Abstract
The crosstalk between cancer cells and tumor microenvironment plays critical roles in hepatocellular carcinoma (HCC). The identification of long non-coding RNAs (lncRNAs) mediating the crosstalk might promote the development of new therapeutic strategies against HCC. Here, we identified a lncRNA, HOMER3-AS1, which is over-expressed in HCC and correlated with poor survival of HCC patients. HOMER3-AS1 promoted HCC cellular proliferation, migration, and invasion, and reduced HCC cellular apoptosis. Furthermore, HOMER3-AS1 promoted macrophages recruitment and M2-like polarization. In vivo, HOMER3-AS1 significantly facilitated HCC progression. Mechanism investigations revealed that HOMER3-AS1 activated Wnt/β-catenin signaling via upregulating HOMER3. Functional rescue experiments revealed that HOMER3/Wnt/β-catenin axis mediated the roles of HOMER3-AS1 in promoting HCC cellular malignant phenotypes. Furthermore, colony stimulating factor-1 (CSF-1) was also identified as a critical downstream target of HOMER3-AS1. HOMER3-AS1 increased CSF-1 expression and secretion. Blocking CSF-1 reversed the roles of HOMER3-AS1 in inducing macrophages recruitment and M2 polarization. Furthermore, positive correlations between HOMER3-AS1 and HOMER3 expression, HOMER3-AS1 and CSF-1 expression, and HOMER3-AS1 expression and M2-like macrophages infiltration were found in human HCC tissues. In summary, our findings demonstrated that HOMER3-AS1 drives HCC progression via modulating the behaviors of both tumor cells and macrophages, which are dependent on the activation of HOMER3/Wnt/β-catenin axis and CSF-1, respectively. HOMER3-AS1 might be a promising prognostic and therapeutic target for HCC.
Highlights
Liver cancer is the sixth most commonly diagnosed malignancy and the third leading cause of malignancy-related death worldwide, with about 905,677 newly diagnosed cases and 830,180 liver cancer-caused deaths [1]
MATERIALS AND METHODS Bioinformatics analyses The correlation between gene expression and overall survival of HCC patients based on the RNA sequencing expression data of HCC tissues from the cancer genome atlas (TCGA) liver hepatocellular carcinoma (LIHC) project was analyzed by the online in silico tool Gene Expression Profiling Interactive Analysis (GEPIA)
HOMER3-AS1 is correlated with advanced stage and poor prognosis in HCC The correlation between HOMER3-AS1 expression levels and overall survival in HCC was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) based on the cancer genome atlas (TCGA) liver hepatocellular carcinoma (LIHC) dataset [38]
Summary
Liver cancer is the sixth most commonly diagnosed malignancy and the third leading cause of malignancy-related death worldwide, with about 905,677 newly diagnosed cases and 830,180 liver cancer-caused deaths [1]. The main subtype of liver cancer is hepatocellular carcinoma (HCC), which accounts for 80%-90% of all liver cancer cases [2]. The molecular alterations of HCC are very complex, with multiple genetic and epigenetic aberrations [7,8,9]. Long non-coding RNAs (lncRNAs) are the most diverse class of non-coding transcripts, which have diversely regulatory roles in various pathophysiological processes [14,15,16,17,18,19]. Several lncRNAs have been revealed to play critical roles in HCC [20, 21]. LncRNA GPC3-AS1 was reported to enhance HCC cellular proliferation and migration [22]. MAGI2-AS3 was found to suppress HCC cellular malignant phenotype [23]. CASC9 depletion decreased HCC cellular viability [24]. lncRNA-ATB promoted HCC invasion-metastasis cascade [25]
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