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Updated: Oct 29, 2025
Induction and Analysis of Epithelial to Mesenchymal Transition
Published on: August 27, 2013
SPNS2 Downregulation Induces EMT and Promotes Colorectal Cancer Metastasis via Activating AKT Signaling Pathway
1Department of Cancer Epigenetics Program, Anhui Provincial Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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.
Insights
Spinster homologue 2 (SPNS2) acts as a tumor suppressor in colorectal cancer (CRC). Its low expression correlates with poor prognosis, and it inhibits CRC cell metastasis through the Akt pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Spinster homologue 2 (SPNS2) transports S1P and is implicated in immune response and vascular development.
- The role and expression of SPNS2 in colorectal cancer (CRC) remain largely unknown.
- Understanding SPNS2's function is crucial for developing new CRC therapies.
Purpose of the Study:
- To investigate the expression profile and biological functions of SPNS2 in colorectal cancer.
- To elucidate the molecular mechanisms underlying SPNS2's role in CRC progression and metastasis.
- To determine the relationship between SPNS2 expression and patient prognosis in CRC.
Main Methods:
- Analysis of SPNS2 expression in normal, adenoma, and CRC tissues, correlating with copy number variation and DNA methylation.
- In vitro experiments involving ectopic SPNS2 expression and SPNS2 silencing in CRC cell lines to assess effects on proliferation, migration, EMT, invasion, and metastasis.
- Measurement of intracellular and extracellular S1P levels, and investigation of the Akt signaling pathway, including the use of AKT inhibitor (MK2206) and activator (SC79).
Main Results:
- SPNS2 expression was upregulated in colon adenoma and CRC but lower in CRC than adenoma.
- Low SPNS2 expression correlated with advanced T/M/N stage and poor CRC prognosis.
- SPNS2 overexpression inhibited CRC cell proliferation, migration, EMT, invasion, and metastasis in an S1P-independent manner, primarily through PTEN upregulation and Akt inactivation.
Conclusions:
- SPNS2 acts as a suppressor of colorectal cancer metastasis.
- SPNS2 exerts its function by upregulating PTEN and inactivating the Akt pathway.
- SPNS2 represents a potential therapeutic target for improving CRC prognosis.
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