JHDM1D-AS1 aggravates the development of gastric cancer through miR-450a-2-3p-PRAF2 axis
Introduction
Gastric cancer (GC) is the fourth most common cancer in the world and represents the second most common type of cancer in China [1,2]. Currently, resection remains a valid therapeutic option for early GC patients who have low risk of lymph node metastasis. However, most late-stage GC patients have regional or distant metastasis at the time of diagnosis. Thus, the global long-term survival rate remains about 20% [3,4]. Thus, identifying the key regulators and clarifying the underlying mechanisms that initiate and promote GC development and metastasis helps in identifying more potential options for GC treatment.
Long non-coding RNAs (lncRNAs) play important roles in the progression of a broad spectrum of tumors via the modulation of malignant activities of cancer cells [[5], [6], [7], [8]]. The levels of various lncRNAs are dysregulated in different cancer tissues, and some of them are strongly associated with poor prognosis, indicating their features of being therapeutic targets or prognostic biomarkers [9,10]. Micro-RNAs, another group of non-coding transcripts, are crucial modulators that participate in the progression of GC. Several studies have shown that lncRNA can trap miRNA to set free target genes of miRNA and influence tumor development [11,12]. For example, LINC01133 can regulate the APC expression level by binding to miR-106a-3p, resulting in the inhibition of malignant activities of cancer cells [13]. Another lncRNA HOTAIR has been reported to increase HER2 level by binding to miR-331-3p and thus leading to GC progression [14]. Collectively, these studies indicated that lncRNA-miRNA-mRNA interaction network has the ability to modulate tumor development.
In the presence of stress induced by nutrient deficiency, the JHDM1D (histone demethylase Jumonji C domain containing histone demethylase 1 homolog D) level was elevated in cancer cells, leading to tumor growth suppression [15]. However, a new lncRNA JHDM1D-AS1, the antisense strand of JHDM1D, was highly expressed in various types of cancer that promoted pancreatic adenocarcinoma growth by upregulating angiogenesis. Moreover, an increased JHDM1D-AS1 level predicted poor prognosis in tumor patients [16]. However, the functions and molecular mechanisms of JHDM1D-AS1 regulation in GC progression remain unclear.
PRAF2 (also called JM4), comprising a prenylated Rab acceptor motif and four transmembrane domains, is identified as a novel oncogene. Increased expression level of PRAF2 has been observed in a series of tumor tissues of the liver [17], esophagus [18], colon [19], and brain [[20], [21], [22]]. High levels of PRAF2 have been positively associated with malignant clinical features and are considered to indicate unfavorable prognosis in various types of cancers. Furthermore, PRAF2 promoted tumorigenesis by suppressing cell apoptosis or by enhancing cell growth and invasion. However, the upstream mechanism that regulates PRAF2 expression remains unknown.
In the present research, we studied the correlation between the JHDM1D-AS1 level and the clinical characteristics in GC and explored the biological functions and underlying mechanisms of JHDM1D-AS1 in regulating GC cell growth and metastasis. Our results suggested that JHDM1D-AS1 promoted tumor progression by upregulating oncogenic PRAF2 level by trapping miR-450a-2-3p. We have reported that the JHDM1D-AS1/miR-450a-2-3p/PRAF2 interaction network participates in GC development.
Section snippets
Samples collection
Forty paired tumor tissues and matched non-tumor tissues were obtained from GC patients who performed surgical resection at Shaanxi Provincial People's Hospital. Patients who had undergone radiotherapy or chemotherapy were excluded from our study. All the resected tissues were properly conserved for the following experiments. Ethical clearance and approval was obtained from the Ethics Review Committee of Shaanxi Provincial People's Hospital.
Cell lines and cell transfection
GES-1 (normal gastric cell line) and NCI-N87, MKN-45,
JHDM1D-AS1 level was elevated in GC
In order to clarify the function of JHDM1D-AS1 in GC, qRT-PCR assay was performed to measure the JHDM1D-AS1 expression in GC cells. The JHDM1D-AS1 level was significantly higher in different GC cell lines (NCI-N87, MKN-45, SNU-1, and KATO-3) as compared to that in normal gastric epithelium cells GES-1 (Fig. 1A, P < 0.05). For the subsequent experiments, two cell lines SNU-1 and KATO-3 were used. Meanwhile, the level of JHDM1D-AS1 in clinical GC samples was measured. Similar to the observation
Discussion
In the previous several decades, in spite of the remarkable progresses in diagnostic and therapeutic methods of GC, the long-term survival of GC patients has remained unsatisfactory owing to cancer recurrence and metastasis [1,23]. Thus, detailed investigation of the key signaling pathway driving GC progression and metastasis is crucial for discovering new therapeutic targets and strategies for GC.
Recent studies have shown that lncRNA participates in multiple stages of cancer development by
Conclusion
Our findings show an unexplored JHDM1D-AS1/miR-450a-2-3p/PRAF2 axis in the regulation of GC progression. Therefore, it may provide a promising therapeutic option for GC treatment.
Funding
This research was financially supported by the National Natural Science Foundation of China (No. 8142012) and Shaanxi Province Innovative Talents Promotion Program (2017-KCT-28).
Availability of data and material
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written informed consent was obtained from all patients and the study protocol was approved by the Ethics Committee of Shaanxi Provincial People's Hospital. Animal care and study was approved by the Institutional Animal Care and Use Committee of Xi'an Jiaotong University.
Patient consent for publication
Not applicable.
CRediT authorship contribution statement
WM and LEQ conceived and designed the experiments. LY and PYS performed the experiments. MY and WJH analyzed and interpreted the data. WM wrote the manuscript. LEQ revised the manuscript. All authors read and approved the final manuscript.
Declaration of competing interest
The authors declare that they have no competing interests.
Acknowledgements
Not applicable.
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