Sphingosine-1-phosphate induced epithelial-mesenchymal transition of hepatocellular carcinoma via an MMP-7/syndecan-1/TGF-β autocrine loop

Zeng, Ye; Yao, Xinghong; Chen, Li; Zhang, Yan; Liu, Jingxia; Zhang, Yingying; Tian, Feng; Wu, Jiang; Liu, Xiaoheng

doi:10.18632/oncotarget.11450

Cited by 104 publications

(91 citation statements)

References 45 publications

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“…We also show that expression of SPHK1 correlates significantly with EMT score in breast cancer, consistent with previous studies that also suggest its involvement in EMT (26,57,58).…”

Section: Discussionsupporting

confidence: 92%

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

et al. 2019

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Epithelial‐mesenchymal transition (EMT) is a critical process implicated in the initial stage of cancer metastasis, which is the major cause of tumor recurrence and mortality. Although key transcription factors that regulate EMT, such as snail family transcriptional repressor 2 (SNAI2), are well characterized, the upstream signaling pathways controlling these transcriptional mediators are largely unknown, which limits therapeutic strategies. Sphingosine 1–phosphate (S1P) is a bioactive lipid mediator, generated by sphingosine kinases (SPHK1 and SPHK2), that mainly exerts its effects by binding to the following 5 GPCRs: S1P1 to S1P5. S1P signaling has been reported to regulate different aspects of cancer progression including cell proliferation, apoptosis, and migration; nevertheless, its role in cancer metastasis, specifically via EMT, is not established. Here we show that SPHK1 expression correlates significantly with EMT score in breast cancer cell lines, and with SNAI2 in patient‐derived breast tumors. Cell‐based assays demonstrate that S1P can rapidly up‐regulate the expression of SNAI2 in breast cancer cells via the activation of cognate receptors S1P2 and S1P3. Knockdown studies suggest that S1P2 and S1P3 mediate this effect by activating myocardin‐related transcription factor A (MRTF‐A) and yes‐associated protein (YAP), respectively. Michigan Cancer Foundation 7 cells stably overexpressing S1P2 or S1P3 exhibit a more invasive phenotype, when compared to control cells. Taken together, our findings suggest that S1P produced by SPHK1 induces SNAI2 expression via S1P2‐YAP and S1P3‐MRTF‐A pathways, leading to enhanced cell invasion. Cumulatively, this study reveals a novel mechanism by which S1P activates parallel pathways that regulate the expression of SNAI2, a master regulator of EMT, and provides new insights into druggable therapeutic targets that may limit cancer metastasis. Wang, W., Hind, T., Lam, B. W. S., Herr, D. R. Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells. FASEB J. 33, 7180–7191 (2019). http://www.fasebj.org

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“…We also show that expression of SPHK1 correlates significantly with EMT score in breast cancer, consistent with previous studies that also suggest its involvement in EMT (26,57,58).…”

Section: Discussionsupporting

confidence: 92%

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

et al. 2019

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“…Though S1P’s role in cancer is multifaceted, the cancer field has mainly explored roles for cer-amide signaling and an inflammatory response; we suggest that dysregulated cell extrusion should also be considered, especially considering the elegant report demonstrating the S1P receptor’s key role in cancer cell extrusion and metastasis (Gu et al, 2015). Intriguingly, S1P is reported to trigger EMT in certain human hepatocellular carcinoma (Zeng et al, 2016) and lung cancer lines (Milara et al, 2012), and S1P was upregulated in patients with idiopathic pulmonary fibrosis, a disease characterized by frequent EMT (Milara et al, 2012); this further hints at the possibility of extrusion-EMT coupling in cancer. Last, Piezo1, the master regulator of live cell extrusion, is mutated or misex-pressed in colorectal, gastric, and thyroid cancers (Gudipaty et al, 2017), and Piezo1 promoted the invasion of gastric cancer cells in vitro (Yang et al, 2014).…”

Section: A Force For Evil: Cell Extrusion In Diseasementioning

confidence: 99%

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

2018

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Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression.

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“…Numerous studies have shown that CCAT1 acts as an oncogene, and is highly expressed in many malignancies, such as colorectal, gastric, ovarian, breast, gallbladder, hepatocellular carcinoma, and lung cancer (Cao et al, ; Gao et al, ; Jia et al, ; Li et al, ; Zhang et al, ; Zhang and Hu, ). CCAT1 exerts its carcinogenic effect by promoting cell invasion and metastasis (Zhao et al, ) and this has been widely studied (Zeng et al, ). Several recent studies suggest that CCAT1 serves as a biomarker for the prognosis of tumors and its expression is often associated with poor clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine protects hepatic cells against oxygen‐glucose deprivation/reperfusion injury via lncRNA CCAT1

Zhou

Chen

Wan

et al. 2018

Cell Biology International

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Dexmedetomidine (Dex) protects different cell types during hypoxia or ischemia-reperfusion injury by inhibiting cell apoptosis. However, the underlying mechanism and its impact on hepatic ischemia reperfusion injury are still not known. In this study, we established a model of oxygen-glucose deprivation/reperfusion (OGD/R) injury in hepatocyte HL7702 cells, and studied the impact of Dex on cell proliferation, apoptosis, and cell cycle during OGD/R. In addition, we explored the role of CCAT1 in this process. We found that Dex increased cell proliferation and inhibited cell apoptosis during OGD/R, in a concentration-dependent manner. Dex partially reversed the OGD-inhibited expression of lncRNA CCAT1. Knockdown of CCAT1 by siRNA inhibited Dex-mediated protection against OGD/R-induced injury and promoted cell apoptosis, caspase-3 expression and cell cycle arrest in the G0/G1 phase, and inhibited cell proliferation and cyclin D1 expression. In contrast, overexpression of CCAT1 by pcDNA3.0-CCAT1 enhanced Dex-mediated protection against OGD/R-induced cell injury. Thus, Dex protects hepatocytes against OGD/R injury by upregulating lncRNA CCAT1. This study suggests a novel role of CCAT1 in ischemia reperfusion injury, and lays the framework for future studies.

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Sphingosine-1-phosphate induced epithelial-mesenchymal transition of hepatocellular carcinoma via an MMP-7/syndecan-1/TGF-β autocrine loop

Cited by 104 publications

References 45 publications

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

Dexmedetomidine protects hepatic cells against oxygen‐glucose deprivation/reperfusion injury via lncRNA CCAT1

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