Surface-bound galectin-4 regulates gene transcription and secretion of chemokines in human colorectal cancer cell lines

Abstract

One long-term complication of chronic intestinal inflammation is the development of colorectal cancer. However, the mechanisms linking inflammation to the colorectal tumorigenesis are poorly defined. Previously, we have demonstrated that galectin-4 is predominantly expressed in the luminal epithelia of the gastrointestinal tract, and its loss of expression plays a key role in the colorectal tumorigenesis. However, the mechanism by which galectin-4 regulates inflammation-induced tumorigenesis is unclear. Here, we show that galectin-4 secreted by the colorectal cancer cell lines was bound to the cell surface. Neutralization of surface-bound galectin-4 with anti-galectin-4 antibody resulted in increased cell proliferation with concomitant secretion of several chemokines into the extracellular medium. Neutralization of the surface-bound galectin-4 also resulted in the up-regulation of transcription of 29 genes, several of which are components of multiple inflammation signaling pathways. In an alternate experiment, binding of recombinant galectin-4 protein to cell surface of the galectin-4-negative colorectal cancer cells resulted in increased p27, and decreased cyclin D1 and c-Myc levels, leading to cell cycle arrest and apoptosis. Together, these data demonstrated that surface-bound galectin-4 is a dual function protein—down-regulating cell proliferation and chemokine secretion in galectin-4-expressing colorectal cancer cells on one hand and inducing apoptosis in galectin-4-negative colorectal cancer cells on the other hand.

The transcriptome difference between colorectal tumor and normal tissues revealed by single-cell sequencing

“…It acts as a tumor suppressor in colorectal carcinoma and suppresses cancer cell growth, migration, and invasion [35]. It is a dual function protein: promote cell proliferation and chemokine secretion in galectin-4-expressing colorectal cancer cells, but induce apoptosis in galectin-4-negative colorectal cancer cells [36].…”

Detection of malignancy‐associated phosphoproteome changes in human colorectal cancer induced by cell surface binding of growth‐inhibitory galectin‐4

“…Our interest in gal‐4 in malignancy had been fueled by reports on its down‐regulation in colon cancer and the evidence for suppressor‐like activity in vitro . Following initial work on mapping expression of members of the galectin network in colon cancer lines , we then proceeded to determine proteome changes triggered by gal‐4, as test‐of‐principle case from this lectin family and tumor growth inhibition .…”

Probing sulfatide-tissue lectin recognition with functionalized glycodendrimersomes

“…Finally, the reported homo- and heterobivalency in the cross-linking assays explains well a role of Gal-4 in detergent-resistant membranes, and it may also underlie its specific role as suppressor for human colon cancer ( Michalak et al., 2017 , 2019 ; Rao and Rao, 2017 ; Rechreche et al., 1997 ; Satelli et al., 2011 ), as factor in oligodendrocyte differentiation and as inhibitor of myelination ( de Jong et al., 2018 , 2020 ; Díez-Revuelta et al., 2017 ; Stancic et al., 2012 ). Thus, the applied synthetic and supramolecular chemistry that led to detection of GDS bridging by sulfatide-Gal-4 pairing identifies a versatile means of letting sulfatide presence appear less enigmatic.…”