Biochemical and Biophysical Research Communications
Long non-coding RNA HOTAIR promotes carcinogenesis and invasion of gastric adenocarcinoma
Introduction
Gastric cancer is one of the major causes of cancer death worldwide, with almost 990,000 cases detected annually [1]. The incidence of gastric cancer varies with geographic location, and is highest in Eastern Asia including Korea, Japan and China. Despite its prevalence, there is still no curative modality for late-diagnosed gastric cancer. The mechanism of gastric carcinogenesis is complex and poorly understood, and is influenced by both infection with Helicobacter pylori and genetic factors. Gastric cancer appears to be caused by the accumulation of both genetic and epigenetic changes [2]. Non-coding RNAs (ncRNAs) like microRNA are major components of epigenetic regulatory networks, and have been shown to be deregulated in gastric cancer [3], [4], [5], [6].
A new class of ncRNA that have been receiving increased attention are long non-coding RNA (lncRNA), with lengths ranging from 200 bp to 100 kbp [7]. HOX transcript antisense intergenic RNA (HOTAIR) is one of the well-studied lncRNAs that regulate gene expression by mediating the modulation of chromatin structure [7], [8]. HOTAIR acts as a scaffold of histone modification complexes to coordinately interact with PRC2 complex and LSD1 histone modifiers [9]. HOTAIR promotes metastasis of breast cancer through the repression of multiple metastasis suppressor genes by interaction with PRC2 complex [10]. HOTAIR levels are also elevated in both primary and metastasized tumors of multiple other cancer types such as colorectal cancer, hepatocellular carcinoma, nasopharyngeal carcinoma and gastric carcinoma [11], [12], [13], [14].
Altered apoptosis, cell proliferation and cell cycle regulation are key features of carcinogenesis of gastric cancer [2], [15]. Although elevated HOTAIR is known to be related to invasiveness [11], metastasis, and poor prognosis, little is known about its relationship with carcinogenesis in gastric cancer.
In this study, we investigated the impact of HOTAIR on apoptosis, cell proliferation and cell cycle as indicators of the carcinogenesis of gastric cancer. We examined the mechanism of invasion and metastasis and analyzed the clinical significance of HOTAIR in patients with gastric cancer.
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Patients and tissue samples
Fifty fresh gastric cancer tissue and paired adjacent gastric tissue samples were obtained from 50 patients who underwent surgical resection for gastric cancer at Severance Hospital, Yonsei University College of Medicine. All samples were frozen in liquid nitrogen immediately after resection and stored at −80 °C until use. The mean age of patients was 60.7 (39–79) years and the male/female ratio was 2.2/1. This study was approved by the Ethics Committee of Yonsei University.
Cell lines and cell culture
A total of 22 gastric
Altered expression of HOTAIR in gastric cancer cell lines and gastric cancer tissues
HOTAIR was expressed at various levels in 22 gastric cancer cell lines compared to normal gastric RNA (Fig. 1A). Nineteen cell lines showed elevated HOTAIR expression compared to normal gastric RNA. Gastric cancer cell lines had an average of 43-fold increase in HOTAIR expression compared to normal gastric RNA. HOTAIR was detected in 48 of 50 gastric cancer tissues and the expression of HOTAIR was significantly higher in cancer tissues compared to adjacent normal tissues (P = 0.007) (Fig. 1B).
The expression of HOTAIR and clinicopathologic characteristics of gastric cancer
Discussion
In this study, HOTAIR was elevated in gastric cancer compared to normal tissue and this finding was supported by our results showing that HOTAIR could inhibit apoptosis in gastric cancer cell lines. We also clearly showed that higher expression of HOTAIR was associated with lymphovascular invasion, lymph node metastasis, advanced stage and poor clinical outcomes. Lastly, HOTAIR promoted the EMT through regulation of E-cadherin, N-cadherin, ZEB1 and Snail.
A considerable number of lncRNAs have
Acknowledgments
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2001479).
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Long noncoding RNA (lncRNA) HOTAIR: Pathogenic roles and therapeutic opportunities in gastric cancer
2022, Genes and DiseasesCitation Excerpt :An increasing body of evidence highlights that HOTAIR may potentially be a useful diagnostic and prognostic marker for peritoneal metastasis, whereas its biological and pathological association with GC has been demonstrated. Another study has also shown the high level of HOTAIR in lymphovascular invasion and lymph node metastasis in GC, while its Knockdown by siRNA caused suppression of viability, motility, and proliferation in GC cells and led to reduction of cell invasiveness and migration, as well as induction of apoptosis; thus, ample evidence support the potential role of HOTAIR in suppressing apoptosis and increasing invasive phenotypes of GC.85 A study applied shRNA and MKN 74 and KATO III cell lines for HOTAIR modulation, in which HOTAIR loss in KATO III cell lines by shRNA led to reduction of peritoneal dissemination.100
Metformin inhibits gastric cancer cell proliferation by regulation of a novel Loc100506691-CHAC1 axis
2021, Molecular Therapy OncolyticsCitation Excerpt :lncRNA MALAT1 was observed to promote cell proliferation by recruiting SF2/ASF and be overexpressed in gastric cancer.15 HOTAIR was upregulated in gastric carcinoma tissues compared with adjacent normal gastric tissues,16 and the overexpression of HOTAIR in gastric cancer cells resulted in the enhancement of metastases of the liver in vivo.17,18 Overexpression of lncRNA H19 enhances cell proliferation and invasion of gastric cancer cells.19–21
Long non-coding RNA SNHG1 suppresses cell migration and invasion and upregulates SOCS2 in human gastric carcinoma
2021, Biochemistry and Biophysics ReportsCitation Excerpt :A growing number of studies have revealed that lncRNAs participate in a wide range of biological processes, and aberrant lncRNAs expression is involved in diverse human diseases, including cancers [4]. Many lncRNAs have been found to play pivotal roles in GC development, such as TINCR, GHET1, and HOTAIR, which were reported to regulate proliferation and/or metastasis in GC cells [5–7]. These findings suggested that lncRNAs play crucial roles in GC carcinogenesis and have great impacts on GC clinical application.
Long non-coding RNA signature in gastric cancer
2020, Experimental and Molecular PathologyHOX transcript antisense RNA (HOTAIR) in cancer
2019, Cancer LetterslncRNA NEAT1 competes against let-7a to contribute to non-small cell lung cancer proliferation and metastasis
2018, Biomedicine and PharmacotherapyCitation Excerpt :Long non-coding RNAs (lncRNAs) are defined as transcripts with >200 nucleotides that have limited coding potential [8,9]. Current studies have demonstrated that lncRNAs play an important role in cancer development, progression and drug resistance [10–12]. For instance, lncRNA metastasis-associated lung adenocarcinoma transcript (MALAT)1 is widely expressed and associated with high metastatic potential and poor prognosis [13,14].
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This work was supported by the Brain Korea 21 PLUS Project for Medical Science, Yonsei University.