Abelson interactor 1 splice isoform-L plays an anti-oncogenic role in colorectal carcinoma through interactions with WAVE2 and full-length Abelson interactor 1

Abstract

BACKGROUND Expression of the full-length isoform of Abelson interactor 1 (ABI1), ABI1-p65, is increased in colorectal carcinoma (CRC) and is thought to be involved in one or more steps leading to tumor progression or metastasis. The ABI1 splice isoform-L (ABI1-SiL) has conserved WAVE2-binding and SH3 domains, lacks the homeo-domain homologous region, and is missing the majority of PxxP- and Pro-rich domains found in full-length ABI1-p65. Thus, ABI1-SiL domain structure suggests that the protein may regulate CRC cell morphology, adhesion, migration, and metastasis via interactions with the WAVE2 complex pathway. AIM To investigate the potential role and underlying mechanisms associated with ABI1-SiL-mediated regulation of CRC. METHODS ABI1-SiL mRNA expression in CC tissue and cell lines was measured using both qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR. A stably ABI1-SiL overexpressing SW480 cell model was constructed using Lipofectamine 2000, and cells selected with G418. Image J software, CCK8, and transwell assays were used to investigate SW480 cell surface area, proliferation, migration, and invasion. Immunoprecipitation, Western blot, and co-localization assays were performed to explore intermolecular interactions between ABI1-SiL, WAVE2, and ABI1-p65 proteins. RESULTS ABI1-SiL was expressed in normal colon tissue and was significantly decreased in CRC cell lines and tissues. Overexpression of ABI1-SiL in SW480 cells significantly increased the cell surface area and inhibited the adhesive and migration properties of the cells, but did not alter their invasive capacity. Similar to ABI1-p65, ABI1-SiL still binds WAVE2, and the ABI1-p65 isoform in SW480 cells. Furthermore, co-localization assays confirmed these intermolecular interactions. CONCLUSION These results support a model in which ABI1-SiL plays an anti-oncogenic role by competitively binding to WAVE2 and directly interacting with phosphorylated and non-phosphorylated ABI1-p65, functioning as a dominant-negative form of ABI1-p65.

The Role of WAVE2 Signaling in Cancer

“…Studies have also shown that TGF-β1 mediates WAVE2 upregulation on hepatic stellate cell (HSC) activation and promotes activated-HSCs metastasis. Thus, these findings imply that WAVE2 plays a critical role in colorectal liver metastasis [ 60 , 61 , 62 , 63 ].…”

Pan-cancer transcriptomic data of ABI1 transcript variants and molecular constitutive elements identifies novel cancer metastatic and prognostic biomarkers

“…Previous studies showed that the abnormal expression and phosphorylation of ABI1 are involved in the invasion and metastasis of various malignant tumors (colorectal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma, breast cancer, leukemia, prostate cancer, and ovarian cancer, etc. ), being closely related to their prognosis [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”

“…The human ABI1 gene is located at chromosome 10p11.2, and its pre-mRNA can be spliced into at least 12 different ABI1-TSVs. They encode twelve different protein isoforms, and their significant differences in functional domains suggest that the regulation of ABI1-TSVs in pathophysiological processes may be meticulous and complex [ 8 , 24 , 25 , 26 ].…”

“…Based on previous data analysis of The Cancer Genomic Atlas (TCGA) and TSVdb database ( ) and in vivo and in vitro studies, we found that alternative splicing is an important mechanism by which ABI1 plays a precise regulatory role in colorectal cancer metastasis, and the key ABI1-TSVs can be used as not only potential molecular markers for colorectal cancer (CRC) metastasis and prognostic assessment [ 25 , 26 ], but also as important therapeutic targets with their molecular constitutive elements, exons and exon-exon junctions (EEJs). By extension, we believe that it is theoretically and practically significant to systematically analyze the roles and potential applications of ABI1-TSVs and their molecular constitutive elements in the diagnosis and treatment of many cancer types.…”

Establishment of quantitative nested-PCR of Abelson interactor 1 transcript variant-11

“…Recent studies have shown that ABI1 is highly expressed in CRC tissues [ 7 ]. In addition to abnormal expression, different transcriptional variants (TSVs) of ABI1 may perform distinct biological functions [ 8 ]and play an important role in the progress of CRC metastasis [ 6 , 9 ]. There are eighteen TSVs generated from ABI1 primary transcript by alternative splicing ( https://www.ncbi.nlm.nih.gov/gene/10006 ).…”