Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling

Fu, Weiming; Zhu, Xiao; Wang, Wei-Mao; Lu, Yuan-Qiang; Hu, Baoguang; Wang, Hua; Liang, Weicheng; Wang, Shanshan; Ko, Chun‐Hay; Waye, Mary Miu Yee; Kung, Hsiang‐Fu; Li, Gang; Zhang, Jinfang

doi:10.1016/j.jhep.2015.05.016

Cited by 166 publications

(167 citation statements)

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“…HOTAIR, a lncRNA initially identified in breast cancer, was demonstrated to be upregulated in a variety of carcinomas (27,28). A large number of studies have focused on the biological role and association of HOTAIR with clinical prognosis (9,29,30), yet the precise factors regulating its expression remain largely unknown. HOTAIR is transcriptionally regulated by estradiol in breast cancer, which is tumor-specific (31).…”

Section: Discussionmentioning

confidence: 99%

HOTAIR, a long non-coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA-1 in hepatocellular carcinoma

Chen

et al. 2016

Oncology Letters

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Abstract.Evidence is rapidly accumulating that long non-coding RNAs (lncRNAs) are involved in human tumorigenesis and are dysregulated in multiple cancers, including hepatocellular carcinoma (HCC). lncRNAs can regulate essential pathways that contribute to tumor initiation and progression with tissue specificity, which suggests that lncRNAs may be valuable biomarkers and therapeutic targets. HOX transcript antisense intergenic RNA (HOTAIR) has previously been demonstrated to be an oncogene and a negative prognostic factor in a variety of cancers; however, the factors that contribute to the upregulation of HOTAIR and the interaction between HOTAIR and microRNAs (miRNAs or miRs) are largely unknown. In the present study, the expression levels of HOTAIR, forkhead box C1 (FOXC1) and miRNA-1 were examined in 50 matched pairs of HCC and HCC cells. The effects of HOTAIR on HCC cell proliferation were tested using trypan blue exclusion assay. The effect of HOTAIR on HCC growth in vivo was determined in a (nu/nu) mouse model. A computational screening of HOTAIR promoter was conducted to search for transcription factor-binding sites. FOXC1 binding to the promoter region of HOTAIR was confirmed using a chromatin immunoprecipitation assay. A search for miRNAs that had complementary base paring with HOTAIR was performed utilizing an online software program.The interaction between miR-1 and HOTAIR was examined using a luciferase reporter assay. Gain and loss of function approaches were used to determine the changes of HOTAIR or miR-1 expression. The relative levels of FOXC1 and HOTAIR expression in HCC tissues and HepG2 cells were significantly higher than those in normal liver LO2 cells and adjacent carcinoma tissues; the relative expression of miR-1 exhibited the opposite pattern. Overexpression of HOTAIR promoted HCC cell proliferation and progression of tumor xenografts. The present authors have demonstrated that FOXC1 binds to the upstream region of HOTAIR in HCC cells and that FOXC1 activates lncRNA HOTAIR expression in HCC HepG2 cells, which suggests that HOTAIR harbors a miRNA-1 binding site. The present data revealed that this binding site is vital for the regulation of miRNA-1 by HOTAIR. Furthermore, HOTAIR negatively regulated the expression of miRNA-1 in HepG2 cells. Additionally, the present study demonstrated that the oncogenic activity of HOTAIR is in part based on the negative regulation of miR-1. Taken together, these results suggest that HOTAIR is a FOXC1-activated driver of malignancy, which acts in part through the repression of miR-1. IntroductionHepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortalities, with nearly 600,000 mortalities occurring worldwide each year (1). Although resection is considered a potentially curative treatment for HCC patients, the 1-year post-operative survival rate is only 30-40% (2). Thus, it is necessary to improve our understanding of the disease-causing mechanisms and to identify specific biomarkers for HCC progression to aid in the predictio...

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Section: Discussionmentioning

confidence: 99%

HOTAIR, a long non-coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA-1 in hepatocellular carcinoma

Chen

et al. 2016

Oncology Letters

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“…HOTAIR was initially identified to be upregulated, and to promote invasiveness and metastasis in breast cancer (8). In addition, HOTAIR was demonstrated to promote proliferation and reduce apoptosis in pancreatic cancer, colorectal cancer, and HCC (10)(11)(12). Overexpression of HOTAIR was positively associated with poor prognosis, tumor progression and recurrence in HCC (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…A recent study reported that HOTAIR also promoted the malignant growth of human liver cancer stem cells (15). A number of studies implicated that HOTAIR has important roles in the tumorigenesis of HCC (12)(13)(14)(15) Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RT-qPCR was performed to determine expression of lncRNA HOTAIR (12), and mRNA expression of ABCB1 (16).…”

Section: Introductionmentioning

confidence: 99%

“…A number of studies implicated that HOTAIR has important roles in the tumorigenesis of HCC (12)(13)(14)(15) Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RT-qPCR was performed to determine expression of lncRNA HOTAIR (12), and mRNA expression of ABCB1 (16). Briefly, at 48 h after transfection, cells were harvested in TRIzol Reagent (Invitrogen; Thermo Fisher Scientific, Inc.) following the manufacturer's protocols.…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of long non‑coding RNA HOTAIR sensitizes hepatocellular carcinoma cell to cisplatin by suppressing the STAT3/ABCB1 signaling pathway

Zhou

Cheng

et al. 2017

Oncol Lett

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Abstract. Long non-coding RNA HOX transcript antisense RNA (HOTAIR) has been demonstrated to exhibit oncogenic activity in several types of cancer, including hepatocellular carcinoma (HCC). However, the association between HOTAIR and HCC multidrug resistance remains uncertain. The present study aimed to investigate the role of HOTAIR in HCC chemoresistance; it was found that knockdown of HOTAIR expression in HCC Huh7 cells resulted in decreased cell proliferation and increased chemosensitivity to cisplatin. Furthermore, expression levels of ATP binding cassette subfamily B member 1 (ABCB1) mRNA and protein were decreased in Huh7 cells upon HOTAIR-knockdown. In addition, HOTAIR-knockdown reduced the levels of phosphorylated signal transducer and activator of transcription 3 (STAT3), and inhibition of STAT3 phosphorylation reduced HOTAIR-mediated ABCB1 expression. Together, these findings indicated that knockdown of HOTAIR in Huh7 cells decreased STAT3 activity and ABCB1 expression, and increased chemosensitivity to cisplatin. Thus HOTAIR could serve as a novel potential therapeutic target to reverse multidrug resistance in HCC.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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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Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling

Cited by 166 publications

References 42 publications

HOTAIR, a long non-coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA-1 in hepatocellular carcinoma

HOTAIR, a long non-coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA-1 in hepatocellular carcinoma

Knockdown of long non‑coding RNA HOTAIR sensitizes hepatocellular carcinoma cell to cisplatin by suppressing the STAT3/ABCB1 signaling pathway

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

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