Expression and Y435-phosphorylation of Abelson interactor 1 (Abi1) promotes tumour cell adhesion, extracellular matrix degradation and invasion by colorectal carcinoma cells

Abstract

BackgroundThe Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion. The c-Abl substrate abelson interactor 1 (Abi1) is a key regulator of actin reorganization and upregulated in colorectal carcinoma. The specific role of Abi1 in relation to extracellular matrix degradation and effects of targeting Abi1 phosphorylation have not yet been examined. Here, we investigated the role of Abi1 in relation to invasive properties in colorectal cancer.Methods and resultsIn 56 primary human colorectal carcinoma samples, we found overexpression of Abi1 in 39% at the invasive edge of the tumour, associated with an infiltrative phenotype and high-grade tumour cell budding (p = 0.001). To explore the role of Abi1 in vitro, we employed the Abi1 expressing and KRAS-mutated CHD1 model and performed matrix degradation assays that showed Abi1 localization at specific sites of matrix degradation. Moreover, quantification of matrix dissolution demonstrated suppression after RNAi knockdown of Abi1 by 95% (p = 0.001). Importantly, treatment with STI571 did abolish Abi1 Y435-phosphorylation, suppressed the matrix dissolution, decreased fibronectin attachment, and suppressed cell invasion through reconstituted extracellular matrix.ConclusionOur data indicate that phosphorylated Abi1 contributes to the invasive properties of colorectal cancer.

Oncogenic function and prognostic significance of Abelson interactor 1 in hepatocellular carcinoma

“…Accumulating evidence has indicated that ABI1 was frequently dysregulated in the development of cancer, however, it remains controversial whether ABI1 acts as a tumor promoter or suppressor. On the one hand, some studies reported that ABI1 over expression was closely associated with tumor progression in breast cancer (20), colon cancer (22,23), HCC (25) and ovarian cancer (24). which revealed a potential carcinogenic role of ABI1 in cancers.…”

“…Initially, ABI1 has been proposed as a potential tumor suppressor based on the evidence that ABI1 gene is deleted in prostate cancer and decreased in gastric cancer and some types of leukemia (14)(15)(16)(17). ABI1 has been reported to be overexpressed and correlated with poor prognosis in a wide variety of tumors, such as breast cancer, BCR-Abl-induced leukemia, colon cancer, HCC and ovarian cancer (18)(19)(20)(21)(22)(23)(24)(25). These studies suggested that ABI1 may play a diverse role during cancer progression under various circumstances.…”

MiR‐181a/b induce the growth, invasion, and metastasis of neuroblastoma cells through targeting ABI1

“…[46][47][48][49] ABI1 localizes to the leading edge of lamellipodia, and its expression correlates with the regulation of directional migration. 46,[50][51][52] In this study, ABI1 was downregulated in high-risk groups of patients with neuroblastoma, and knockdown of ABI1 enhanced neuroblastoma cell growth and metastasis. These findings are consistent the finding that the downregulation of ABI1 is associated with the development of prostate cancer.…”

“…Subsequent studies have implicated ABI1 proteins in the regulation of cell motility, intercellular adhesion, macropinocytosis, mitosis, megakaryocyte development, and synaptic maturation in neurons . ABI1 localizes to the leading edge of lamellipodia, and its expression correlates with the regulation of directional migration . In this study, ABI1 was downregulated in high‐risk groups of patients with neuroblastoma, and knockdown of ABI1 enhanced neuroblastoma cell growth and metastasis.…”

Metastasierung und Progressionsmechanismen von Weichteiltumoren

“…Die meisten Untersuchungen zur zellulären Migration im Bereich der Tumorbiologie wurden bislang an epithelialen Tumoren gewonnen; verschiedene Arbeitsgruppen konnten allerdings zeigen, dass die involvierten Regulatorproteine in kultivierten Fibroblasten sowie in Sarkomzellen ebenfalls exprimiert werden und in diesen vergleichbare biologische Prozesse nachweisbar sind (eigene unveröffentlichte Daten sowie [7][8][9][10]). …”