CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer

Son, Sang Jun; Kim, Hyungjoo; Lim, Hogeun; Lee, Joo-hyung; Lee, Kyung-min; Shin, Incheol

doi:10.1038/s41419-023-05608-3

Cited by 12 publications

(7 citation statements)

References 63 publications

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“…An example of this has been reported by Son et al (2023) demonstrating an oncogenic role for CCN3 in TNBC. Whether one can actually target CCN3 in advanced breast cancer has yet to be realized.…”

Section: Conclusion: a Birds’ Eye View Of The Ccn Field And Emerging ...mentioning

confidence: 76%

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CCN proteins: opportunities for clinical studies—a personal perspective

Yeger

2023

J. Cell Commun. Signal.

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The diverse members of the CCN family now designated as CCN1(CYR61), CCN2 (CTGF), CCN3(NOV), CCN4(WISP1), CCN5(WISP2), CCN6(WISP3) are a conserved matricellular family of proteins exhibiting a spectrum of functional properties throughout all organs in the body. Interaction with cell membrane receptors such as integrins trigger intracellular signaling pathways. Proteolytically cleaved fragments (constituting the active domains) can be transported to the nucleus and perform transcriptional relevant functional activities. Notably, as also found in other protein families some members act opposite to others creating a system of functionally relevant checks and balances. It has become apparent that these proteins are secreted into the circulation, are quantifiable, and can serve as disease biomarkers. How they might also serve as homeostatic regulators is just becoming appreciated. In this review I have attempted to highlight the most recent evidence under the subcategories of cancer and non‐cancer relevant that could lead to potential therapeutic approaches or ideas that can be factored into clinical advances. I have added my own personal perspective on feasibility.

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Section: Conclusion: a Birds’ Eye View Of The Ccn Field And Emerging ...mentioning

confidence: 76%

“…In another cancer, ovarian carcinoma, progression is also inhibited by downregulating CCN5 (Shi et al 2020). In terms of tumor vascularization studies from the Sabbah lab, Ferrand et al (2022) showed that enforced expression of CCN5 decreased network formation while knockdown of CCN5 increased vascular mimicry (VM).…”

Section: Ccn5 (Wisp-2)mentioning

confidence: 99%

CCN proteins: opportunities for clinical studies—a personal perspective

Yeger

2023

J. Cell Commun. Signal.

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“…However, it fulfills different roles in different cell types [ 23 , 24 ]. For example, in breast cancer cells, CCN3 increased cell proliferation by upregulating the expression of cyclin D1 [ 25 ]. Similarly, in pancreatic cancer cells, the overexpression of CCN3 facilitated cell proliferation and migration by inducing an epithelial–mesenchymal transition [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

CCN3/NOV Regulates Proliferation and Neuronal Differentiation in Mouse Hippocampal Neural Stem Cells via the Activation of the Notch/PTEN/AKT Pathway

Luan

Zhang

et al. 2023

IJMS

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Neural stem cells (NSCs) persist in the subgranular zone (SGZ) throughout the lifespan and hold immense potential for the repair and regeneration of the central nervous system, including hippocampal-related diseases. Several studies have demonstrated that cellular communication network protein 3 (CCN3) regulates multiple types of stem cells. However, the role of CCN3 in NSCs remains unknown. In this study, we identified CCN3 expression in mouse hippocampal NSCs and observed that supplementing CCN3 improved cell viability in a concentration-dependent manner. Additionally, in vivo results showed that the injection of CCN3 in the dentate gyrus (DG) increased Ki-67- and SOX2-positive cells while decreasing neuron-specific class III beta-tubulin (Tuj1) and doublecortin (DCX)-positive cells. Consistently with the in vivo results, supplementing CCN3 in the medium increased the number of BrdU and Ki-67 cells and the proliferation index but decreased the number of Tuj1 and DCX cells. Conversely, both the in vivo and in vitro knockdown of the Ccn3 gene in NSCs had opposite effects. Further investigations revealed that CCN3 promoted cleaved Notch1 (NICD) expression, leading to the suppression of PTEN expression and eventual promotion of AKT activation. In contrast, Ccn3 knockdown inhibited the activation of the Notch/PTEN/AKT pathway. Finally, the effects of changes in CCN3 protein expression on NSC proliferation and differentiation were eliminated by FLI-06 (a Notch inhibitor) and VO-OH (a PTEN inhibitor). Our findings imply that while promoting proliferation, CCN3 inhibits the neuronal differentiation of mouse hippocampal NSCs and that the Notch/PTEN/AKT pathway may be a potential intracellular target of CCN3. Our findings may help develop strategies to enhance the intrinsic potential for brain regeneration after injuries, particularly stem cell treatment for hippocampal-related diseases.

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“…In prostate cancer, CCN3 promotes the synthesis of bone morphogenetic proteins BMP, Runx2 and osterix in osteoblasts through GSK3β and β‐catenin signaling cascades (Chen et al 2021). CCN3 expression is upregulated in triple‐negative breast cancer patients, and it was found that CCN3 activates the EGFR pathway by inducing glycoprotein nonmetastatic melanoma protein B (GPNMB) expression (Son et al 2023). In primary rat chondrocytes, CCN3 exerts chondroprotective effects by inhibiting the PI3K/AKT/mTOR pathway (Huang et al 2019).…”

Section: The Expression Regulation Mechanism Of Ccn3mentioning

confidence: 99%

The advance of CCN3 in fibrosis

Yin

Liu

Zhou

et al. 2023

J. Cell Commun. Signal.

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The extracellular matrix (ECM) is comprised of various extracellular macromolecules, including collagen, enzymes, and glycoproteins, which offer structural and biochemical support to neighboring cells. After tissue injury, extracellular matrix proteins deposit in the damaged tissue to promote tissue healing. However, an imbalance between ECM production and degradation can result in excessive deposition, leading to fibrosis and subsequent organ dysfunction. Acting as a regulatory protein within the extracellular matrix, CCN3 plays a crucial role in numerous biological processes, such as cell proliferation, angiogenesis, tumorigenesis, and wound healing. Many studies have demonstrated that CCN3 can reduce the production of ECM in tissues through diverse mechanisms thereby exerting an inhibitory effect on fibrosis. Consequently, CCN3 emerges as a promising therapeutic target for ameliorating fibrosis.

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CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer

Cited by 12 publications

References 63 publications

CCN proteins: opportunities for clinical studies—a personal perspective

CCN proteins: opportunities for clinical studies—a personal perspective

CCN3/NOV Regulates Proliferation and Neuronal Differentiation in Mouse Hippocampal Neural Stem Cells via the Activation of the Notch/PTEN/AKT Pathway

The advance of CCN3 in fibrosis

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