Expression of Abelson interactor 1 (Abi1) correlates with inflammation, KRAS mutation and adenomatous change during colonic carcinogenesis.
BACKGROUND
Abelson interactor 1 (Abi1) is an important regulator of actin dynamics during cytoskeletal reorganization. In this study, our aim was to investigate the expression of Abi1 in colonic mucosa with and without inflammation, colonic polyps, colorectal carcinomas (CRC) and metastases as well as in CRC cell lines with respect to BRAF/KRAS mutation status and to find out whether introduction of KRAS mutation or stimulation with TNFalpha enhances Abi1 protein expression in CRC cells.


RESULTS
We immunohistochemically analyzed Abi1 protein expression in 126 tissue specimens from 95 patients and in 5 colorectal carcinoma cell lines with different mutation status by western immunoblotting. We found that Abi1 expression correlated positively with KRAS, but not BRAF mutation status in the examined tissue samples. Furthermore, Abi1 is overexpressed in inflammatory mucosa, sessile serrated polyps and adenomas, tubular adenomas, invasive CRC and CRC metastasis when compared to healthy mucosa and BRAF-mutated as well as KRAS wild-type hyperplastic polyps. Abi1 expression in carcinoma was independent of microsatellite stability of the tumor. Abi1 protein expression correlated with KRAS mutation in the analyzed CRC cell lines, and upregulation of Abi1 could be induced by TNFalpha treatment as well as transfection of wild-type CRC cells with mutant KRAS. The overexpression of Abi1 could be abolished by treatment with the PI3K-inhibitor Wortmannin after KRAS transfection.


CONCLUSIONS
Our results support a role for Abi1 as a downstream target of inflammatory response and adenomatous change as well as oncogenic KRAS mutation via PI3K, but not BRAF activation. Furthermore, they highlight a possible role for Abi1 as a marker for early KRAS mutation in hyperplastic polyps. Since the protein is a key player in actin dynamics, our data encourages further studies concerning the exact role of Abi1 in actin reorganization upon enhanced KRAS/PI3K signalling during colonic tumorigenesis.
Institute of Pathology, University of Ulm, Ulm, Germany. konrad@steinestel.com
Konrad
K
Steinestel
Silke
S
Brüderlein
Julie
J
Steinestel
Bruno
B
Märkl
Michael J
MJ
Schwerer
Annette
A
Arndt
Klaus
K
Kraft
Christian
C
Pröpper
Peter
P
Möller
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000368:Aged; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics*
C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins