β5 Integrin Up-Regulation in Brain-Derived Neurotrophic Factor Promotes Cell Motility in Human Chondrosarcoma

Lin, Chih-Yang; Chen, Hui-Jye; Li, Te‐Mao; Fong, Yi‐Chin; Liu, Shan‐Chi; Chen, Po-Chun; Tang, Chih‐Hsin

doi:10.1371/journal.pone.0067990

Cited by 16 publications

(20 citation statements)

References 44 publications

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“…Exploration of signalling pathways in our study showed that PI3/Akt pathway seemed to be more activated than ERK1/2 pathway in GCA patients compared to controls. Though PI3/Akt signalling pathway can be activated by TNF-α in human smooth muscle cells [ 32 ] or IL-1β in rat brain astrocytes [ 33 ], our results are consistent with BDNF-induced migration in human chondrosarcoma [ 34 ] through a transducing signal involving TrkB.…”

Section: Discussionsupporting

confidence: 84%

Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling

Régent

Molina

et al. 2014

Arthritis Res Ther

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Introduction: Giant cell arteritis (GCA) is characterized by intimal hyperplasia leading to ischaemic manifestations that involve large vessels. Neurotrophins (NTs) and their receptors (NTRs) are protein factors for growth, differentiation and survival of neurons. They are also involved in the migration of vascular smooth muscle cells (VSMCs). Our aim was to investigate whether NTs and NTRs are involved in vascular remodelling of GCA. Methods: We included consecutive patients who underwent a temporal artery biopsy for suspected GCA. We developed an enzymatic digestion method to obtain VSMCs from smooth muscle cells in GCA patients and controls. Neurotrophin protein and gene expression and functional assays were studied from these VSMCs. Neurotrophin expression was also analysed by immunohistochemistry in GCA patients and controls.Results: Whereas temporal arteries of both GCA patients (n = 22) and controls (n = 21) expressed nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and sortilin, immunostaining was more intense in GCA patients, especially in the media and intima, while neurotrophin-3 (NT-3) and P75 receptor (P75 NTR ) were only detected in TA from GCA patients. Expression of TrkB, a BDNF receptor, was higher in GCA patients with ischaemic complications. Serum NGF was significantly higher in GCA patients (n = 28) vs. controls (n = 48), whereas no significant difference was found for BDNF and NT-3. NGF and BDNF enhanced GCA-derived temporal artery VSMC proliferation and BDNF facilitated migration of temporal artery VSMCs in patients with GCA compared to controls. Conclusions: Our results suggest that NTs and NTRs are involved in vascular remodelling of GCA. In GCA-derived temporal artery VSMC, NGF promoted proliferation and BDNF enhanced migration by binding to TrkB and p75 NTR receptors. Further experiments are needed on a larger number of VSMC samples to confirm these results.

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Section: Discussionsupporting

confidence: 84%

Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling

Régent

Molina

et al. 2014

Arthritis Res Ther

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“…Our previous studies have shown that BDNF is associated with chondrosarcoma metastasis and angiogenesis. 16 , 17 , 18 VEGF-C has been reported to mediate tumor lymphangiogenesis in many human cancers. 19 , 20 However, the effect of BDNF on VEGF-C expression and lymphangiogenesis in chondrosarcoma has not been well explored.…”

Section: Resultsmentioning

confidence: 99%

“… 14 , 15 Our previous research has proposed that BDNF promotes chondrosarcoma metastasis through the upregulation of integrin β 5 and matrix metalloproteinase-1 expression. 16 , 17 Moreover, we have described how BDNF induces VEGF-A expression and angiogenesis in human chondrosarcoma cells. 18 VEGF-C is known to mediate tumor lymphangiogenesis in many human cancers.…”

mentioning

confidence: 99%

Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells

et al. 2017

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Chondrosarcoma is the second most common primary malignancy of bone, and one of the most difficult bone tumors to diagnose and treat. It is well known that increased levels of vascular endothelial growth factor-C (VEGF-C) promote active tumor lymphangiogenesis and lymphatic tumor spread to regional lymph nodes. Brain-derived neurotrophic factor (BDNF) is known to promote metastasis in human chondrosarcoma cells. Knowing more about the mechanism of BDNF in VEGF-C expression and lymphangiogenesis in human chondrosarcoma would improve our understanding as how to prevent chondrosarcoma angiogenesis and metastasis, which currently lacks effective adjuvant treatment. Here, we found that BDNF expression was at least 2.5-fold higher in the highly migratory JJ012(S10) cell line as compared with the primordial cell line (JJ012). In addition, VEGF-C expression and secretion was markedly increased in JJ012(S10) cells. Conditioned medium from JJ012(S10) cells significantly promoted migration and tube formation of human lymphatic endothelial cells (LECs), whereas knockdown of BDNF attenuated LEC migration and tube formation by suppressing VEGF-C production in JJ012(S10) cells. Mechanistic investigations indicated that BDNF facilitated VEGF-C-dependent lymphangiogenesis through the MEK/ERK/mTOR signaling pathway. We also showed that microRNA (miR)-624-3p expression was negatively regulated by BDNF via the MEK/ERK/mTOR cascade. Importantly, BDNF knockdown profoundly inhibited tumor-associated lymphangiogenesis in vivo. Further analyses identified that BDNF promoted tumor lymphangiogenesis by downregulating miR-624-3p in human chondrosarcoma tissues. In conclusion, this study is the first to reveal the mechanism underlying BDNF-induced lymphangiogenesis. We suggest that BDNF may serve as a promising therapeutic target for the restriction of VEGF-C-mediated tumor lymphangiogenesis and lymphatic metastasis.

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“…14,21 In BDNF-enhanced migration of chondrosarcoma, integrin β5 expression was up-regulated through TrkB/AKT signalling cascade, while in BDNF-mediated migration of microvascular endothelial cells, the up-expression of integrin β3 was made via TrkB/ERK1/2 pathway. 14,21 Besides integrin β3 and integrin β5, our study found BDNF also could regulate integrin β1 expression for the first time and both AKT and EKR1/2 acted as two parallel downstream kinases in BDNF/TrkB signalling. As integrins often appeared as α/β heterodimeric receptors, further studies should be made to understand which α subunit was involved in BDNF-integrin β1 controlled osteoblasts migration.…”

Section: Discussionmentioning

confidence: 99%

“…Cooperating with kinds of growth factors, integrins transduce signals from the environment into cells and often mediate cell adhesion and migration. 14,[19][20][21] Xiong suggested TGFβ1 induced endometrial cancer cell adhesion and migration by up-regulating integrin αvβ3 while Furmento indicated granulocyte colony-stimulating factor (G-CSF) up-regulated integrin β1 and increased migration of human trophoblast Swan 71 cells. 19,20 For BDNF signalling, integrin β3 and β5 has already been proved to be up-regulated and participate in manipulating endothelial and chondrosarcoma cells migration, respectively.…”

mentioning

confidence: 99%

BDNF promoted osteoblast migration and fracture healing by up‐regulating integrin β1 via TrkB‐mediated ERK1/2 and AKT signalling

Zhang

Wang

et al. 2020

J Cellular Molecular Medi

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Brain‐derived neurotrophic factor (BDNF) has been reported to participate in fracture healing, whereas the mechanism is still unclear. Since osteoblast migration is important for fracture healing, investigating effects of BDNF on osteoblasts migration may help to reveal its mechanism. Here, MC3T3‐E1 cells were used in vitro while closed femur fracture mice were applied in vivo. Cells migration was assessed with Transwell assay. The protein expression was analysed by immunoblotting. X‐ray and Micro‐CT were performed at different time after fracture. Our results showed that BDNF promoted MC3T3‐E1 cells migration, integrin β1 expression and ERK1/2 and AKT phosphorylation. K252a, a specific inhibitor for TrkB, suppressed BDNF‐induced migration, integrin β1 expression and activation of ERK1/2 and AKT. PD98059 (an ERK1/2 inhibitor) and LY294002 (an AKT inhibitor) both inhibited BDNF‐induced migration and integrin β1 expression while integrin β1 blocking antibody only suppressed cell migration. X‐ray and Micro‐CT analyses showed that the adenoviral carried integrin β1 shRNA group had slower fracture healing at 7 and 21 days, but not 35 days compared to the control group. Thus, we proposed that BDNF stimulated MC3T3‐E1 cells migration by up‐regulating integrin β1 via TrkB mediated ERK1/2 and AKT signalling, and this may help to enhance the fracture healing.

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β5 Integrin Up-Regulation in Brain-Derived Neurotrophic Factor Promotes Cell Motility in Human Chondrosarcoma

Cited by 16 publications

References 44 publications

Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling

Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling

Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells

BDNF promoted osteoblast migration and fracture healing by up‐regulating integrin β1 via TrkB‐mediated ERK1/2 and AKT signalling

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