TY  - JOUR
A1  - Ackermann, Anne
A1  - Schrecker, Christopher
A1  - Bon, Dimitra
A1  - Friedrichs, Nicolaus
A1  - Bankov, Katrin
A1  - Wild, Peter Johannes
A1  - Plotz, Guido
A1  - Zeuzem, Stefan
A1  - Herrmann, Eva
A1  - Hansmann, Martin-Leo
A1  - Brieger, Angela
T1  - Downregulation of SPTAN1 is related to MLH1 deficiency and metastasis in colorectal cancer
T2  - PLoS one
N2  - 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.
KW  - Colorectal cancer
KW  - Caco-2 cells
KW  - Immunohistochemistry techniques
KW  - Metastasis
KW  - Metastatic tumors
KW  - SW480 cells
KW  - Cell motility
KW  - Cytoskeletal proteins
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/48451
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-484514
SN  - 1932-6203
N1  - 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.
VL  - 14
IS  - (3): e0213411
SP  - 1
EP  - 19
PB  - PLoS
CY  - Lawrence, Kan.
ER  -