SPHK1 Promotes Pancreatic Cancer Lymphangiogenesis Through the Activation of ERK in LECs

Overview

Journal Mol Biotechnol

Publisher Springer

Specialties Biotechnology
Molecular Biology

Date 2024 Jun 11

PMID 38861202

Authors

Mengsi Yu

Song Wang

Yujie Zeng

Pingli Liu

Hui Li

Affiliations

Soon will be listed here.

Abstract

Lymphatic metastasis is related to an unsatisfactory prognosis in pancreatic cancer. Sphingosine kinase 1 (SPHK1) is an oncogene in cancer. However, the potential effect of SPHK1 on the lymphangiogenesis of pancreatic cancer is little known. In this study, the expression level and role of SPHK1 in pancreatic cancer were evaluated to explore the underlying mechanism involved. The expression of SPHK1 and the lymphatic vessel density (LVD) in pancreatic cancer patient tissue were investigated by immunohistochemistry. The role of SPHK1 in lymphangiogenesis was verified in vitro. Elevated expression of SPHK1 was strongly related to high LVD in pancreatic cancer patient tissue. Silencing of SPHK1 in pancreatic cancer cells observably inhibited lymphangiogenesis. Furthermore, the downregulation of SPHK1 markedly attenuated the phosphorylation of extracellular signal-regulated kinase in lymphatic endothelial cells. This study revealed that SPHK1 might play a crucial role in pancreatic cancer lymphangiogenesis.

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References

Zorgetto V, Silveira G, Oliveira-Costa J, Soave D, Soares F, Ribeiro-Silva A . The relationship between lymphatic vascular density and vascular endothelial growth factor A (VEGF-A) expression with clinical-pathological features and survival in pancreatic adenocarcinomas. Diagn Pathol. 2013; 8:170. PMC: 3816792. DOI: 10.1186/1746-1596-8-170. View

Li A, Zhu L, Lei N, Wan J, Duan X, Liu S . S100A4-dependent glycolysis promotes lymphatic vessel sprouting in tumor. Angiogenesis. 2022; 26(1):19-36. DOI: 10.1007/s10456-022-09845-6. View

Luo Y, Li Z, Kong Y, He W, Zheng H, An M . KRAS mutant-driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer. J Clin Invest. 2022; 132(14). PMC: 9282935. DOI: 10.1172/JCI157644. View

Ren B, Cui M, Yang G, Wang H, Feng M, You L . Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer. 2018; 17(1):108. PMC: 6065152. DOI: 10.1186/s12943-018-0858-1. View

Hinshaw D, Shevde L . The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019; 79(18):4557-4566. PMC: 6744958. DOI: 10.1158/0008-5472.CAN-18-3962. View

Kurahara H, Takao S, Maemura K, Shinchi H, Natsugoe S, Aikou T . Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer: its relationship to lymph node metastasis. Clin Cancer Res. 2004; 10(24):8413-20. DOI: 10.1158/1078-0432.CCR-04-0379. View

Korhonen E, Murtomaki A, Kumar Jha S, Anisimov A, Pink A, Zhang Y . Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression. J Clin Invest. 2022; 132(15). PMC: 9337826. DOI: 10.1172/JCI155478. View

Khoei S, Sadeghi H, Samadi P, Najafi R, Saidijam M . Relationship between Sphk1/S1P and microRNAs in human cancers. Biotechnol Appl Biochem. 2020; 68(2):279-287. DOI: 10.1002/bab.1922. View

Yu M, Zhang K, Wang S, Xue L, Chen Z, Feng N . Increased SPHK1 and HAS2 Expressions Correlate to Poor Prognosis in Pancreatic Cancer. Biomed Res Int. 2021; 2021:8861766. PMC: 7806397. DOI: 10.1155/2021/8861766. View

10.

Li J, Wu H, Li W, Yin L, Guo S, Xu X . Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling. Oncogene. 2016; 35(42):5501-5514. PMC: 5078861. DOI: 10.1038/onc.2016.90. View

11.

Nagahashi M, Ramachandran S, Kim E, Allegood J, Rashid O, Yamada A . Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res. 2012; 72(3):726-35. PMC: 3289261. DOI: 10.1158/0008-5472.CAN-11-2167. View

12.

Nemoto M, Ichikawa H, Nagahashi M, Hanyu T, Ishikawa T, Kano Y . Phospho-Sphingosine Kinase 1 Expression in Lymphatic Spread of Esophageal Squamous Cell Carcinoma. J Surg Res. 2018; 234:123-131. DOI: 10.1016/j.jss.2018.09.012. View

13.

Aoki H, Aoki M, Katsuta E, Ramanathan R, Idowu M, Spiegel S . Host sphingosine kinase 1 worsens pancreatic cancer peritoneal carcinomatosis. J Surg Res. 2016; 205(2):510-517. PMC: 5656061. DOI: 10.1016/j.jss.2016.05.034. View

14.

Di D, Chen L, Wang L, Sun P, Liu Y, Xu Z . Downregulation of human intercellular adhesion molecule-1 attenuates the metastatic ability in human breast cancer cell lines. Oncol Rep. 2016; 35(3):1541-8. DOI: 10.3892/or.2016.4543. View

15.

Lu Y, Han G, Zhang Y, Zhang L, Li Z, Wang Q . M2 macrophage-secreted exosomes promote metastasis and increase vascular permeability in hepatocellular carcinoma. Cell Commun Signal. 2023; 21(1):299. PMC: 10614338. DOI: 10.1186/s12964-022-00872-w. View

16.

Wang S, Guo C, Yu M, Ning X, Yan B, Zhao J . Identification of HO induced oxidative stress associated microRNAs in HLE-B3 cells and their clinical relevance to the progression of age-related nuclear cataract. BMC Ophthalmol. 2018; 18(1):93. PMC: 5899325. DOI: 10.1186/s12886-018-0766-6. View

17.

Yu M, Zhang H, Liu Y, He Y, Yang C, Du Y . The cooperative role of S1P3 with LYVE-1 in LMW-HA-induced lymphangiogenesis. Exp Cell Res. 2015; 336(1):150-7. DOI: 10.1016/j.yexcr.2015.06.014. View

18.

Tiwari A, Tashiro K, Dixit A, Soni A, Vogel K, Hall B . Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis. Gastroenterology. 2020; 159(5):1882-1897.e5. PMC: 7680408. DOI: 10.1053/j.gastro.2020.07.046. View

19.

Yu X, Zhu W, Di Y, Gu J, Guo Z, Li H . Triple-functional albumin-based nanoparticles for combined chemotherapy and photodynamic therapy of pancreatic cancer with lymphatic metastases. Int J Nanomedicine. 2017; 12:6771-6785. PMC: 5602453. DOI: 10.2147/IJN.S131295. View

20.

Paduch R . The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol (Dordr). 2016; 39(5):397-410. PMC: 5052283. DOI: 10.1007/s13402-016-0281-9. View