Contributed equally
Long non-coding RNAs (lncRNAs) have been found to be pervasively transcribed in the genome and are critical regulators of the epigenome. Increasing evidence suggests that lncRNAs are aberrantly expressed in several types of human cancer and that they are important in the initiation, development and metastasis of human cancer. Previous studies have revealed that HOX transcript antisense intergenic RNA (HOTAIR) was frequently upregulated in various types of cancer, including breast cancer, esophageal cancer, lung cancer and gastric cancer. In addition, patients with high expression levels of HOTAIR have a significantly poorer prognosis, compared with those with low levels of expression. HOTAIR is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair and tumor cells metabolism. The present review provides an overview of the current knowledge concerning the role of HOTAIR in tumor development and progression.
An oncogene is defined as a mutated gene, whose product contributes to the initiation or progression of cancer (
Hox transcript antisense intergenic RNA (HOTAIR) was one of the first lincRNAs reported to be involved in the development of cancer (
The present review aims to discuss the current knowledge of the properties of HOTAIR, its status in human tumors, the mechanism in tumorigenesis and their potential implications in cancer management.
HOTAIR, first identified from a custom-tilling array of the HOXC locus, is encoded from the HOXC locus on chromosome 12q13.13 (
Polycomb proteins are a group of proteins involved in the repression of transcription of thousands of genes, which are critical in differentiation, maintenance of cell identity and cancer development (
Since its identification in breast cancer, the aberrant expression of HOTAIR has been reported in various types of human cancer (
A significantly higher level of HOTAIR expression is observed in primary and metastatic breast cancer, as compared with normal breast epithelium, and HOTAIR is an independent biomarker for predicting the risk of metastasis and mortality in breast cancer (
HOTAIR is upregulated in esophageal squamous cell cancer (ESCC). A positive correlation exists between high levels of HOTAIR and clinical stage, serving as an independent prognostic factor in ESCC patients and cell lines (
Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis in 42 non-small cell lung cancer (NSCLC) samples, HOTAIR levels were found to be significantly higher in the cancerous tissues, compared with normal lung cells, correlating positively with the pathological stage and lymph node metastasis (
The expression level of HOTAIR are significantly increased in gastric cancer tissues, significantly correlating with lymph node metastasis and tumor-node-metastasis stage (
HOTAIR is significantly upregulated in hepatocellular carcinoma (HCC) tissues compared with adjacent normal tissues (
The levels of HOTAIR are significantly higher in endometrial cancer (EC) tissues than the normal tissues (
The expression of HOTAIR is upregulated in castration-resistant prostate cancer (PCa) cell lines, compared with normal prostate cells. Knockdown of the expression of HOTAIR by small interfering RNA leads to a reduction in PCa cell proliferation, migration and invasion, and increased apoptosis and cell cycle arrest (
The expression of HOTAIR is higher in nasopharyngeal cancer, compared with non-cancerous tissue, which is positively associated with tumor size, clinical stage and lymph node burden. Furthermore, HOTAIR overexpression has been associated with significantly decreased survival rates (
According to qPCR analysis, HOTAIR is significantly overexpressed in laryngeal squamous cell carcinoma, compared with adjacent non-neoplastic tissue (
The expression of HOTAIR is high in pancreatic cancerous tissue, compared with non-cancerous tissue (
qPCR analysis has revealed that the expression levels of HOTAIR are higher in colorectal cancer compared with non-tumor tissues (
Melanoma is a type of skin cancer with high potential to metastasize to the vital organs. HOTAIR has been demonstrated to be involved in the metastasis of melanoma. Expression levels of HOTAIR are higher in metastatic lymph nodes than in corresponding primary melanoma (
Glioma is the most common primary tumor in the brain (
Sarcomas consist of a heterogenous group of soft tissue and bone malignant tumors (
Pituitary adenomas belong to primary intracranial tumors, the majority of which secrete pituitary hormones that result in increased levels of blood hormones and clinical syndromes. A non-functioning pituitary adenoma (NFPA) is defined as a pituitary adenomas, which does not cause clinical hormone hypersecretion. The majority of pituitary adenomas are histologically benign; however, they have a marked ability to invade surrounding structures. The expression of HOTAIR has been reported to increase between normal anterior pituitaries, non-invasive NFPAs and invasive NFPAs, indicating a potential role of HOTAIR in NFPA invasion (
In conclusion, a substantial number of studies have revealed that HOTAIR is upregulated in multiple types of human cancer, and its overexpression is correlated with metastasis and poor prognosis. HOTAIR may serve as a potential tumor marker and therapeutic target in the future. Further investigations are required to clarify its expression in other types of cancer, particularly of the molecular mechanisms associated with the suppression and activation of genes by HOTAIR in cancer.
The EMT is a multistep process by which epithelial cells lose epithelial characteristics and gain mesenchymal characteristics, including motility and invasive properties (
CSCs are pluripotent tumor-initiating cells, which have the ability to self-renew. Due to their unique characteristics, CSCs are considered the basis for tumor initiation, development, metastasis and recurrence (
The overexpression of HOTAIR has been reported to induce EMT and support CSCs, with HOTAIR silencing leading to the failure of EMT and CSC establishment (
It has been suggested that HOTAIR may be involved in EMT/CSC establishment by regulating certain critical molecular signaling pathways. A potential explanation may be found in the HOTAIR targeting of intercellular adhesion molecule (ICAM)-1 and members of the matrix metalloproteinase (MMP) family, including MMP1, MMP3 and MMP9 in gastric cancer (
Several genes are induced or repressed by HOTAIR, including WIF-1, HOX D10, M M P1/3, PTEN and snail (
A significant role of lncRNAs is in the regulation of gene expression via a mechanism involving interaction with the epigenetic silencing complex, polycomb repressive complex 2 (PRC2), with ~20% of all lncRNA transcripts estimated to bind PRC2 (
Ubiquitination is a process commonly leading to the proteasome-mediated degradation of the target protein (
In conclusion, by binding PRC2, HOTAIR can regulate the expression of genes that are conducive to cell motility, matrix invasion and remodeling the chromatin state in cancer cells.
As mentioned above, HOTAIR is frequently increased in a variety of human malignances. However, the mechanism leading to its deregulation in human cancer remains to be elucidated. In lung cancer cells, HOTAIR is induced by type I collagen (Col-1), a type of interstitial ECM that is aberrantly enriched in the tumor microenvironment, indicating that the expression of HOTAIR in cancer cells may result from the response of the cancer cells to Col-1 (
As the overexpression of HOTAIR has been documented in a number of human malignancies, it provides a promising approach for anti-cancer therapies. Firstly, HOTAIR can be used as a biomarker for cancer diagnosis. High expression levels of HOTAIR are correlated with enhanced metastasis and is presents a negative prognostic factor for patient survival rates. By monitoring the levels of HOTAIR in certain types of tumor, including alterations in gene or protein levels, the risk of tumor development and progression, and the prognosis of the tumor, can be predicted. The observation in murine xenograft models that HOTAIR knockout can reduce tumor growth
Since its first observation, high expression levels of HOTAIR in various types of human tumor have been well documented. High expression levels of HOTAIR correlate with enhanced metastasis in cancer, and overexpression of HOTAIR is associated with poorer prognosis in cancer patients, most notably due to the increased metastasis.
To further clarify its role, the expression of HOTAIR in other types of cancer requires investigation. Although the expression of HOTAIR has been extensively investigated in various types of cancer, the molecular mechanism underlying the effects of HOTAIR in tumorigenesis remain to be elucidated. It appears that HOTAIR is involved in modulating the cancer epigenome and reprogramming the chromatin state, which is accomplished through the interaction with PRC2. HOTAIR binding can induce PRC2 to specific regions of the genome, which can repress or promote the transcription of genes, including WIF-1, HOXD10, MMP1/3, PTEN and snail. The majority of these genes regulate cancer cell proliferation and invasion, and are associated with tumor progression. By binding PRC2, HOTAIR can regulate gene expression and remodel chromatin states, which is conducive to cell motility and matrix invasion in cancer cells.
The molecular mechanism underlying the upregulation of HOTAIR in cancer also requires further investigation, to determine which transcription factors or signaling pathways mediate HOTAIR induction in cancer, In lung cancer cells, HOTAIR is induced by Col-1, which is a type of ECM aberrantly enriched in the tumor microenvironment. Col-1 has been demonstrated to promote the development of cancer, indicating that the expression of HOTAIR in cancer cells may result from the response of cancer cells to Col-1 (
The present study was supported by the National Natural Science Foundation of China (grant no. 81401847).
Proposed mechanism of HOTAIR-mediated gene silencing of 40 kb of the HOXD locus, which is involved in developmental pattering. The HOTAIR lncRNA is transcribed from the HOXC locus and functions in the binding, and the recruitment and binding of the LSD1 and PRC2 complex to the HOXD locus. Through an undetermined mechanism, the HOTAIR-PRC2-LSD1 complex is redirected to the HOXD locus on chromosome 2, where genes involved in metastasis suppression are silenced through H3K27 methylation and H3K4 demethylation. HOTAIR, HOX transcript antisense intergenic RNA; lncRNA, long non-coding RNA; PRC. polycomb repressive complex; LSD1, lysine-specific demethylase 1.
HOTAIR regulates EMT/MET and cancer metastasis. HOTAIR targets ICAM-1, E-cadherin, MMP1, MMP3 and MMP9, and is important at the early and late stages of metastasis. HOTAIR, HOX transcript antisense intergenic RNA; EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition; ICAM, intercellular adhesion molecule 1; MMP, matrix metalloproteinase.
Changes in the expression of HOTAIR in different types of human cancer.
Type of cancer | Expression | Effect on invasion/metastasis | Reference |
---|---|---|---|
Breast cancer | Increased | Promote | |
Esophageal cancer | Increased | Promote | |
Lung cancer | Increased | Promote | |
Gastric cancer | Increased | Promote | |
Liver cancer | Increased | Promote | |
Endometrial cancer | Increased | Unknown | |
Prostate cancer | Increased | Promote | |
Nasopharyngeal cancer | Increased | Promote | |
Laryngeal cancer | Increased | Promote | |
Pancreatic cancer | Increased | Promote | |
Colorectal cancer | Increased | Unknown | |
Melanoma | Increased | Promote | |
Glioma | Increased | Promote | |
Sarcoma | Increased | Promote | |
Pituitary adenoma | Increased | Unknown |