15) Plays a Crucial Rolmentioning

confidence: 99%

Visfatin Mediates Malignant Behaviors through Adipose-Derived Stem Cells Intermediary in Breast Cancer

Huang

et al. 2019

Cancers

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Adipose-derived stem cells (ADSCs) have been implicated in tumor growth and metastasis in breast cancer. ADSCs exhibit tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for breast reconstruction. Although we have previously shown that a high level of the adipocytokine visfatin in human breast cancer tissues correlated with tumor progression mediated by cAbl and STAT3, the effects of visfatin in the tumor microenvironment are unclear. To understand how visfatin modulates breast cancer within the tumor-stromal environment, we examined determinants of breast cancer progression using a visfatin-primed ADSCs-tumor co-culture model. ADSCs were isolated from tumor-free adipose tissue adjacent to breast tumors. ADSCs were treated with or without visfatin for 48 h and then collected for co-culture with breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs). Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture conditioned medium, with GDF15 neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231Cancers 2020, 12, 29 2 of 18 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger tumor mass than with uADSCs. Positive correlations were noted between visfatin, GDF15, and phosphor-AKT expressions in human breast cancer specimens. In conclusion, visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate breast cancer progression.

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GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2

Cited by 131 publications

References 41 publications

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

c‐Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment

Visfatin Mediates Malignant Behaviors through Adipose-Derived Stem Cells Intermediary in Breast Cancer

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