Abstract
Recent evidence shows the emerging roles of intelectin 1 (ITLN1), a secretory lectin, in human cancers. Our previous studies have implicated the potential roles of ITLN1 in the aggressiveness of gastric cancer. Herein, we investigated the functions, downstream targets, and clinical significance of ITLN1 in the progression of gastric cancer. We demonstrated that ITLN1 increased the levels of hepatocyte nuclear factor 4 alpha (HNF4α), resulting in suppression of nuclear translocation and transcriptional activity of β-catenin in gastric cancer cells. Mechanistically, ITLN1 attenuated the activity of nuclear factor-kappa B, a transcription factor repressing the HNF4α expression, in gastric cancer cells through inactivating the phosphoinositide 3-kinase/AKT/Ikappa B kinase signaling. Gain- and loss-of-function studies demonstrated that ITLN1 suppressed the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. In addition, restoration of HNF4α expression prevented the gastric cancer cells from ITLN1-mediated changes in these biological features. In clinical gastric cancer tissues, HNF4α expression was positively correlated with that of ITLN1. Patients with high ITLN1 or HNF4α expression had greater survival probability. Taken together, these data indicate that ITLN1 suppresses the progression of gastric cancer through up-regulation of HNF4α, and is associated with improved survival in patients with gastric cancer.
Highlights
Gastric cancer is one of the most common cancers worldwide, with approximately 1 million new cases being diagnosed annually [1]
Microarray and gene ontology analyses revealed that stable transfection of intelectin 1 (ITLN1) into SGC-7901 cells resulted in altered transcript levels of 1592 human genes, including 547 up-regulated and 1045 down-regulated ones, and regulation of cellular process was the top-ranked function of ITLN1 in gastric cancer cells (Figure S1)
Stable over-expression or knockdown of ITLN1 in gastric cancer cells decreased and increased the β-catenin activity and transcription of downstream genes axin 2 (AXIN2) [21], cyclin D2 (CCND2) [22], runt-related transcription factor 2 (RUNX2) [23], and matrix metallopeptidase 3 (MMP3) [24], respectively, which was abolished by knockdown or ectopic expression of HNF4α (Figure 1H, Figure S2E, Figure S2F, and Figure S3B)
Summary
Gastric cancer is one of the most common cancers worldwide, with approximately 1 million new cases being diagnosed annually [1]. Better elucidating the mechanisms of tumorigenesis and aggressiveness is important for improving the therapeutic efficiency of gastric cancer [2]. Recent studies have shown that galectins, a family of mammalian lectins that bind β-galactoside, are frequently over-expressed in many human solid and blood malignancies, and exert important functions in tumor biology, including the transformation, growth, adhesion, invasion, and metastasis of cancer cells [3]. Galectin-1 promotes the adhesion of ovarian and prostate cancer cells to extracellular matrix [5, 6], while galectin-3 significantly suppresses the growth and metastasis of breast cancer cells [7]. Galectin-8 reduces the migration of colon cancer cells, indicating its suppressive roles in tumor aggressiveness [8]. It is necessary to investigate the roles of lectins in the progression of gastric cancer
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