HOTAIR contributes to the carcinogenesis of gastric cancer via modulating cellular and exosomal miRNAs level

Abstract

Gastric cancer (GC) is one of the most leading malignancies. Long noncoding RNA is related to GC. In this study, 11 miRNAs in the exosomes and six lncRNAs in the tissues was examined by qRT-PCR. Correlation analysis was used to analyze the relationship between miRNAs in exosome and lncRNAs in the tissues. Four miRNAs level in GC tissues were examined by qRT-PCR. MTT was used to determine cell viability. Flow cytometry was used to quantify the apoptotic cells. Transwell assay was used to examine the migration and invasion capacity. Dual-luciferase assay was used to examine the interaction between HOTAIR and miR-30a or -b. Capillary formation was used to determine the capillary formation capacity. Weak negative correlations were found between HOTAIR and miR-30a or -b in GC tissue samples. Interestingly, strong negative correlations were identified between the HOTAIR level in GC tissue samples and the miR-30a or -b levels in plasma exosomes. HOTAIR knockdown GC cells exhibited decreased migration, invasion, proliferation, and upregulated apoptosis, which released more miR-30a and -b into the exosomes. KRAS was upregulated when co-cultured with exosomes from HOTAIR overexpressed cells, and promoted GC cells proliferation, migration, and invasion. Meanwhile, HUVEC cells expressed increased VEGF-A and formatted more capillaries. Subsequently, we identified a 10mer target site of miR-30a or -b in HOTAIR sequence, and the overexpression of HOTAIR induced the degradation of miR-30a or -b, indicating a ceRNA role of HOTAIR. We report the negative correlation between the plasma miRNAs level and GC tissue HOTAIR expression for the first time and unveiled the ceRNA role of HOTAIR in GC. HOTAIR functions as an onco-lncRNA regulating the level of miR-30a and -b in both GC cells and exosomes. These findings may give insight into understanding the mechanism of GC pathogenesis and provide new biomarkers for clinical diagnosis.

The HOTAIR lncRNA: A remarkable oncogenic promoter in human cancer metastasis (Review)

“…In addition, Wang et al ( 89 ) demonstrated that HOTAIR is significantly associated with clinical parameters of laryngeal squamous cell carcinoma (LSCC), suggesting its potential as a valuable biomarker for screening LSCC and a promising predictive tool for patients with LSCC patients. Similar results have been reported in lung cancer, stomach cancer and liver cancer ( 90 – 93 ). In summary, HOTAIR functions as follows: i) Promotes epigenetic activation/repression of tumour suppressor gene function, ii) affects the inhibition of target gene expression by competitively binding miRNA and iii) modifies genes to ensure their compatibility with transcription factors, while ribosomes can post-transcriptionally interact with splicing factors ( 30 ).…”

The role and application of small extracellular vesicles in gastric cancer

“…Moreover, circSHKBP1 can directly bind to HSP90 and hinder its interaction with STUB1, inhibiting the ubiquitination of HSP90 and promoting the proliferation, migration, invasion and angiogenesis of GC cells [ 69 ]. Recently, Zhang et al showed that degradation of miR-30a or miR-30b could be induced by HOTAIR to promote the carcinogenesis of GC [ 72 ]. In addition, other cargo [ 60 – 62 , 65 – 67 , 70 ] plays a role in tumorigenesis and tumour progression.…”

Potential Therapeutic Targeting of lncRNAs in Cholesterol Homeostasis

“…For example, prostate-specific lncRNA prostate cancer antigen 3 (PCA3) levels have been suggested as a diagnostic biomarker of prostate cancer (98). Other lncRNAs used as biomarkers include circulating plasma H19 for gastric cancer (99), HULC in hepatocellular carcinoma (100), circulating lncRNA in SNHG11 colorectal cancer (101), circulating exosomal lncRNA-GC1 in gastric cancer (102), and HOTAIR in various cancers, including breast, colorectal, liver, gastric, lung, and thyroid (103)(104)(105)(106)(107).…”