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Published on: July 28, 2010
Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1
Inga Hinrichsen, Benjamin Philipp Ernst, Franziska Nuber
1Medical Clinic I, Biomedical Research Laboratory, Goethe-University, Frankfurt a,M, Germany. a.brieger@em.uni-frankfurt.de.
Introduction:
Defects in the DNA mismatch repair (MMR) protein MLH1 are frequently observed in sporadic and hereditary colorectal cancers (CRC). Affected tumors generate much less metastatic potential than the MLH1 proficient forms. Although MLH1 has been shown to be not only involved in postreplicative MMR but also in several MMR independent processes like cytoskeletal organization, the connection between MLH1 and metastasis remains unclear. We recently identified non-erythroid spectrin αII (SPTAN1), a scaffolding protein involved in cell adhesion and motility, to interact with MLH1. In the current study, the interaction of MLH1 and SPTAN1 and its potential consequences for CRC metastasis was evaluated.
Methods:
Nine cancer cell lines as well as fresh and paraffin embedded colon cancer tissue from 12 patients were used in gene expression studies of SPTAN1 and MLH1. Co-expression of SPTAN1 and MLH1 was analyzed by siRNA knock down of MLH1 in HeLa, HEK293, MLH1 positive HCT116, SW480 and LoVo cells. Effects on cellular motility were determined in MLH1 deficient HCT116 and MLH1 deficient HEK293T compared to their MLH1 proficient sister cells, respectively.
Results:
MLH1 deficiency is clearly associated with SPTAN1 reduction. Moreover, siRNA knock down of MLH1 decreased the mRNA level of SPTAN1 in HeLa, HEK293 as well as in MLH1 positive HCT116 cells, which indicates a co-expression of SPTAN1 by MLH1. In addition, cellular motility of MLH1 deficient HCT116 and MLH1 deficient HEK293T cells was impaired compared to the MLH1 proficient sister clones. Consequently, overexpression of SPTAN1 increased migration of MLH1 deficient cells while knock down of SPTAN1 decreased cellular mobility of MLH1 proficient cells, indicating SPTAN1-dependent migration ability.
Conclusions:
These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be related to SPTAN1.
Insights
Defects in DNA mismatch repair (MMR) protein MLH1 reduce SPTAN1 levels and impair colon cancer cell motility. MLH1-positive colorectal cancer (CRC) aggressiveness may be linked to SPTAN1 expression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Defects in DNA mismatch repair (MMR) protein MLH1 are common in colorectal cancer (CRC) and reduce metastatic potential.
- MLH1's role in metastasis is unclear, despite its involvement in MMR and cytoskeletal organization.
- SPTAN1, a protein interacting with MLH1, is crucial for cell adhesion and motility.
Purpose of the Study:
- To investigate the interaction between MLH1 and SPTAN1.
- To evaluate the consequences of this interaction on colorectal cancer metastasis.
Main Methods:
- Gene expression analysis of SPTAN1 and MLH1 in cancer cell lines and patient tissues.
- siRNA-mediated knockdown of MLH1 to study SPTAN1 co-expression.
- Assessment of cellular motility in MLH1-deficient and proficient cells.
Main Results:
- MLH1 deficiency correlated with reduced SPTAN1 levels.
- MLH1 knockdown decreased SPTAN1 mRNA levels, indicating co-expression.
- MLH1-deficient cells showed impaired motility, which was rescued by SPTAN1 overexpression.
Conclusions:
- SPTAN1 levels decrease with MLH1 reduction, impairing colon cancer cell mobility.
- SPTAN1-dependent migration is crucial for the aggressiveness of MLH1-positive CRC.
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