The Experts below are selected from a list of 52425 Experts worldwide ranked by ideXlab platform
Adam J Engler - One of the best experts on this subject based on the ideXlab platform.
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Matrix Stiffness drives epithelial mesenchymal transition and tumour metastasis through a twist1 g3bp2 mechanotransduction pathway
Nature Cell Biology, 2015Co-Authors: Laurent Fattet, Jeff H Tsai, Hannah E Majeski, Albert C Chen, Susan S Taylor, Adam J Engler, Jing YangAbstract:Yang and colleagues report that increased extracellular Matrix Stiffness promotes nuclear localization of Twist1 to drive epithelial–mesenchymal transition, cancer cell invasion and metastasis.
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Matrix Stiffness drives epithelial mesenchymal transition and tumour metastasis through a twist1 g3bp2 mechanotransduction pathway
Nature Cell Biology, 2015Co-Authors: Spencer C. Wei, Laurent Fattet, Jeff H Tsai, Hannah E Majeski, Albert C Chen, Susan S Taylor, Yurong Guo, Vincent Pai, Robert L. Sah, Adam J EnglerAbstract:Matrix Stiffness potently regulates cellular behaviour in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased Matrix Stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing Matrix Stiffness. High Matrix Stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing Matrix Stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fibre alignment, a marker of increasing Matrix Stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion and metastasis.
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Matrix Stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway
Nature cell biology, 2015Co-Authors: Spencer C. Wei, Laurent Fattet, Jeff H Tsai, Hannah E Majeski, Albert C Chen, Susan S Taylor, Yurong Guo, Vincent Pai, Robert L. Sah, Adam J EnglerAbstract:Matrix Stiffness potently regulates cellular behaviour in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased Matrix Stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing Matrix Stiffness. High Matrix Stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing Matrix Stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fibre alignment, a marker of increasing Matrix Stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion and metastasis.
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interplay of Matrix Stiffness and protein tethering in stem cell differentiation
Nature Materials, 2014Co-Authors: Ludovic G Vincent, Alexander Fuhrmann, Yu Suk Choi, Kolin C Hribar, Hermes Taylorweiner, Shaochen Chen, Adam J EnglerAbstract:Recent work has proposed that both protein tethering to the extracellular Matrix and Matrix porosity can regulate stem cell differentiation. It is now shown that differentiation is driven by Matrix Stiffness independently of tethering and porosity.
O. Rahaman - One of the best experts on this subject based on the ideXlab platform.
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TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization.
Frontiers in immunology, 2020Co-Authors: Bidisha Dutta, Rishov Goswami, O. RahamanAbstract:Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological conditions. We have now determined key aspects of the molecular mechanism by which mechanical cues regulate macrophage polarization. We show that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel, mediates substrate Stiffness-induced macrophage polarization. Using atomic force microscopy, we showed that genetic ablation of TRPV4 function abrogated fibrosis-induced Matrix Stiffness generation in skin tissues. We have determined that stiffer skin tissue promotes the M1 macrophage subtype in a TRPV4-dependent manner; soft tissue does not. These findings were further validated by our in vitro results which showed that stiff Matrix (50 kPa) alone increased expression of macrophage M1 markers in a TRPV4-dependent manner, and this response was further augmented by the addition of soluble factors; neither of which occurred with soft Matrix (1 kPa). A direct requirement for TRPV4 in M1 macrophage polarization spectrum in response to increased Stiffness was evident from results of gain-of-function assays, where reintroduction of TRPV4 significantly upregulated the expression of M1 markers in TRPV4 KO macrophages. Together, these data provide new insights regarding the role of TRPV4 in Matrix Stiffness-induced macrophage polarization spectrum that may be explored in tissue engineering and regenerative medicine and targeted therapeutics.
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Role of TRPV4 in Matrix Stiffness-induced expression of EMT-specific LncRNA.
Molecular and cellular biochemistry, 2020Co-Authors: Shweta Sharma, O. RahamanAbstract:Long non-coding RNAs (LncRNAs) are long (> 200 bases), non-coding, single-stranded RNAs that have emerged as major regulators of gene expression, cell differentiation, development, and oncogenesis. In view of the fact that Matrix Stiffness plays a role in cellular functions associated with these processes, it is important to ask what role Matrix Stiffness plays in regulating expression of LncRNAs. In this report, we show that (i) Matrix Stiffness causes differential expression of epithelial-mesenchymal transition (EMT)-related LncRNAs and mRNAs in primary mouse normal epidermal keratinocytes, (ii) differential expression of EMT-related LncRNAs and mRNAs occurs in response to combined stimulation of transforming growth factor β1 and Matrix Stiffness, and (iii) transient receptor potential (TRP) channel of the vanilloid subfamily, TRPV4, a Matrix Stiffness-sensitive ion channel, plays a role in differential expression of EMT-related LncRNAs and mRNAs in response to combined stimulation by TGFβ1 and Matrix Stiffness. These data identify TRPV4 as a candidate plasma membrane mechanosensor that transmits Matrix-sensing signals essential to LncRNA expression. Our results also show that we have established and validated an assay system capable of discovering novel LncRNAs and mRNAs sensitive to Matrix stiffening.
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TRPV4 regulates Matrix Stiffness and TGFβ1‐induced epithelial‐mesenchymal transition
Journal of cellular and molecular medicine, 2018Co-Authors: Shweta Sharma, Rishov Goswami, David X. Zhang, O. RahamanAbstract:Substrate Stiffness (or rigidity) of the extracellular Matrix has important functions in numerous pathophysiological processes including fibrosis. Emerging data support a role for both a mechanical signal, for example, Matrix Stiffness, and a biochemical signal, for example, transforming growth factor β1 (TGFβ1), in epithelial-mesenchymal transition (EMT), a process critically involved in fibrosis. Here, we report evidence showing that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive channel, is the likely mediator of EMT in response to both TGFβ1 and Matrix Stiffness. Specifically, we found that: (a) genetic ablation or pharmacological inhibition of TRPV4 blocked Matrix Stiffness and TGFβ1-induced EMT in normal mouse primary epidermal keratinocytes (NMEKs) as determined by changes in morphology, adhesion, migration and alterations of expression of EMT markers including E-cadherin, N-cadherin (NCAD) and α-smooth muscle actin (α-SMA), and (b) TRPV4 deficiency prevented Matrix Stiffness-induced EMT in NMEKs over a pathophysiological range. Intriguingly, TRPV4 deletion in mice suppressed expression of mesenchymal markers, NCAD and α-SMA, in a bleomycin-induced murine skin fibrosis model. Mechanistically, we found that: (a) TRPV4 was essential for the nuclear translocation of YAP/TAZ (yes-associated protein/transcriptional coactivator with PDZ-binding motif) in response to Matrix Stiffness and TGFβ1, (b) TRPV4 deletion inhibited both Matrix Stiffness- and TGFβ1-induced expression of YAP/TAZ proteins and (c) TRPV4 deletion abrogated both Matrix Stiffness- and TGFβ1-induced activation of AKT, but not Smad2/3, suggesting a mechanism by which TRPV4 activity regulates EMT in NMEKs. Altogether, these data identify a novel role for TRPV4 in regulating EMT.
Yaohui Wang - One of the best experts on this subject based on the ideXlab platform.
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Matrix Stiffness-mediated effects on macrophages polarization and their LOXL2 expression.
The FEBS journal, 2020Co-Authors: Xiaoxia Xing, Xi Zhang, Yaohui Wang, Xiangyu Gao, Yan Zhao, Jie Chen, Dong-mei Gao, Rong-xin ChenAbstract:Previously, we reported that the secreted lysyl oxidase like 2 (LOXL2) from hepatocellular carcinoma (HCC) cells under higher Stiffness stimulation contributed to the formation of lung premetastatic niche. To further clarify whether Matrix Stiffness also alters LOXL2 expression in other cells within tumor microenvironment, we developed a gel-based culture system combined with a model of macrophage polarization to evaluate the effects of Matrix Stiffness on the polarization of M2 macrophages and their LOXL2 expression. THP-1 cells cultured on 6KPa, 10KPa, and 16KPa Stiffness substrates were first incubated with 100nM phorbol 12-myristate 13-acetate (PMA) for 24 hours and subsequently treated with 20nM interleukin-4 (IL-4) and 20nM interleukin-13 (IL-13) for 48 hours. The polarization states of M2 macrophages under different Stiffness stimulation were comparatively analyzed, and their LOXL2 expressions as well as the underlying molecular mechanism were further explored. Our results demonstrated that increased Matrix Stiffness remarkably strengthened M2 macrophage polarization and promoted their LOXL2 expression. Activation of integrin β5-FAK-MEK1/2-ERK1/2 pathway participated in Matrix Stiffness-mediated HIF-1α upregulation, and HIF-1α upregulation resulted in a significant improvement in LOXL2 expression. Additionally, M2 macrophage polarization state and LOXL2 expression in HCC tissues with COL1High /LOXHigh were consistent with the results in vitro, further confirming the regulation roles of Matrix Stiffness in macrophage polarization and LOXL2 expression. The findings about LOXL2 upregulation in the polarized macrophages under higher Stiffness stimulation will be helpful to better understand the underlying mechanism of Matrix Stiffness-induced premetastatic niche formation in HCC.
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Integrin αVβ5/Akt/Sp1 pathway participates in Matrix Stiffness-mediated effects on VEGFR2 upregulation in vascular endothelial cells.
American journal of cancer research, 2020Co-Authors: Yaohui Wang, Xi Zhang, Xiaoxia Xing, Rong-xin Chen, Wei-min Wang, Yinying Dong, Yang You, Zhenggang Ren, Weijian GuoAbstract:Our previous study has validated that higher Matrix Stiffness obviously improves vascular endothelial growth factor (VEGF) expression in HCC cells, highlighting a linkage between Matrix Stiffness and HCC angiogenesis. However, the effects of Matrix Stiffness on vascular endothelial cells in HCC and its underlying mechanism remain largely uncharacterized. Here we further analyzed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in human umbilical vein endothelial cells (HUVECs) grown on different Stiffness substrates and explored its regulatory mechanism for better understanding Matrix Stiffness-regulated angiogenesis in HCC. Our results revealed that increased Matrix Stiffness significantly upregulated the expression of VEGFR2 in HUVECs, and the expression level of VEGFR2 was positively correlated with the expression levels of COL1 and lysyl oxidase in human HCC tissues and rat HCC tissue, moreover VEGFR2 and CD34 were co-localized at blood vessel of HCC tissues, indicating an obvious regulation role of Matrix Stiffness in VEGFR2 expression. Simultaneously, increased Matrix Stiffness also elevated the phosphorylation level of Akt and the expressions of integrin αV/β5 and nuclear Sp1 in HUVECs. Inhibition of integrin αVβ5 remarkably reversed the expression of VEGFR2 and phosphorylation level of Akt in HUVECs grown on higher Stiffness substrate. Except that, PI3K inhibitor also suppressed the phosphorylation level of Akt and the expressions of VEGFR2 and nuclear Sp1 evidently. Taken together, higher Matrix Stiffness increased VEGFR2 expression in HUVECs, and integrin αVβ5/Akt/Sp1 pathway participated in Stiffness-mediated effects on VEGFR2 upregulation. This study combining with our previous report discloses a new paradigm in which higher Matrix Stiffness as an initiator drives HCC angiogenesis via upregulating both VEGFR2 expression in vascular endothelial cells and VEGF expression in HCC cells.
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Higher Matrix Stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis.
Journal of hematology & oncology, 2019Co-Authors: Yinying Dong, Yaohui Wang, Yang You, Qiongdan Zheng, Xiaoying Xie, Zhiming Wang, Xia-hui Lin, Jie ChenAbstract:Background Increased liver Stiffness exerts a detrimental role in driving hepatocellular carcinoma (HCC) malignancy and progression, and indicates a high risk of unfavorable outcomes. However, it remains largely unknown how liver Matrix Stiffness as an independent cue triggers epithelial-mesenchymal transition (EMT) and facilitates HCC metastasis.
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Matrix Stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation.
Journal of experimental & clinical cancer research : CR, 2018Co-Authors: Qiongdan Zheng, Xiaoxia Xing, Yaohui Wang, Jie Chen, Rong-xin Chen, Yinying Dong, Yang You, Dong-mei GaoAbstract:Higher Matrix Stiffness affects biological behavior of tumor cells, regulates tumor-associated gene/miRNA expression and stemness characteristic, and contributes to tumor invasion and metastasis. However, the linkage between higher Matrix Stiffness and pre-metastatic niche in hepatocellular carcinoma (HCC) is still largely unknown. We comparatively analyzed the expressions of LOX family members in HCC cells grown on different Stiffness substrates, and speculated that the secreted LOXL2 may mediate the linkage between higher Matrix Stiffness and pre-metastatic niche. Subsequently, we investigated the underlying molecular mechanism by which Matrix Stiffness induced LOXL2 expression in HCC cells, and explored the effects of LOXL2 on pre-metastatic niche formation, such as BMCs recruitment, fibronectin production, MMPs and CXCL12 expression, cell adhesion, etc. Higher Matrix Stiffness significantly upregulated LOXL2 expression in HCC cells, and activated JNK/c-JUN signaling pathway. Knockdown of integrin β1 and α5 suppressed LOXL2 expression and reversed the activation of above signaling pathway. Additionally, JNK inhibitor attenuated the expressions of p-JNK, p-c-JUN, c-JUN and LOXL2, and shRNA-c-JUN also decreased LOXL2 expression. CM-LV-LOXL2-OE and rhLOXL2 upregulated MMP9 expression and fibronectin production obviously in lung fibroblasts. Moreover, activation of Akt pathway contributed to LOXL2-induced fibronectin upregulation. LOXL2 in CM as chemoattractant increased motility and invasion of BMCs, implicating a significant role of LOXL2 in BMCs recruitment. Except that, CM-LV-LOXL2-OE as chemoattractant also increased the number of migrated HCC cells, and improved chemokine CXCL12 expression in lung fibroblasts. The number of HCC cells adhered to surface of lung fibroblasts treated with CM-LV-LOXL2-OE was remarkably higher than that of the control cells. These results indicated that the secreted LOXL2 facilitated the motility of HCC cells and strengthened CTCs settlement on the remodeled Matrix “soil”. Integrin β1/α5/JNK/c-JUN signaling pathway participates in higher Matrix Stiffness-induced LOXL2 upregulation in HCC cells. The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation.
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Matrix Stiffness-mediated effects on stemness characteristics occurring in HCC cells
Oncotarget, 2016Co-Authors: Yang You, Yaohui Wang, Yinying Dong, Qiongdan Zheng, Xiaoying Xie, Tong-chun Xue, Lan Zhang, Yingcong Wang, Zhiming WangAbstract:// Yang You 1, * , Qiongdan Zheng 1, * , Yinying Dong 1 , Xiaoying Xie 1 , Yaohui Wang 2 , Sifan Wu 1 , Lan Zhang 1 , Yingcong Wang 1 , Tongchun Xue 1 , Zhiming Wang 3 , Rongxin Chen 1 , Yanhong Wang 1 , Jiefeng Cui 1 , Zhenggang Ren 1 1 Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China 2 Department of Interventional Radiology, Shanghai Cancer Center, Fudan University, Shanghai 200032, PR China 3 Department of Oncology, Zhongshan Hospital Subdivision, Fudan University, Shanghai 200052, PR China * These authors have contributed equally to this work Correspondence to: Jiefeng Cui, e-mail: cui.jiefeng@zs-hospital.sh.cn Zhenggang Ren, e-mail: ren.zhenggang@zs-hospital.sh.cn Keywords: Matrix Stiffness, hepatocellular carcinoma, stemness, mTOR, integrin β1 Received: November 13, 2015 Accepted: February 23, 2016 Published: March 31, 2016 ABSTRACT Matrix Stiffness as an important physical attribute of extracellular Matrix exerts significant impacts on biological behaviors of cancer cells such as growth, proliferation, motility, metabolism and invasion. However, its influence on cancer stemness still remains elusive. Here, we explore whether Matrix Stiffness-mediated effects on stemness characteristics occur in HCC cells. As the substrate Stiffness increased, HCC cells exhibited high proportion of cells with CD133(+)/EpCAM(+), high expression levels of CD133, EpCAM, Nanog and SOX2, greater self-renewing ability and oxaliplatin resistance. Simultaneously, their phosphorylation levels of Akt and mTOR, as well as p-4E-BP and SOX2 expressions were also obviously upregulated. Conversely, knockdown of integrin β1 partially attenuated higher Stiffness-mediated stemness characteristics in HCC cells, and reversed the phosphorylation levels of Akt and mTOR, and expressions of p-4E-BP and SOX2, suggesting that integrin β1 may deliver higher Stiffness signal into HCC cells and activate mTOR signaling pathway. Additionally, mTOR inhibitor suppressed the mTOR phosphorylation level and expression levels of p-4E-BP and SOX2 in HCC cells grown on higher Stiffness substrate, as well as depressed their stemness properties significantly, favoring a regulating role of mTOR signaling pathway in Matrix Stiffness-mediated effects on stemness. In summary, Matrix Stiffness may be involved in the process of stemness regulation via activating integrin β1/Akt/mTOR/SOX2 signaling pathway. To the best of our knowledge, this study first reveals a novel regulating pathway to direct the stemness characteristics in HCC cells.
Laurent Fattet - One of the best experts on this subject based on the ideXlab platform.
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Matrix Stiffness drives epithelial mesenchymal transition and tumour metastasis through a twist1 g3bp2 mechanotransduction pathway
Nature Cell Biology, 2015Co-Authors: Laurent Fattet, Jeff H Tsai, Hannah E Majeski, Albert C Chen, Susan S Taylor, Adam J Engler, Jing YangAbstract:Yang and colleagues report that increased extracellular Matrix Stiffness promotes nuclear localization of Twist1 to drive epithelial–mesenchymal transition, cancer cell invasion and metastasis.
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Matrix Stiffness drives epithelial mesenchymal transition and tumour metastasis through a twist1 g3bp2 mechanotransduction pathway
Nature Cell Biology, 2015Co-Authors: Spencer C. Wei, Laurent Fattet, Jeff H Tsai, Hannah E Majeski, Albert C Chen, Susan S Taylor, Yurong Guo, Vincent Pai, Robert L. Sah, Adam J EnglerAbstract:Matrix Stiffness potently regulates cellular behaviour in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased Matrix Stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing Matrix Stiffness. High Matrix Stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing Matrix Stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fibre alignment, a marker of increasing Matrix Stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion and metastasis.
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Matrix Stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway
Nature cell biology, 2015Co-Authors: Spencer C. Wei, Laurent Fattet, Jeff H Tsai, Hannah E Majeski, Albert C Chen, Susan S Taylor, Yurong Guo, Vincent Pai, Robert L. Sah, Adam J EnglerAbstract:Matrix Stiffness potently regulates cellular behaviour in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased Matrix Stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing Matrix Stiffness. High Matrix Stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing Matrix Stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fibre alignment, a marker of increasing Matrix Stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion and metastasis.
Rong-xin Chen - One of the best experts on this subject based on the ideXlab platform.
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Matrix Stiffness-mediated effects on macrophages polarization and their LOXL2 expression.
The FEBS journal, 2020Co-Authors: Xiaoxia Xing, Xi Zhang, Yaohui Wang, Xiangyu Gao, Yan Zhao, Jie Chen, Dong-mei Gao, Rong-xin ChenAbstract:Previously, we reported that the secreted lysyl oxidase like 2 (LOXL2) from hepatocellular carcinoma (HCC) cells under higher Stiffness stimulation contributed to the formation of lung premetastatic niche. To further clarify whether Matrix Stiffness also alters LOXL2 expression in other cells within tumor microenvironment, we developed a gel-based culture system combined with a model of macrophage polarization to evaluate the effects of Matrix Stiffness on the polarization of M2 macrophages and their LOXL2 expression. THP-1 cells cultured on 6KPa, 10KPa, and 16KPa Stiffness substrates were first incubated with 100nM phorbol 12-myristate 13-acetate (PMA) for 24 hours and subsequently treated with 20nM interleukin-4 (IL-4) and 20nM interleukin-13 (IL-13) for 48 hours. The polarization states of M2 macrophages under different Stiffness stimulation were comparatively analyzed, and their LOXL2 expressions as well as the underlying molecular mechanism were further explored. Our results demonstrated that increased Matrix Stiffness remarkably strengthened M2 macrophage polarization and promoted their LOXL2 expression. Activation of integrin β5-FAK-MEK1/2-ERK1/2 pathway participated in Matrix Stiffness-mediated HIF-1α upregulation, and HIF-1α upregulation resulted in a significant improvement in LOXL2 expression. Additionally, M2 macrophage polarization state and LOXL2 expression in HCC tissues with COL1High /LOXHigh were consistent with the results in vitro, further confirming the regulation roles of Matrix Stiffness in macrophage polarization and LOXL2 expression. The findings about LOXL2 upregulation in the polarized macrophages under higher Stiffness stimulation will be helpful to better understand the underlying mechanism of Matrix Stiffness-induced premetastatic niche formation in HCC.
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Integrin αVβ5/Akt/Sp1 pathway participates in Matrix Stiffness-mediated effects on VEGFR2 upregulation in vascular endothelial cells.
American journal of cancer research, 2020Co-Authors: Yaohui Wang, Xi Zhang, Xiaoxia Xing, Rong-xin Chen, Wei-min Wang, Yinying Dong, Yang You, Zhenggang Ren, Weijian GuoAbstract:Our previous study has validated that higher Matrix Stiffness obviously improves vascular endothelial growth factor (VEGF) expression in HCC cells, highlighting a linkage between Matrix Stiffness and HCC angiogenesis. However, the effects of Matrix Stiffness on vascular endothelial cells in HCC and its underlying mechanism remain largely uncharacterized. Here we further analyzed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in human umbilical vein endothelial cells (HUVECs) grown on different Stiffness substrates and explored its regulatory mechanism for better understanding Matrix Stiffness-regulated angiogenesis in HCC. Our results revealed that increased Matrix Stiffness significantly upregulated the expression of VEGFR2 in HUVECs, and the expression level of VEGFR2 was positively correlated with the expression levels of COL1 and lysyl oxidase in human HCC tissues and rat HCC tissue, moreover VEGFR2 and CD34 were co-localized at blood vessel of HCC tissues, indicating an obvious regulation role of Matrix Stiffness in VEGFR2 expression. Simultaneously, increased Matrix Stiffness also elevated the phosphorylation level of Akt and the expressions of integrin αV/β5 and nuclear Sp1 in HUVECs. Inhibition of integrin αVβ5 remarkably reversed the expression of VEGFR2 and phosphorylation level of Akt in HUVECs grown on higher Stiffness substrate. Except that, PI3K inhibitor also suppressed the phosphorylation level of Akt and the expressions of VEGFR2 and nuclear Sp1 evidently. Taken together, higher Matrix Stiffness increased VEGFR2 expression in HUVECs, and integrin αVβ5/Akt/Sp1 pathway participated in Stiffness-mediated effects on VEGFR2 upregulation. This study combining with our previous report discloses a new paradigm in which higher Matrix Stiffness as an initiator drives HCC angiogenesis via upregulating both VEGFR2 expression in vascular endothelial cells and VEGF expression in HCC cells.
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Matrix Stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation.
Journal of experimental & clinical cancer research : CR, 2018Co-Authors: Qiongdan Zheng, Xiaoxia Xing, Yaohui Wang, Jie Chen, Rong-xin Chen, Yinying Dong, Yang You, Dong-mei GaoAbstract:Higher Matrix Stiffness affects biological behavior of tumor cells, regulates tumor-associated gene/miRNA expression and stemness characteristic, and contributes to tumor invasion and metastasis. However, the linkage between higher Matrix Stiffness and pre-metastatic niche in hepatocellular carcinoma (HCC) is still largely unknown. We comparatively analyzed the expressions of LOX family members in HCC cells grown on different Stiffness substrates, and speculated that the secreted LOXL2 may mediate the linkage between higher Matrix Stiffness and pre-metastatic niche. Subsequently, we investigated the underlying molecular mechanism by which Matrix Stiffness induced LOXL2 expression in HCC cells, and explored the effects of LOXL2 on pre-metastatic niche formation, such as BMCs recruitment, fibronectin production, MMPs and CXCL12 expression, cell adhesion, etc. Higher Matrix Stiffness significantly upregulated LOXL2 expression in HCC cells, and activated JNK/c-JUN signaling pathway. Knockdown of integrin β1 and α5 suppressed LOXL2 expression and reversed the activation of above signaling pathway. Additionally, JNK inhibitor attenuated the expressions of p-JNK, p-c-JUN, c-JUN and LOXL2, and shRNA-c-JUN also decreased LOXL2 expression. CM-LV-LOXL2-OE and rhLOXL2 upregulated MMP9 expression and fibronectin production obviously in lung fibroblasts. Moreover, activation of Akt pathway contributed to LOXL2-induced fibronectin upregulation. LOXL2 in CM as chemoattractant increased motility and invasion of BMCs, implicating a significant role of LOXL2 in BMCs recruitment. Except that, CM-LV-LOXL2-OE as chemoattractant also increased the number of migrated HCC cells, and improved chemokine CXCL12 expression in lung fibroblasts. The number of HCC cells adhered to surface of lung fibroblasts treated with CM-LV-LOXL2-OE was remarkably higher than that of the control cells. These results indicated that the secreted LOXL2 facilitated the motility of HCC cells and strengthened CTCs settlement on the remodeled Matrix “soil”. Integrin β1/α5/JNK/c-JUN signaling pathway participates in higher Matrix Stiffness-induced LOXL2 upregulation in HCC cells. The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation.
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Higher Matrix Stiffness Upregulates Osteopontin Expression in Hepatocellular Carcinoma Cells Mediated by Integrin β1/GSK3β/β-Catenin Signaling Pathway
PloS one, 2015Co-Authors: Yang You, Yaohui Wang, Yinying Dong, Qiongdan Zheng, Xiaoying Xie, Zhiming Wang, Tong-chun Xue, Lan Zhang, Rong-xin ChenAbstract:Increased stromal Stiffness is associated with hepatocellular carcinoma (HCC) development and progression. However, the molecular mechanism by which Matrix Stiffness stimuli modulate HCC progress is largely unknown. In this study, we explored whether Matrix Stiffness-mediated effects on osteopontin (OPN) expression occur in HCC cells. We used a previously reported in vitro culture system with tunable Matrix Stiffness and found that OPN expression was remarkably upregulated in HCC cells with increasing Matrix Stiffness. Furthermore, the phosphorylation level of GSK3β and the expression of nuclear β-catenin were also elevated, indicating that GSK3β/β-catenin pathway might be involved in OPN regulation. Knock-down analysis of integrin β1 showed that OPN expression and p-GSK3β level were downregulated in HCC cells grown on high Stiffness substrate compared with controls. Simultaneously, inhibition of GSK-3β led to accumulation of β-catenin in the cytoplasm and its enhanced nuclear translocation, further triggered the rescue of OPN expression, suggesting that the integrin β1/GSK-3β/β-catenin pathway is specifically activated for Matrix Stiffness-mediated OPN upregulation in HCC cells. Tissue microarray analysis confirmed that OPN expression was positively correlated with the expression of LOX and COL1. Taken together, high Matrix Stiffness upregulated OPN expression in HCC cells via the integrin β1/GSK-3β/β-catenin signaling pathway. It highlights a new insight into a pathway involving physical mechanical signal and biochemical signal molecules which contributes to OPN expression in HCC cells.
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Increasing Matrix Stiffness upregulates vascular endothelial growth factor expression in hepatocellular carcinoma cells mediated by integrin β1
Biochemical and biophysical research communications, 2014Co-Authors: Yinying Dong, Yaohui Wang, Jie Chen, Rong-xin Chen, Qiongdan Zheng, Xiaoying Xie, Zhiming Wang, Tong-chun Xue, Dong-mei GaoAbstract:Matrix Stiffness as a novel regulation factor involves in modulating the pathogenesis of hepatocellular carcinoma (HCC) invasion or metastasis. However, the mechanism by which Matrix Stiffness modulates HCC angiogenesis remains unknown. Here, using buffalo rat HCC models with different liver Matrix Stiffness backgrounds and an in vitro cell culture system of mechanically tunable Collagen1 (COL1)-coated polyacrylamide gel, we investigated the effects of different Matrix Stiffness levels on vascular endothelial growth factor (VEGF) expression in HCC cells and explored its regulatory mechanism for controlling HCC angiogenesis. Tissue microarray analysis showed that the expression levels of VEGF and CD31 were gradually upregulated in tumor tissues with increasing COL1 and lysyl oxidase (LOX) expression, indicating a positive correlation between tumor angiogenesis and Matrix rigidity. The expression of VEGF and the phosphorylation levels of PI3K and Akt were all upregulated in HCC cells on high-Stiffness gel than on low-Stiffness gel. Meanwhile, alteration of intergrin β1 expression was found to be the most distinctive, implying that it might mediate the response of HCC cells to Matrix Stiffness simulation. After integrin β1 was blocked in HCC cells using specific monoclonal antibody, the expression of VEGF and the phosphorylation levels of PI3K and Akt at different culture times were accordingly suppressed and downregulated in the treatment group as compared with those in the control group. All data suggested that the extracellular Matrix Stiffness stimulation signal was transduced into HCC cells via integrin β1, and this signal activated the PI3K/Akt pathway and upregulated VEGF expression. This study unveils a new paradigm in which Matrix Stiffness as initiators to modulate HCC angiogenesis.