Downregulation of SPTAN1 is related to MLH1 deficiency and metastasis in colorectal cancer

  • 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 αII (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.
Author:Anne Ackermann, Christopher Schrecker, Dimitra Bon, Nicolaus Friedrichs, Katrin BankovORCiDGND, Peter Johannes WildORCiDGND, Guido PlotzORCiDGND, Stefan ZeuzemORCiDGND, Eva HerrmannORCiDGND, Martin-Leo HansmannGND, Angela BriegerORCiDGND
Pubmed Id:
Parent Title (English):PLoS one
Place of publication:Lawrence, Kan.
Contributor(s):Hiromu Suzuki
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/03/11
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/03/12
Tag:Caco-2 cells; Cell motility; Colorectal cancer; Cytoskeletal proteins; Immunohistochemistry techniques; Metastasis; Metastatic tumors; SW480 cells
Issue:(3): e0213411
Page Number:19
First Page:1
Last Page:19
Copyright: © 2019 Ackermann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0