Universität zu Köln

Ackermann, Anne, Schrecker, Christopher, Bon, Dimitra, Friedrichs, Nicolaus, Bankov, Katrin, Wild, Peter, Plotz, Guido, Zeuzem, Stefan, Herrmann, Eva, Hansmann, Martin-Leo and Brieger, Angela (2019). Downregulation of SPTAN1 is related to MLH1 deficiency and metastasis in colorectal cancer. PLoS One, 14 (3). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Introduction Colorectal cancers (CRCs) deficient in the DNA mismatch repair protein MutL homolog 1 (MLH1) display distinct clinicopathological features and require a different therapeutic approach compared to CRCs with MLH1 proficiency. However, the molecular basis of this fundamental difference remains elusive. Here, we report that MLH1-deficient CRCs exhibit reduced levels of the cytoskeletal scaffolding protein non-erythroid spectrin alpha II (SPTAN1), and that tumor progression and metastasis of CRCs correlate with SPTAN1 levels. Methods and results To investigate the link between MLH1 and SPTAN1 in cancer progression, a cohort of 189 patients with CRC was analyzed by immunohistochemistry. Compared with the surrounding normal mucosa, SPTAN1 expression was reduced in MLH1-deficient CRCs, whereas MLH1-proficient CRCs showed a significant upregulation of SPTAN1. Overall, we identified a strong correlation between MLH1 status and SPTAN1 expression. When comparing TNM classification and SPTAN1 levels, we found higher SPTAN1 levels in stage I CRCs, while stages II to IV showed a gradual reduction of SPTAN1 expression. In addition, SPTAN1 expression was lower in metastatic compared with non-metastatic CRCs. Knockdown of SPTAN1 in CRC cell lines demonstrated decreased cell viability, impaired cellular mobility and reduced cell-cell contact formation, indicating that SPTAN1 plays an important role in cell growth and cell attachment. The observed weakened cell-cell contact of SPTAN1 knockdown cells might indicate that tumor cells expressing low levels of SPTAN1 detach from their primary tumor and metastasize more easily. Conclusion Taken together, we demonstrate that MLH1 deficiency, low SPTAN1 expression, and tumor progression and metastasis are in close relation. We conclude that SPTAN1 is a candidate molecule explaining the tumor progression and metastasis of MLH1-deficient CRCs. The detailed analysis of SPTAN1 is now mandatory to substantiate its relevance and its potential value as a candidate protein for targeted therapy, and as a predictive marker of cancer aggressiveness.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ackermann, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrecker, Christopher UNSPECIFIED UNSPECIFIED UNSPECIFIED Bon, Dimitra UNSPECIFIED UNSPECIFIED UNSPECIFIED Friedrichs, Nicolaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Bankov, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Wild, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Plotz, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeuzem, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Herrmann, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansmann, Martin-Leo UNSPECIFIED UNSPECIFIED UNSPECIFIED Brieger, Angela UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-153946
DOI:	10.1371/journal.pone.0213411
Journal or Publication Title:	PLoS One
Volume:	14
Number:	3
Date:	2019
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MICROSATELLITE INSTABILITY; ALPHA-SPECTRIN; CLINICOPATHOLOGICAL FEATURES; E-CADHERIN; FODRIN; DNA; CARCINOMA; COMPLEX; SYSTEM Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15394