Long non-coding RNA HOTAIR up‑regulates chemokine (C‑C motif) ligand 2 and promotes proliferation of macrophages and myeloid‑derived suppressor cells in hepatocellular carcinoma cell lines

Abstract

Abstract. Accumulating evidence demonstrated that Hox antisense intergenic RNA (HOTAIR) serves essential roles in the development and metastasis of several types of cancer. In hepatocellular carcinoma (HCC), high expression of HOTAIR is associated with poor prognosis, and HOTAIR regulates cell migration and proliferation. However, the downstream molecular targets of HOTAIR depend on the cancer cell types, and little is known about the precise molecular mechanisms of HOTAIR involved in cancer development. The present study investigated the role of HOTAIR in HCC cell lines. Notably, the overexpression of HOTAIR in HCC cell lines did not affect cell migration and proliferation capability. In the microarray analysis, C-C motif chemokine ligand (CCL)2 was identified to be differentially expressed in HOTAIR-overexpressing cells, and it was confirmed that HOTAIR promotes the secretion of CCL2. Furthermore, it was revealed that the proportion of macrophages and myeloid-derived suppressor cells (MDSCs) were increased when peripheral blood mononuclear cells were co-cultured with HOTAIR-overexpressing cells. Collectively, these data suggest that HOTAIR regulates CCL2 expression, which may be involved in the recruitment of macrophages and MDSCs to the tumor microenvironment. IntroductionHox antisense intergenic RNA (HOTAIR), a lncRNA that acts as an oncogenic molecule in various types of cancer, is localized to the HOXC gene cluster. HOTAIR interacts with PRC2 (polycomb repressive complex 2) to enhance H3K27 trimethylation, and thereby decreases the expression of a large number of genes. Several groups, including our laboratory, have reported that high HOTAIR expression is correlated with a poor prognosis in several types of cancer, including breast (1), colorectal (2), non-small lung cell (3), and gastric cancer (4). Interestingly, recent report suggested that effects of HOTAIR are strongly tissue-dependent and can even differ within the same type of cancer (5). Thus, the underlying mechanism by which HOTAIR is involved in malignant progression remains uncertain.Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer and second leading cause of cancer-related mortality worldwide. More than 600,000 deaths are associated with HCC every year worldwide (6). Previous report suggested that the expression of HOTAIR is associated with tumor recurrence and poor prognosis in hepatocellular carcinoma (7,8). Several in vitro analyses were reported using HCC cell line, HepG2; HOTAIR is a FOXC1-activated driver of malignancy, which acts in part through the repression of miR-1 in HepG2 cells (9). HOTAIR silence activates P16 Ink4a and P14 ARF signaling by enhancing miR-218 expression and suppressing Bmi-1 expression, resulting in the suppression of tumorigenesis in HepG2 cells (10). Introduction of human HOTAIR into HepG2 cells revealed that HOTAIR promoted more rapid proliferation (7). Although different intracellular signaling are expected among multiple HCC cell lines, the research of HOTAIR using HCC cell lines except for...

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