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  • Taken together our studies uncovered that the RP antibody re

    2021-11-25

    Taken together, our studies uncovered that the RP215 antibody recognize a novel CIgG molecule N-glycan modification at a non-consensus site within the CH1 domain expressed in LSCC tumors. RP215-CIgG interacts with the integrin α6β4 complex and the unique N-glycan epitope mediates the activation of downstream FAK and Src signaling. The functional blocking effects of RP215 using in vitro and in vivo models imply that targeting RP215-CIgG may provide novel LSCC therapeutic strategies in the future.
    Declarations of interest
    Acknowledgements We would like to thank laboratory member Chi Zhang for data analysis. We also thank Panpan Zhang and Yuanyuan Ma, Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute for technical assistance in establishment of PDX model. We also thank Xiajuan Zou, Health Analysis Center, Peking University Health Science Center for assistance in LC-MS/MS analysis of RP215-CIgG co-precipitated proteins. This work was supported by research grants to Xiaoyan Qiu from the Major international cooperation projects of the National Natural Science Foundation (81320108020) and Key support projects of the National Natural Science Foundation's major research program (91642206), to Liang Zhang from Shenzhen Science and Technology Program (R-BTC4201) and the Research Grant Council of Hong Kong (21101917).
    Introduction Cerebral ischemia is the leading cause of Pyronaridine Tetraphosphate mg stroke, and is accompanied by complications such as the loss of memory, inability to learn, and physical motor dysfunction [1]. The recovery of patients depends on the regeneration of nerves in the ischemic lesions [[2], [3], [4]], which in turn requires revascularization and the establishment of collateral circulation [[5], [6]]. There is evidence that angiogenesis may be at least partially dependent on the nervous system or neurogenesis. Nerve growth factor (NGF), which is derived from the peripheral and central nervous systems, has various roles in mediating nerve function, including promoting nerve growth [7]. The previous studies have shown that NGF produced by breast cancer cells can promote the formation of blood vessels around the tumor, in a mouse model of breast cancer and glial tumor [[8], [9]]. Furthermore, NGF increased the secretion of vascular endothelial growth factor (VEGF) in endothelial cells and breast cancer cells, and the inhibition of VEGF significantly reduced NGF-induced angiogenesis. Previous studies have indicated that focal adhesion kinase (FAK) is involved in the phosphorylation of NGF-mediated nerve growth [[10], [11]]. Studies have shown that the recovery of patients with cerebral infarction depends mainly on the subventricular zone and subgranular zone (SVZ and SGZ, respectively) neurogenesis [12]. Therefore, the NGF-FAK signal pathway plays a dual role in the regeneration of new nerves and reconstruction of collateral circulation, specifically in the SVZ and SGZ. The neurogenesis mediated by the NGF-FAK signal pathway in the SVZ and SGZ may be an important treatment target for patients with cerebral infarction. Considering that the basement membrane, which is a form of extracellular matrix, is crucial for the formation of new blood vessels, including those in cerebral ischemic lesions [13]. For the current study, the matrigel was used as a carrier of basement membrane matrik proteins [14]. Matrigel proteins were implanted in the subcutaneous tissue of rats to identify the relevant components of the NGF-P-FAK signaling pathway related to observed angiogenesis. These components were then investigated for an association with angiogenesis in the SVZ and SGZ of a rat model of ischemia, which was established by ligation of the middle cerebral artery. Our results demonstrated that the NGF/FAK signal pathway potently is implicated in angiogenesis after acute cerebral ischemia of patents.
    Materials and methods
    Results
    Discussion The current studies showed that the NGF/FAK signal pathway may play a key role in promoting angiogenesis in the post-acute cerebral ischemia. It was established that rehabilitation of patients suffering from cerebral infarction is closely associated with neurogenesis in the ischemic area [[1], [2], [3], [4]], and a continuous blood supply guaranteeing stable metabolism and nutrients around the lesion is important in regeneration of the nerves [[2], [3]]. It is also well known that NGF is essential in mediating central nerve function, including promoting angiogenesis and axonal growth in the central nervous system [21]. Studies have shown that the basement membrane is essential in the process of angiogenesis [[22], [23]]. Given that the Matrigel is composed primarily of basement membrane [22], it was used in our model to study the angiogenesis. Our results showed that the CD31 and α-SMA protein levels in the Matrigel in the NGF-treated group were significantly higher than that in the control group. However, these levels were significantly decreased by anti-NGF and antagonizing P-FAK. Furthermore, the tissue scores based on vascularity significantly increased by NGF. However, these scores in the anti-NGF group and NGF + TAE226 group were significantly decreased. This results suggests that NGF may promote proliferation, differentiation, and migration of endothelial and smooth muscle cells. Meanwhile, the inhibition of FAK reduced the effects of NGF. These data consistently suggest that the effector role of NGF in cerebral ischemia. Therefore, the establishment of the validity of experimental platform of Matrigel was important to explore the underlying effectors that was crucial to cerebral ischemic rehabilitation.