An Autocrine Wnt5a Loop Promotes NF-κB Pathway Activation and Cytokine/Chemokine Secretion in Melanoma

Wnt5a signaling has been implicated in the progression of cancer by regulating multiple cellular processes, largely migration and invasion, epithelial-mesenchymal transition (EMT), and metastasis. Since Wnt5a signaling has also been involved in inflammatory processes in infectious and inflammatory diseases, we addressed the role of Wnt5a in regulating NF-κB, a pivotal mediator of inflammatory responses, in the context of cancer. The treatment of melanoma cells with Wnt5a induced phosphorylation of the NF-κB subunit p65 as well as IKK phosphorylation and IκB degradation. By using cDNA overexpression, RNA interference, and dominant negative mutants we determined that ROR1, Dvl2, and Akt (from the Wnt5a pathway) and TRAF2 and RIP (from the NF-κB pathway) are required for the Wnt5a/NF-κB crosstalk. Wnt5a also induced p65 nuclear translocation and increased NF-κB activity as evidenced by reporter assays and a NF-κB-specific upregulation of RelB, Bcl-2, and Cyclin D1. Further, stimulation of melanoma cells with Wnt5a increased the secretion of cytokines and chemokines, including IL-6, IL-8, IL-11, and IL-6 soluble receptor, MCP-1, and TNF soluble receptor I. The inhibition of endogenous Wnt5a demonstrated that an autocrine Wnt5a loop is a major regulator of the NF-κB pathway in melanoma. Taken together, these results indicate that Wnt5a activates the NF-κB pathway and has an immunomodulatory effect on melanoma through the secretion of cytokines and chemokines.

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WNT1 Inducible Signaling Pathway Protein 1 (WISP1) stimulates melanoma cell invasion and metastasis by promoting epithelial – mesenchymal transition

10.1101/427088 ◽

2018 ◽

Cited By ~ 2

Author(s):

Wentao Deng ◽

Audry Fernandez ◽

Sarah L. McLaughlin ◽

David J. Klinke

Keyword(s):

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

Primary Melanoma ◽

Gene Expression Signature ◽

Melanoma Cells ◽

Migration And Invasion ◽

Matricellular Protein ◽

Invasion And Metastasis ◽

Mesenchymal Transition

ABSTRACTBesides intrinsic changes, malignant cells release soluble signals to reshape their microenvironment. Among the signaling factors is WNT1 inducible signaling pathway protein 1 (WISP1), a secreted matricellular protein that is elevated in a variety of cancers including melanoma and is associated with reduced overall survival of patients diagnosed with primary melanoma. In this work, we found thatWISP1knockout both increased cell proliferation and repressed wound healing, migration and invasion of mouse and human melanoma cells in an ensemble ofin vitroassays.In vivometastasis assays showed that WISP1 knockout repressed tumor metastasis in both C57BL/6Ncrl and NOD-scid IL2Rgammanull (NSG) mice with B16F10 and YUMM1.7 melanoma cells. Mechanistically, B16F10 cells that invaded in a transwell assay possessed a gene expression signature similar to Epithelial - Mesenchymal Transition (EMT), including coincident repression of E-cadherin and induction of fibronectin and N-cadherin. Upon WISP1 knockout, these EMT signature genes went in opposite directions in both mouse and human cell lines and were rescued by media containing WISP1 or recombinant WISP1 protein.In vivo,metastasis repression by WISP1 knockout was reversed by the reintroduction of either WISP1 or SNAI1. A set of EMT gene activation and inhibition experiments using recombinant WISP1 or kinase inhibitors in B16F10 and YUMM1.7 cells suggested that WISP1 activates Akt and MAP kinase signaling pathways to shift melanoma cells from a proliferative to invasive phenotype. Collectively, the results supported a model that WISP1 within the tumor microenvironment stimulates melanoma invasion and metastasis by promoting an EMT-like process.

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SOCS1 favors the epithelial-mesenchymal transition in melanoma, promotes tumor progression and prevents antitumor immunity by PD-L1 expression

Scientific Reports ◽

10.1038/srep40585 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 8

Author(s):

R. Berzaghi ◽

V. S. C. Maia ◽

F. V. Pereira ◽

F. M. Melo ◽

M. S. Guedes ◽

...

Keyword(s):

Growth Factor ◽

Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Tumor Development ◽

Growth Factor Receptor ◽

Melanoma Cells ◽

Migration And Invasion ◽

Fibroblast Growth Factor Receptors ◽

Mesenchymal Transition

Abstract Silencing of SOCS1 protein with shRNAi lentivirus (shR-SOCS1) led to partial reversion of the tumorigenic phenotype of B16F10-Nex2 melanoma cells. SOCS1 silencing inhibited cell migration and invasion as well as in vitro growth by cell cycle arrest at S phase with increased cell size and nuclei. Down-regulation of SOCS1 decreased the expression of epidermal growth factor receptor, Ins-Rα, and fibroblast growth factor receptors. The present work aimed at analyzing the SOCS1 cell signaling and expression of proteins relevant to tumor development. An RNA microarray analysis of B16F10-Nex2 melanoma cells with SOCS1 silenced by shRNAi-SOCS1 was undertaken in comparison with cells transduced with the empty vector. Among 609 differentially expressed genes, c-Kit, Met and EphA3 cytokine/tyrosine-kinase (TK) receptors were down regulated. A significant decrease in the expression of TK receptors, the phosphorylation of mediators of ERK1/2 and p38 pathways and STAT3 (S727) were observed. Subcutaneous immunization with shR-SOCS1-transduced viable tumor cells rendered protection against melanoma in a syngeneic model, with decreased expression of PD-L1 and of matrix metallo-proteinases (MMPs) and CD-10 in those cells. The present work shows the role of SOCS1 in murine melanoma development and the potential of SOCS1-silenced tumor cells in raising an effective anti-melanoma immune response.

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YAP-Dependent BiP Induction Is Involved in Nicotine-Mediated Oral Cancer Malignancy

Cells ◽

10.3390/cells10082080 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2080

Author(s):

Chu-Yen Chien ◽

Ying-Chen Chen ◽

Chia-Chen Hsu ◽

Yu-Ting Chou ◽

Shine-Gwo Shiah ◽

...

Keyword(s):

Oral Cancer ◽

Er Stress ◽

Cancer Progression ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Significant Risk ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Α7 Nachr

Cigarette smoking is a significant risk factor for the development and progression of oral cancer. Previous studies have reported an association between nicotine and malignancy in oral cancer. Recent studies have also demonstrated that nicotine can induce endoplasmic reticulum (ER) stress in tumor cells. Binding immunoglobulin protein (BiP) acts as a master regulator of ER stress and is frequently overexpressed in oral cancer cell lines and tissues. However, the effect of nicotine on BiP in oral cancer is unknown. Therefore, this study aimed to evaluate the role of BiP and its underlying regulatory mechanisms in nicotine-induced oral cancer progression. Our results showed that nicotine significantly induced the expression of BiP in time- and dose-dependent manners in oral squamous cell carcinoma (OSCC) cells. In addition, BiP was involved in nicotine-mediated OSCC malignancy, and depletion of BiP expression remarkably suppressed nicotine-induced malignant behaviors, including epithelial–mesenchymal transition (EMT) change, migration, and invasion. In vivo, BiP silencing abrogated nicotine-induced tumor growth and EMT switch in nude mice. Moreover, nicotine stimulated BiP expression through the activation of the YAP-TEAD transcriptional complex. Mechanistically, we observed that nicotine regulated YAP nuclear translocation and its interaction with TEAD through α7-nAChR-Akt signaling, subsequently resulting in increased TEAD occupancy on the HSPA5 promoter and elevated promoter activity. These observations suggest that BiP is involved in nicotine-induced oral cancer malignancy and may have therapeutic potential in tobacco-related oral cancer.

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STAT3α Is Oncogenic for Endometrial Carcinoma Cells and Mediates the Oncogenic Effects of Autocrine Human Growth Hormone

Endocrinology ◽

10.1210/en.2010-0273 ◽

2010 ◽

Vol 151 (9) ◽

pp. 4133-4145 ◽

Cited By ~ 28

Author(s):

Jian-Zhong Tang ◽

Xiang-Jun Kong ◽

Arindam Banerjee ◽

Nethaji Muniraj ◽

Vijay Pandey ◽

...

Keyword(s):

Endometrial Carcinoma ◽

Small Interfering Rna ◽

Epithelial Mesenchymal Transition ◽

Dominant Negative ◽

Migration And Invasion ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Stat3 Phosphorylation ◽

Ec Cells ◽

Interfering Rna

We herein demonstrate an oncogenic role for signal transducer and activator of transcription (STAT)-3α (the full length STAT3 isoform), which also mediates autocrine human GH (hGH)-stimulated oncogenicity, in human endometrial carcinoma (EC) cells. Autocrine hGH stimulated Y705 phosphorylation of STAT3 and STAT3-mediated transcriptional activity in a SRC and Janus-2 Kinase dependent manner in human EC cell lines. Forced expression of a constitutively active variant of STAT3α increased proliferation, anchorage-independent, three-dimensional (3D) Matrigel, and xenograft growth and promoted epithelial-mesenchymal transition, migration, and invasion of EC cells. Conversely, the oncogenic capacity of EC cells was significantly impaired by treatment with JSI-124, an inhibitor of STAT3 phosphorylation and activity, small interfering RNA-mediated depletion of STAT3α, or a dominant-negative variant of STAT3α. Furthermore, the enhanced EC cell oncogenicity stimulated by autocrine hGH, was also abrogated by functional inhibition or small interfering RNA-mediated depletion of STAT3α. STAT3α may therefore be a common mediator of oncogenic signaling pathways stimulating progression of EC.

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Knockdown of Delta-like 3 restricts lipopolysaccharide-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated epithelial-mesenchymal transition

Life Sciences ◽

10.1016/j.lfs.2019.04.024 ◽

2019 ◽

Vol 226 ◽

pp. 149-155 ◽

Cited By ~ 4

Author(s):

Xiaojie Ding ◽

Fuyao Li ◽

Li Zhang

Keyword(s):

Epithelial Mesenchymal Transition ◽

Melanoma Cells ◽

Migration And Invasion ◽

Mesenchymal Transition

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Gemifloxacin, a Fluoroquinolone Antimicrobial Drug, Inhibits Migration and Invasion of Human Colon Cancer Cells

BioMed Research International ◽

10.1155/2013/159786 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 16

Author(s):

Jung-Yu Kan ◽

Ya-Ling Hsu ◽

Yen-Hsu Chen ◽

Tun-Chieh Chen ◽

Jaw-Yuan Wang ◽

...

Keyword(s):

Colon Cancer ◽

Cell Migration ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Human Colon ◽

Inhibitory Effect ◽

Migration And Invasion ◽

Human Colon Cancer ◽

Mesenchymal Transition ◽

Cell Migration And Invasion

Gemifloxacin (GMF) is an orally administered broad-spectrum fluoroquinolone antimicrobial agent used to treat acute bacterial exacerbation of pneumonia and bronchitis. Although fluoroquinolone antibiotics have also been found to have anti-inflammatory and anticancer effects, studies on the effect of GMF on treating colon cancer have been relatively rare. To the best of our knowledge, this is the first report to describe the antimetastasis activities of GMF in colon cancer and the possible mechanisms involved. Results have shown that GMF inhibits the migration and invasion of colon cancer SW620 and LoVo cells and causes epithelial mesenchymal transition (EMT). In addition, GMF suppresses the activation of NF-κB and cell migration and invasion induced by TNF-αand inhibits the TAK1/TAB2 interaction, resulting in decreased IκB phosphorylation and NF-κB nuclear translocation in SW620 cells. Furthermore, Snail, a critical transcriptional factor of EMT, was downregulated after GMF treatment. Overexpression of Snail by cDNA transfection significantly decreases the inhibitory effect of GMF on EMT and cell migration and invasion. In conclusion, GMF may be a novel anticancer agent for the treatment of metastasis in colon cancer.

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Dihydrocapsaicin Inhibits Cell Proliferation and Metastasis in Melanoma via Down-regulating β-Catenin Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.648052 ◽

2021 ◽

Vol 11 ◽

Author(s):

Shaomin Shi ◽

Chongyang Li ◽

Yanli Zhang ◽

Chaowei Deng ◽

Wei Liu ◽

...

Keyword(s):

Cell Proliferation ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

Melanoma Cells ◽

Migration And Invasion ◽

Mice Model ◽

Mesenchymal Transition ◽

Cancer Breast

Dihydrocapsaicin (DHC) is one of the main components of capsaicinoids in Capsicum. It has been reported that DHC exerts anti-cancer effects on diverse malignant tumors, such as colorectal cancer, breast cancer, and glioma. However, studies focused on the effect of DHC upon melanoma have rarely been done. In the present study, melanoma A375 and MV3 cell lines were treated with DHC and the cell proliferation, migration, and invasion were significantly suppressed. Furthermore, DHC effectively inhibited xenograft tumor growth and pulmonary metastasis of melanoma cells in NOD/SCID mice model. It was identified that β-catenin, which plays significant roles in cell proliferation and epithelial-mesenchymal transition, was down-regulated after DHC treatment. In addition, cyclin D1, c-Myc, MMP2, and MMP7, which are critical in diverse cellular process regulation as downstream proteins of β-catenin, were all decreased. Mechanistically, DHC accelerates ubiquitination of β-catenin and up-regulates the beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) in melanoma cells. The DHC induced suppression of cell proliferation, migration, and invasion were partly rescued by exogenous β-catenin overexpression, both in vitro and in vivo. Taken together, DHC may serve as a candidate natural compound for human melanoma treatment through β-catenin pathway.

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RBBP6, a RING finger-domain E3 ubiquitin ligase, induces epithelial–mesenchymal transition and promotes metastasis of colorectal cancer

Cell Death and Disease ◽

10.1038/s41419-019-2070-7 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 2

Author(s):

Chao Xiao ◽

Gang Wu ◽

Zhijie Zhou ◽

Xin Zhang ◽

YuPeng Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Ubiquitin Ligase ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

E3 Ubiquitin Ligase ◽

Ring Finger ◽

Migration And Invasion ◽

Ring Finger Domain ◽

Mesenchymal Transition ◽

Cell Metastasis

Abstract RBBP6 has been implicated in tumorigenesis but its role in tumor metastasis and progression has not been evaluated. Interestingly, here we show that RBBP6 is upregulated in colorectal cancer (CRC) where its expression level is positively correlated with distant metastasis. In this study, we identified RBBP6, a RING Finger-domain E3 ubiquitin ligase, served as an independent prognostic factor and predicted poor outcome for CRC patients. RBBP6 promoted cell proliferation, migration, and invasion in CRC cells and promoted tumor growth, lung metastasis, and liver metastasis in mouse models. Mechanistically, we revealed that RBBP6 bound and ubiquitylated IκBα, an inhibitor of the NF-κB-signaling pathway. RBBP6-mediated ubiquitination and degradation of IκBα significantly enhanced p65 nuclear translocation, which triggered the activation of NF-κB pathway and then induced the epithelial–mesenchymal transition (EMT) process and cell metastasis. Furthermore, by DNA methylation results and ChIP analysis, we demonstrated that the promoter of RBBP6 was hypomethylated, and was activated by multi-oncogenic transcription factors. In conclusion, our findings suggest that RBBP6 may be a potential prognostic biomarker and therapeutic target for CRC invasion and metastasis.

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MiR-597 Targeting 14-3-3σ Enhances Cellular Invasion and EMT in Nasopharyngeal Carcinoma Cells

Current Molecular Pharmacology ◽

10.2174/1874467212666181218113930 ◽

2019 ◽

Vol 12 (2) ◽

pp. 105-114 ◽

Cited By ~ 1

Author(s):

Lisha Xie ◽

Tao Jiang ◽

Ailan Cheng ◽

Ting Zhang ◽

Pin Huang ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Cell Lines ◽

Western Blotting ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Suppressor Gene ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Downstream Target ◽

Before And After

Background: Alterations in microRNAs (miRNAs) are related to the occurrence of nasopharyngeal carcinoma (NPC) and play an important role in the molecular mechanism of NPC. Our previous studies show low expression of 14-3-3σ (SFN) is related to the metastasis and differentiation of NPC, but the underlying molecular mechanisms remain unclear. Methods: Through bioinformatics analysis, we find miR-597 is the preferred target miRNA of 14-3-3σ. The expression level of 14-3-3σ in NPC cell lines was detected by Western blotting. The expression of miR-597 in NPC cell lines was detected by qRT-PCR. We transfected miR-597 mimic, miR-597 inhibitor and 14-3-3σ siRNA into 6-10B cells and then verified the expression of 14-3-3σ and EMT related proteins, including E-cadherin, N-cadherin and Vimentin by western blotting. The changes of migration and invasion ability of NPC cell lines before and after transfected were determined by wound healing assay and Transwell assay. Results: miR-597 expression was upregulated in NPC cell lines and repaired in related NPC cell lines, which exhibit a potent tumor-forming effect. After inhibiting the miR-597 expression, its effect on NPC cell line was obviously decreased. Moreover, 14-3-3σ acts as a tumor suppressor gene and its expression in NPC cell lines is negatively correlated with miR-597. Here 14-3-3σ was identified as a downstream target gene of miR-597, and its downregulation by miR-597 drives epithelial-mesenchymal transition (EMT) and promotes the migration and invasion of NPC. Conclusion: Based on these findings, our study will provide theoretical and experimental evidences for molecular targeted therapy of NPC.

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Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽

10.3390/cells10030558 ◽

2021 ◽

Vol 10 (3) ◽

pp. 558

Author(s):

Jin Kyung Seok ◽

Eun-Hee Hong ◽

Gabsik Yang ◽

Hye Eun Lee ◽

Sin-Eun Kim ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Autophagic Flux ◽

Oxidized Phospholipids ◽

Mcf7 Cells ◽

Mesenchymal Transition ◽

Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

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