Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors.
Finally, over-expressing miR-128 apparently reduced the tumor growth rate and tumor weight in vivo using xenograft tumor model, accompanied with a remarkable decrease of SPHK1.
Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness.
Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL.
Statistical analyses revealed that high levels of SPHK1 expression were associated with tumor size, lymph node metastasis and the Tumor-Node-Metastasis stage.
Together, our findings indicated that SPK1 enhanced tumor growth in lung cancer and induced metastasis by activating the ERK1/2 signaling pathway, indicating its potential application in NSCLC diagnosis and therapy.
Our results unraveled that increased SphK1 kinase activation defines an important mechanism for sunitinib resistance, therefore contributes to tumour development and represents therapeutic targets for ccRCC.
It is remarkable that SphK1 deficiency in HER2-positive breast cancer model inhibited tumor formation by the different mechanism from ER-positive breast cancer.
Our study provides evidence that SPHK1 was promotive for GC tumor growth and cell biological behaviors, and that miR-330-3p targeted 3'-UTR of SPHK1 and inhibited its expression.
These findings suggest that export of S1P via ABCC1 functions in a malicious feed-forward manner to amplify the S1P axis involved in breast cancer progression and metastasis, which has important implications for prognosis of breast cancer patients and for potential therapeutic targets.<b>Implication:</b> Multidrug resistant transporter ABCC1 and activation of SPHK1 in breast cancer worsen patient's survival by export of S1P to the tumor microenvironment to enhance key processes involved in cancer progression.<i></i>.
Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis.
Immunofluorescent staining of tumour sections from human oestrogen receptor (ER)-negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression.
Thirty-four (30.9%) of 110 papillary thyroid carcinomas exhibited high sphingosine kinase 1 expression, that was significantly associated with tumor multiplicity (p=0.004), extrathyroidal extension (p=0.013), presence of lymph node metastasis (p<0.001), and number of metastatic lymph nodes (p=0.042).
Increased SPHK1 protein expression was also associated with human epidermal growth factor receptor 2 status (P=0.0100), initial symptoms (P=0.0025) and tumor location (P=0.0457).
Next, SphK1 overexpression in HT-29 enhanced tumor growth as compared to GFP control in nude mice (229.5 mm<sup>3</sup> vs. 90.9 mm<sup>3</sup>, respectively, P < 0.05).
Immunohistochemistry of xenograft tumors showed significant enhancement of caspase-3 cleavage and suppression of Ki67 and phospho-EGFR by the drug combination, but SphK1 downregulation occurred only in MDA-MB-468 tumors, so is unlikely to be integral to treatment efficacy.
High IGF1R and SphK1 protein co-expression in tumor tissue was associated with improved OS specifically in ER-positive disease and stratified for anti-endocrine therapy.