Abstract
Increasing evidence suggests that dysregulation of long non-coding RNAs (lncRNAs) is implicated in chemoresistance in cancers. However, the function and molecular mechanisms of lncRNAs in gastric cancer chemoresistance are still not well understood. In this study, we aimed to investigate the functional role and the underlying molecular mechanisms of lncRNA HOXD cluster antisense RNA 1 (HOXD-AS1) in cisplatin (DDP) resistance in gastric cancer. Our results revealed that HOXD-AS1 was upregulated in DDP-resistant gastric cancer tissues and cells. Patients with gastric cancer with high HOXD-AS1 expression levels had a poor prognosis. Knockdown of HOXD-AS1 facilitated the sensitivity of DDP-resistant gastric cancer cells to DDP. Additionally, HOXD-AS1 epigenetically silenced PDCD4 through binding to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) on the promoter of PDCD4, thus increasing H3K27me3. More importantly, PDCD4 silencing counteracted HOXD-AS1 knockdown-mediated enhancement of DDP sensitivity in DDP-resistant gastric cancer cells. In summary, HOXD-AS1 led to DDP resistance in gastric cancer by epigenetically suppressing PDCD4 expression, providing a novel therapeutic strategy for patients with gastric cancer with chemoresistance.
Highlights
Gastric cancer is the second most common cause of mortality and morbidity throughout the world, representing a major public health problem [1]
Among the differentially expressed Long non-coding RNAs (lncRNAs), HOXD-AS1 was highly expressed in the gastric cancer tumour tissues compared with normal tissues in all three above-mentioned datasets
To confirm the result from GEO DataSets, the expression of HOXD-AS1 was further analysed in gastric cancer tissues from the The Cancer Genome Atlas (TCGA) dataset
Summary
Gastric cancer is the second most common cause of mortality and morbidity throughout the world, representing a major public health problem [1]. Cisplatin (DDP) was used as the first-line chemotherapeutic agent for gastric cancer treatment [3,4]. Acquired resistance to DDP is a key barrier to the effective treatment of gastric cancer [5]. Revealing the underlying mechanism and discovering novel therapeutic approaches are imperative for developing effective therapies for patients with gastric cancer. LncRNAs have been reported to exert oncogenic or tumour suppressor roles and have been elucidated to regulate the biological processes and cell functions in many malignancies [6,7,8]. HOXD-AS1 has been widely recognized as an oncogenic lncRNA in many cancers [13,14]. The functional role of HOXD-AS1 and the underlying mechanism in gastric cancer chemoresistance are still not well understood
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