SPNS2 Downregulation Induces EMT and Promotes Colorectal Cancer Metastasis via Activating AKT Signaling Pathway

Abstract

Spinster homologue 2 (SPNS2), a transporter of S1P (sphingosine-1-phosphate), has been reported to mediate immune response, vascular development, and pathologic processes of diseases such as cancer via S1P signaling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) is elusive. In this study, we disclosed that SPNS2 expression, which was regulated by copy number variation and DNA methylation of its promoter, was dramatically upregulated in colon adenoma and CRC compared to normal tissues. However, its expression was lower in CRC than in colon adenoma, and low expression of SPN2 correlated with advanced T/M/N stage and poor prognosis in CRC. Ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial–mesenchymal transition (EMT), invasion, and metastasis in CRC cell lines, while silencing SPNS2 had the opposite effects. Meanwhile, measuring the intracellular and extracellular level of S1P after overexpression of SPNS2 pinpointed a S1P-independent model of SPNS2. Mechanically, SPNS2 led to PTEN upregulation and inactivation of Akt. Moreover, AKT inhibitor (MK2206) abrogated SPNS2 knockdown-induced promoting effects on the migration and invasion, while AKT activator (SC79) reversed the repression of migration and invasion by SPNS2 overexpression in CRC cells, confirming the pivotal role of AKT for SPNS2’s function. Collectively, our study demonstrated the suppressor role of SPNS2 during CRC metastasis, providing new insights into the pathology and molecular mechanisms of CRC progression.

CTSG Suppresses Colorectal Cancer Progression through Negative Regulation of Akt/mTOR/Bcl2 Signaling Pathway

“…These data reveal that CTSG absence exhibits cancer stimulative impacts through Akt/mTOR signaling pathway activation and Akt signaling pathway suppression by MK2206 abolishes CTSG silenced expression-induced up-regulation of Bcl2 and cell viability in vitro and in vivo . Moreover, SC79, an Akt activator, could promote cell proliferation and metastasis through positive regulation of Akt 35 - 37 . Our results also showed that up-regulation of CTSG reversed SC79-induced CRC cell proliferation ( Figure S7 ).…”

Clinical relevance of CERK and SPHK1 in breast cancer and their association with metastasis and drug resistance

“…Similar to our findings, a recent study suggests that SPNS2 expression was markedly lower in ten kinds of tumor (including breast invasive carcinoma) as compared to adjacent non-cancerous samples. The authors reported that the levels of SPNS2 were downregulated in colorectal cancer and were associated with poor differentiation, advanced pTNM stage and poor prognosis of the disease 52 . Being a S1P transporter, the levels of SPNS2 were found to be positively associated with SPHK1 expression in tumor tissue in the current study.…”

Keep a Little Fire Burning—The Delicate Balance of Targeting Sphingosine-1-Phosphate in Cancer Immunity

“…However, low SPNS2 expression correlated with poor prognosis in CRC and ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial-mesenchymal transition, invasion, and metastasis in CRC cell lines. This appeared to be S1P independent, rather acting directly via inactivation of AKT signaling [142]. These data also need to be considered when proposing SPNS2 as a target to improve anti-tumor immunity and combat metastasis.…”