Dataset Information

Stiffer Matrix Accelerates Migration of Hepatocellular Carcinoma Cells through Enhanced Aerobic Glycolysis Via the MAPK-YAP Signaling.

ABSTRACT: Increased extracellular matrix (ECM) stiffness and metabolic reprogramming of cancer cells are two fundamental mediators of tumor progression, including hepatocellular carcinoma (HCC). Yet, the correlation between ECM stiffness and excessive aerobic glycolysis in promoting the development of HCC remains unknown. Here, we demonstrated that stiffer ECM promotes HCC cell migration depending on their accelerated aerobic glycolysis. Our results also indicated that stiffer ECM-induced YAP activation plays a major role in promoting aerobic glycolysis of HCC cells. Moreover, we showed that JNK and p38 MAPK signaling are critical for mediating YAP activation in HCC cells. Together, our findings established that the MAPK-YAP signaling cascade that act as a mechanotransduction pathway is essential for promoting HCC cell aerobic glycolysis and migration in response to ECM stiffness.

SUBMITTER: Liu QP

PROVIDER: S-EPMC7072284 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Stiffer Matrix Accelerates Migration of Hepatocellular Carcinoma Cells through Enhanced Aerobic Glycolysis Via the MAPK-YAP Signaling.

Liu Qiu-Ping QP Luo Qing Q Deng Bin B Ju Yang Y Song Guan-Bin GB

Cancers 20200219 2

Increased extracellular matrix (ECM) stiffness and metabolic reprogramming of cancer cells are two fundamental mediators of tumor progression, including hepatocellular carcinoma (HCC). Yet, the correlation between ECM stiffness and excessive aerobic glycolysis in promoting the development of HCC remains unknown. Here, we demonstrated that stiffer ECM promotes HCC cell migration depending on their accelerated aerobic glycolysis. Our results also indicated that stiffer ECM-induced YAP activation p ...[more]

PMID: 32093118

Similar Datasets

Project description:Angiogenesis is a fundamental process that involves in tumor progression and metastasis. Vascular endothelial growth factor (VEGF) family and their receptors are identified as the most prominent regulators of angiogenesis. However, the clinical efficacy of anti-VEGF/VEGFR therapy is not ideal, prompting the needs to further understand mechanisms behind tumor angiogenesis. Here, we found that Dickkopf associated protein 2 (DKK2), a secretory protein highly expressed in metastatic colorectal cancer tissues, could stimulate angiogenesis via a classic VEGF/VEGFR independent pathway. Methods: DKK2 was screened out from microarray data analyzing gene expression profiles of eight pairs of non-metastatic and metastatic human colorectal cancer (CRC) tissues. Immunofluorescence histochemical staining (IHC) was used to detect the expression of DKK2 and angiogenesis in CRC tissues. Chicken chorioallantoic membrane (CAM) assay and Human umbilical vein endothelial cells (HUVEC) tubule formation assay was used for in vitro and in vivo angiogenesis study, respectively. Lactate and glucose concentration in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA). Luciferase reporter assay was used to verify the interaction between miR-493-5p and the 3'UTR of DKK2. Results: DKK2 could stimulate angiogenesis via accelerating the aerobic glycolysis of CRC cells, through which lactate is produced from glucose and accumulated in tumor microenvironment. Lactate functions as the final executor of DDK2 to stimulate tube formation of endothelial cells, and blockage of lactate secretion by lactate transporter (MCT) inhibitors dramatically neutralize the progression and metastasis of CRC both in vitro and in vivo. DKK2 could cooperate with lipoprotein receptor-related protein 6, which is required for glucose uptake, and activated the downstream mTOR signal pathway to accelerate lactate secretion. In addition, the expression of DKK2 is switched on via the demethylation of miR-493-5p, which allows the dissociated of miR-493-5p from the 3'-UTRs of DKK2 and initiates its stimulatory role on CRC progression in an autocrine or paracrine manner. Conclusion: DKK2 promotes tumor metastasis and angiogenesis through a novel VEGF-independent, but energy metabolism related pathway. DKK2 might be a potential anti-angiogenic target in clinical treatment for the advanced CRC patients.

Project description:BackgroundOsteosarcoma (OS) is a malignant tumor mainly occurring in young people. Due to the limited effective therapeutic strategies, OS patients cannot achieve further survival improvement. G-protein-coupled receptors (GPCRs) constitute the largest family of cell membrane receptors and consequently hold the significant promise for tumor imaging and targeted therapy. We aimed to explore the biological functions of Sphingosine 1-phosphate receptor 3 (S1PR3), one of the members of GPCRs family, in OS and the possibility of S1PR3 as an effective target for the treatment of osteosarcoma.MethodsThe quantitative real time PCR (qRT-PCR) and western blotting were used to analyze the mRNA and protein expressions. Cell counting kit-8 (CCK8), colony formation assay and cell apoptosis assay were performed to test the cellular proliferation in vitro. Subcutaneous xenograft mouse model was generated to evaluate the functions of S1PR3 in vivo. RNA sequencing was used to compare gene expression patterns between S1PR3-knockdown and control MNNG-HOS cells. In addition, metabolic alternations in OS cells were monitored by XF96 metabolic flux analyzer. Co-immunoprecipitation (Co-IP) assay was used to explore the interaction between Yes-associated protein (YAP) and c-MYC. Chromatin immunoprecipitation was used to investigate the binding capability of PGAM1 and YAP or c-MYC. Moreover, the activities of promoter were determined by the luciferase reporter assay.FindingsS1PR3 and its specific ligand Sphingosine 1-phosphate (S1P) were found elevated in OS, and the higher expression of S1PR3 was correlated with the poor survival rate. Moreover, our study has proved that the S1P/S1PR3 axis play roles in proliferation promotion, apoptosis inhibition, and aerobic glycolysis promotion of osteosarcoma cells. Mechanistically, the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted the nuclear translocation of YAP, which contributed to the formation of the YAP-c-MYC complex and enhanced transcription of the important glycolysis enzyme PGAM1. Moreover, the S1PR3 antagonist TY52156 exhibited in vitro and in vivo synergistic inhibitory effects with methotrexate on OS cell growth.InterpretationOur study unveiled a role of S1P, a bioactive phospholipid, in glucose metabolism reprogram through interaction with its receptor S1PR3. Targeting S1P/S1PR3 axis might serve as a potential therapeutic target for patients with OS. FUND: This research was supported by National Natural Science Foundation of China (81472445 and 81672587).

Dataset Information

Stiffer Matrix Accelerates Migration of Hepatocellular Carcinoma Cells through Enhanced Aerobic Glycolysis Via the MAPK-YAP Signaling.

Publications

Stiffer Matrix Accelerates Migration of Hepatocellular Carcinoma Cells through Enhanced Aerobic Glycolysis Via the MAPK-YAP Signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets