Sphingosine Kinase 1 and Sphingosine-1-Phosphate Signaling in Colorectal Cancer

Bao, Yonghua; Guo, Yanning; Zhang, Chenglan; Fan, Fenghua; Yang, Wancai

doi:10.3390/ijms18102109

Cited by 42 publications

(34 citation statements)

References 62 publications

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“…SPHK1 and UGGT2 were significantly upregulated in CRC tissues. This result is in accordance with those of recent studies that indicated that SPHK1 is overexpressed and serves an important role in tumorigenesis, proliferation, invasiveness and metastasis in CRC (42,43). On the other hand, HPGD, LPAR1, NAAA, SMPD1 and SMPDL3A were all significantly downregulated in CRC tissues.…”

Section: Discussionsupporting

confidence: 93%

Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer

Jang

Park

Min³

et al. 2018

Oncol Rep

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Ceramide synthases (CerSs) synthesize various ceramides of different acyl chain lengths and serve important roles in the proliferation and death of cancer cells by regulating sphingolipid metabolism-related signaling pathways. The present study investigated the mRNA expression levels of various CerS genes using mRNA expression data from six independent colorectal cancer (CRC) cohorts and a Korean CRC dataset. Expression levels of CERS2, CERS5 and CERS6 mRNA were significantly increased in the majority of the studied groups. However, CERS4 expression was only significantly altered in two groups. Additionally, a positive correlation was observed between altered CERS4 and CERS5 mRNA levels in The Cancer Genome Atlas Colon and Rectal Cancer dataset. Notably, CERS2 and CERS4, as well as CERS5 and CERS6 levels, were positively correlated with each other in Korean patients with CRC. However, the mRNA expression levels of these four CerS genes were not associated with any clinicopathological characteristics in Korean patients with CRC. Finally, overexpressing CERS2 or CERS6 inhibited the in vitro viability of various CRC cells. Taken together, these findings indicated that CERS2, CERS4, CERS5, and CERS6 are significantly dysregulated in CRC, suggesting they may serve important roles in the pathophysiology of this malignancy.

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Section: Discussionsupporting

confidence: 93%

Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer

Jang

Park

Min³

et al. 2018

Oncol Rep

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“…Chronic intestinal inflammation has been linked to colorectal cancer and reports demonstrated that S1P mediates pro-inflammatory cytokines such as TNF-α [233,234].…”

Section: A Role Of S1p In Gastrointestinal Diseasesmentioning

confidence: 99%

The role of sphingosine kinase 2 in alcoholic liver disease

Kwong

Liu

Zhao

et al. 2019

Digestive and Liver Disease

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Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end-stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic

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“…A number of therapeutics have been developed to target components of this pathway for cancer treatment (23,24). Specifically, studies have shown the importance of SPHK1 signaling in cancer metastasis with the likely involvement of EMT (25)(26)(27). Nevertheless, the mechanism by which S1P signaling affects EMT remains to be elucidated.…”

mentioning

confidence: 99%

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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Sphingosine Kinase 1 and Sphingosine-1-Phosphate Signaling in Colorectal Cancer

Cited by 42 publications

References 62 publications

Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer

Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer

The role of sphingosine kinase 2 in alcoholic liver disease

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

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