Abstract
Islet-1 (ISL1) belongs to the LIM homeodomain transcription factor family, which is specifically expressed in certain tissue types only. Previously, we reported that ISL1 is aberrantly overexpressed in gastric cancer (GC). However, its role in GC is not clear. Here, we report that ISL1 is aberrantly upregulated not only in human gastric carcinoma tissues but also in some GC cell lines. Upregulated ISL1 expression enhanced xenografted gastric carcinoma development, while ISL1 knockdown inhibited GC growth in nude mice. ISL1 overexpression promoted GC cell proliferation, colony formation, and cell growth in soft agar, and facilitated cell cycle transition in GC cells, demonstrated an increase in the proportion of cells in the G2/M and S phases and a decrease in the proportion of cells in the G1 phase. Furthermore, we provide evidence that ISL1 is a novel regulator of the cyclin B1 (CCNB1), cyclin B2 (CCNB2) and c-myc (c-MYC) genes. ISL1 activated the expression of these genes in GC cells by binding to the conserved binding sites on their promoters or enhancers. The expression levels of the genes were decreased in response to ISL1 knockdown. Therefore, ISL1 may serve as a potential therapeutic target in GC.
Highlights
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer death worldwide [1]
We demonstrate that ISL1 expression was upregulated in 24 gastric cancer (GC) biopsies (18 poorly differentiated adenocarcinoma, 4 moderately differentiated adenocarcinoma, 2 welldifferentiated adenocarcinoma) by immunohistochemistry (IHC) (12 normal gastric tissues were used as the control)
We examined ISL1 expression by western blot analysis in six GC cell lines; a normal human gastric epithelium cell line was used as the control
Summary
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer death worldwide [1]. GC malignancy is caused by uncontrolled cell proliferation, invasion and metastasis [2]. ISL1 plays a key role in the development of specialized cells in multiple tissue types, including nervous system, skeletal muscle, heart, kidneys, and endocrine organs such as the pituitary gland and pancreas [4]. Previous studies have demonstrated that ISL1 is a marker for well-differentiated pancreatic neuroendocrine tumors [5]. Recent studies have identified ISL1 as a sensitive lineage-specific marker for pancreatic neuroendocrine neoplasms and their metastases [6], and it is commonly expressed in rhabdomyosarcoma [7]. We recently reported that ISL1 is highly expressed in GC and is correlated with advanced tumor-nodes-metastasis stage, lymph node metastasis, and poorer overall survival [8]. The role and detailed mechanism of ISL1 in cancer development remain unknown
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