Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1

  • 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.

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Author:Inga Hinrichsen, Benjamin Philipp Ernst, Franziska Nuber, Sandra Passmann, Dieter Schäfer, Verena Steinke, Nicolaus Friedrichs, Guido PlotzORCiDGND, Stefan ZeuzemORCiDGND, Angela BriegerORCiDGND
URN:urn:nbn:de:hebis:30:3-327561
DOI:https://doi.org/10.1186/1476-4598-13-11
ISSN:1476-4598
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/24456667
Parent Title (English):Molecular cancer
Publisher:Biomed Central
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2014/01/31
Date of first Publication:2014/01/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/01/31
Tag:Cellular; Cytoskeletal proteins; DNA mismatch repair; MLH1; SPTAN1
Volume:13
Issue:Art. 11
Page Number:12
First Page:1
Last Page:12
Note:
© 2014 Hinrichsen et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
HeBIS-PPN:363691901
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 2.0