Oncostatin M receptor, positively regulated by SP1, promotes gastric cancer growth and metastasis upon treatment with Oncostatin M

Zhou, Yu; Li, Zhen; Wang, Chenchen; Pan, Tao; Chang, Xiaohong; Wang, Xiaofeng; Zhou, Quan; Xin, Wu; Li, Jianfang; Zhang, Jinping; Liu, Bingya; Zhu, Zhenggang; Su, Liping

doi:10.1007/s10120-019-00934-y

Cited by 40 publications

(34 citation statements)

References 26 publications

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“…OSM, another IL-6 cytokine family member, is crucial for JAK/STAT activation. It interacts with the extracellular matrix (ECM) proteins, and OSM/OSM receptor (OSMR)-mediated JAK2/STAT3/FAK/Src activation promotes EMT and CSC production [34][35][36][37][38][39]. Other pro-inflammatory cytokines, IL-32β and IL-23, are highly expressed in cancers.…”

Section: Critical Modulators Of the Jak2/stat3 Signaling Pathway In Emtmentioning

confidence: 99%

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

Jin

2020

Cells

272

169

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The JAK/STAT3 signaling pathway plays an essential role in various types of cancers. Activation of this pathway leads to increased tumorigenic and metastatic ability, the transition of cancer stem cells (CSCs), and chemoresistance in cancer via enhancing the epithelial–mesenchymal transition (EMT). EMT acts as a critical regulator in the progression of cancer and is involved in regulating invasion, spread, and survival. Furthermore, accumulating evidence indicates the failure of conventional therapies due to the acquisition of CSC properties. In this review, we summarize the effects of JAK/STAT3 activation on EMT and the generation of CSCs. Moreover, we discuss cutting-edge data on the link between EMT and CSCs in the tumor microenvironment that involves a previously unknown function of miRNAs, and also discuss new regulators of the JAK/STAT3 signaling pathway.

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Section: Critical Modulators Of the Jak2/stat3 Signaling Pathway In Emtmentioning

confidence: 99%

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

Jin

2020

Cells

272

169

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“…IHC staining was performed on the tissue microarray according to a previously reported standard protocol used in Shanghai Institute of Digestive Surgery [36]. In brief, freshly cut 5-μm-thick tissue microarray was stained with antibodies against CTSL (1:200, ab203028, Abcam, Cambridge, MA, USA), VEGF-D (1:1000; 26915-1-AP; ProteinTech Group, Chicago, IL, USA) and PECAM1 (1:200, ab268100; Abcam, Cambridge, MA, USA).…”

Section: Immunohistochemistry Stainingmentioning

confidence: 99%

Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer

et al. 2020

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Background Increasing evidence indicates that angiogenesis plays an important role in tumor progression. The function of cathepsin L (CTSL), an endosomal proteolytic enzyme, in promoting tumor metastasis is well recognized. The mechanisms by which CTSL has promoted the angiogenesis of gastric cancer (GC), however, remains unclear. Methods The nuclear expression levels of CTSL were assessed in GC samples. The effects of CTSL on GC angiogenesis were determined by endothelial tube formation analysis, HUVEC migration assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the CDP/Cux/VEGF-D pathway was analyzed by angiogenesis antibody array, Western blot, co-immunoprecipitation (Co-IP) and dual-luciferase reporter assay. Results In this study, we found that the nuclear CTSL expression level in GC was significantly higher than that in adjacent nontumor gastric tissues and was a potential important clinical prognostic factor. Loss- and gain-of-function assays indicated that CTSL promotes the tubular formation and migration of HUVEC cells in vitro. The CAM assay also showed that CTSL promotes angiogenesis of GC in vivo. Mechanistic analysis demonstrated that CTSL can proteolytically process CDP/Cux and produce the physiologically relevant p110 isoform, which stably binds to VEGF-D and promotes the transcription of VEGF-D, thus contributing to the angiogenesis of GC. Conclusion The findings of the present study suggested that CTSL plays a constructive role in the regulation of angiogenesis in human GC and could be a potential therapeutic target for GC.

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“…The crystal structure of OSM reveals that the protein comprises four α helices ranging from 15 to 22 amino acids in length (termed A, B, C, and D) and linked by polypeptide loops (Figure 1A) (Deller et al, 2000). The OSMR is a member of the IL-6 receptor family that transduces signaling events of OSM (Yu et al, 2019). Currently, available antibodies, such as GSK315234 and GSK2330811, have already been proven to affect the OSM signal (Verstockt et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Molecular Simulation of Oncostatin M and Receptor (OSM–OSMR) Interaction as a Potential Therapeutic Target for Inflammatory Bowel Disease

Yan

Xue

2020

Front. Mol. Biosci.

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Therapeutics targeting cytokines such as the oncostatin M (OSM)-mediated inflammation represent a potential strategy for the treatment of inflammatory bowel disease (IBD). Despite the investigation of the specific role of the interactions between OSM and the receptor (OSMR) in IBD pathogenesis, the 3D structure of the OSM-OSMR complex remains elusive. In this work, the interaction mode between OSM and OSMR at atomic level was predicted by computational simulation approach. The interaction domain of the OSMR was built with the homology modeling method. The near-native structure of the OSM-OSMR complex was obtained by docking, and long-time scale molecular dynamics (MD) simulation in an explicit solvent was further performed to sample the conformations when OSM binds to the OSMR. After getting the equilibrated states of the simulation system, per-residue energy contribution was calculated to characterize the important residues for the OSM-OSMR complex formation. Based on these important residues, eight residues (OSM: Arg100, Leu103, Phe160, and Gln161; OSMR: Tyr214, Ser223, Asp262, and Trp267) were identified as the "hot spots" through computational alanine mutagenesis analysis and verified by additional MD simulation of R100A (one of the identified "hotspots") mutant. Moreover, six cavities were detected at the OSM-OSMR interface through the FTMap analysis, and they were suggested as important binding sites. The predicted 3D structure of the OSM-OSMR complex and the identified "hot spots" constituting the core of the binding interface provide helpful information in understanding the OSM-OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions.

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Oncostatin M receptor, positively regulated by SP1, promotes gastric cancer growth and metastasis upon treatment with Oncostatin M

Cited by 40 publications

References 26 publications

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer

Molecular Simulation of Oncostatin M and Receptor (OSM–OSMR) Interaction as a Potential Therapeutic Target for Inflammatory Bowel Disease

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