Abstract
Emerging studies have indicated the essential functions of long noncoding RNAs (lncRNAs) during cancer progression. However, whether lncRNAs contribute to the upregulation of v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1), an established oncogenic protein facilitating tumor invasion and metastasis, in gastric cancer remains elusive. Herein, we identified Ets-1 promoter-associated noncoding RNA (pancEts-1) as a novel lncRNA associated with the gastric cancer progression via mining of publicly available datasets and rapid amplification of cDNA ends. RNA pull-down, RNA immunoprecipitation, in vitro binding, and RNA electrophoretic mobility shift assays indicated the binding of pancEts-1 to non-POU domain containing octamer binding (NONO) protein. Mechanistically, pancEts-1 facilitated the physical interaction between NONO and Ets related gene (ERG), resulting in increased ERG transactivation and transcription of Ets-1 associated with gastric cancer progression. In addition, pancEts-1 facilitated the growth and aggressiveness of gastric cancer cells via interacting with NONO. In gastric cancer tissues, pancEts-1, NONO, and ERG were upregulated and significantly correlated with Ets-1 levels. High levels of pancEts-1, NONO, ERG, or Ets-1 were respectively associated with poor survival of gastric cancer patients, whereas simultaneous expression of all of them (HR = 3.012, P = 0.105) was not an independent prognostic factor for predicting clinical outcome. Overall, these results demonstrate that lncRNA pancEts-1 exhibits oncogenic properties that drive the progression of gastric cancer via regulating the NONO/ERG/Ets-1 axis.
Highlights
These authors contributed : Dan Li, Yajun Chen, Hong Mei and Wanju Jiao.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Gastric cancer is the second leading cause of cancer-related death around the world [1]
Mining of public datasets derived from Kaplan-Meier plotter [20] and Gene Expression Omnibus (GEO) indicated that patients with high pancEts-1 expression had lower overall (OS) and first progression (FP) survival possibility in gastric cancer, breast cancer, Ewing sarcoma, glioma, and lymphoma (Fig. 1h and Supplementary Figure S2)
Since first indentified as the cellular proto-oncogene of retroviral v-ETS [22], a series of studies have demonstrated that E26 transformation-specific (Ets)-1 regulates transcription through recognizing binding sites within gene promoters, and participates in many biological processes, such as cellular differentiation, proliferation, transformation, angiogenesis, and cancer progression [9]
Summary
Despite recent progress in surgical and comprehensive therapies, the clinical consequence of gastric cancer patients suffering from tumor invasion and metastasis remains to be improved [1]. It has been a focus to investigate the mechanisms essential for the development and progression of gastric cancer [2]. Ets-1 promotes the growth and metastasis of different cancer cell lines [9], while knockdown of Ets-1 inhibits cell transformation [10] and reverses the multiple drug resistance of breast cancer cells [11]. Our previous evidence shows that Ets-1 levels are elevated in gastric cancer, and knockdown of Ets-1 inhibits the invasiveness and metastasis of gastric cancer cells [12, 13]. The mechanisms contributing to high expression of Ets-1 in gastric cancer remain to be determined
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