Epiregulin reprograms cancer-associated fibroblasts and facilitates oral squamous cell carcinoma invasion via JAK2-STAT3 pathway

Yin

et al. 2020

OTT

Background: Several studies have indicated that the anoikis effector Bcl-2 inhibitor of transcription 1 (Bit1) can promote or inhibit tumor progression depending on the nature of the malignancy. However, its regulatory effects on gliomas are unknown. Methods: This study aimed at assessing Bit1 expression in glioma tissues and cells, its subsequent effects on glioma cell apoptosis, proliferation, invasion, and migration, and the underlying molecular mechanisms. Results: The findings showed that lower Bit1 expressions in glioma tissues as well as a negative correlation between Bit1 expression and glioma grade. Additional findings also revealed that Bit1 silencing significantly inhibited anoikis and enhanced glioma cell proliferation, invasion, and migration. Further analysis showed that the decrease in Bit1 expressions led to malignancy proliferation and anoikis resistance through activation of the IL-6/ STAT3 signaling pathway. Conclusion: Our data suggested that Bit1 may play an anti-oncogenic role in glioma cells and that a decrease in its expressions might induce glioma cell proliferation, migration, and invasion through the IL-6/STAT3 signaling pathway.

Section: Discussionmentioning

confidence: 99%

<p>Bit1 Silencing Enhances the Proliferation, Migration, and Invasion of Glioma Cells Through Activation of the IL-6/STAT3 Pathway</p>

Yin

et al. 2020

OTT

“…CAFs, as the most critical stromal cells in TME, participate in the process of tumor growth and development [6][7][8][9][10][11][12][13]. As an important supplement to tumor microcirculation, VM occurs in certain highly aggressive malignancies, and is closely related to tumor progression and poor prognosis [18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…Tumor microenvironment (TME), also known as tumor stroma, is composed of extracellular matrix (ECM) and a variety of stromal cells [4][5]. Cancer-associated broblasts (CAFs) are the most important stromal cells in TME, which play an important role in tumor growth and development, and participate in many biological processes such as tumor proliferation, invasion and metastasis, angiogenesis [6][7][8][9][10][11][12], and are related to poor prognosis [13][14][15]. In these biological processes, angiogenesis and effective blood supply are the basic conditions for tumor growth and metastasis [16,17].…”

Section: Introductionmentioning

confidence: 99%

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

Pan

Ansari

et al. 2020

Preprint

Background: Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism.Methods: A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (-) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored. Results: GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the upregulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway.Conclusions: GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is overexpressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.

“…While rCCL18 treatment led to down-regulation of E-cadherin and elevation of N-cadherin and ZEB2 in OSCC cells, silencing NIR1 and/or GPR3 caused the opposite, indicating that NIR1 and GPR3 may play essential roles in the CCL18-induced malignant progression of OSCC. JAK2/STAT3 signalling is an evolutionarily conserved signalling pathway and known to interfere with tumour growth and metastasis of OSCC [11,22]. Activation of JAK2 protein kinase can catalyze STAT3 protein phosphorylation which regulates the expression of oncogenic genes [23].…”

Section: Discussionmentioning

confidence: 99%

“…Based on this theory, we believe that it is necessary to identify the downstream pathway of CCL18-receptors signalling pathway. JAK2/STAT3 (Janus kinase 2/signal transducers and activators of transcription 3) signalling as an oncogenic pathway involved in many solid cancers including OSCC [11]has been shown to be activated by several chemokine-signalling axes, for instance, CXCL12-CXCR4 axis [12], CXCL8-CXCR1/CXCR2 axis [13], and CXCL9-CXCR3 axis [14]. The interaction between JAK2/STAT3 and these chemokine-receptor axes arouse our interest and made us wonder: if the CCL18-receptors signalling is coupled with the JAK2/STAT3 pathway and if the interaction between both pathways plays a contributing role in the metastasis of OSCC.…”

Section: Ccl18 (Chemokine (C-mentioning

confidence: 99%

CCL18-NIR1/GPR3 promotes oral cancer cell growth and metastasis by activating the JAK2/STAT3 signalling pathway

Chen

Jiang

Sun

et al. 2019

Preprint

Background Chemokine (C-C motif) ligand 18 (CCL18) affects the malignant progression of varying cancers by activating chemokine receptors. Our previous study have shown that CCL18 promotes hyperplasia and invasiveness of oral cancer cells; however, the cognate receptors of CCL18 involved in the pathogenesis of oral squamous cell carcinoma (OSCC) has not yet been identified. This study aimed to investigate the underlying molecular mechanisms through which CCL18 promotes OSCC progression by binding to specific functional receptors.Methods The properties of CCL18 receptors (i.e., NIR1, CCR6, CCR8, and GPR3) in OSCC were detected by conducting western blotting, immunofluorescence, and immunocytochemistry assays. The binding between CCL18 and its receptors was verified by performing coimmunoprecipitation (CO-IP) assays. The χ2 test was applied to analyze the relationship between CCL18 receptor expression patterns and clinicopathological factors. Recombinant CCL18 (rCCL18) and receptor siRNA were used to confirm the effects of CCL18 receptor axis on the morphology of cancer cells (i.e., proliferation, and metastasis), epithelial-mesenchymal transition (EMT) and the expression of the JAK2/STAT3 signalling pathway.Results NIR1 and GPR3 as specific receptors of CCL18 in OSCC were found to be significantly increased and positively related to the TNM stage of OSCC patients. rCCL18 induced phenotype alterations of oral cancer cells including cell growth, metastasis, and EMT. Knockdown of NIR1 and/or GPR3 expression could block the effects of rCCL18-induced OSCC. Furthermore, JAK2/STAT3 signalling was confirmed to be a downstream pathway of the CCL18-NIR1/GPR3 axis.Conclusion CCL18 can promote the progression of OSCC by binding specific receptors (NIR1 and GPR3), and the CCL18-receptor signalling can activate JAK2/STAT3 pathway. The identification of the mechanisms of CCL18 promoting OSCC progression could implicate potential therapeutic targets for treating oral cancer.