Rs145204276 and rs4759314 affect the prognosis of prostate cancer by modulating the GAS5/miR-1284/HMGB1 and HOTAIR/miR-22/HMGB1 signalling pathways

Abstract

Non-coding RNAs play an important role in the pathogenesis of prostate cancer (PC). This study aims to characterize the role of GAS5 rs145204276 and HOTAIR rs4759314 polymorphisms in the pathogenesis of PC. Both INS allele of GAS5 rs145204276 and A allele of HOTAIR rs4759314 were identified to increase the survival of PC patients. And patients carrying DEL/DEL þ AG genotypes tend to present higher levels of HMGB1, GAS5, HOTAIR and lower levels of miR-1284 and miR-22. In addition, the transcription activity of GAS5 promoter was increased by the deletion allele of rs145204276 polymorphism, while the G allele of rs4759314 polymorphism increased the transcription activity of HOTAIR promoter. GAS5 and HOTAIR could bind to miR-1284 and miR-22, respectively, while miR-1284 and miR-22 could bind to the 3 0 UTR of HMGB1. Compared with the control group, the expressions of miR-1284 or miR-22 were decreased with the presence of GAS5 or HOTAIR, and the expression of HMGB1 was the highest in the GAS5 þ HOTAIR group. In summary, the findings of this study demonstrated that both GAS5 rs145204276 and HOTAIR rs4759314 polymorphisms could affect the prognosis of PC by modulating the expression of HMGB1 via modulating the GAS5/miR-1284/HMGB1 and HOTAIR/miR-22/HMGB1 signalling pathways.

Long Noncoding RNA Small Nucleolar Host Gene: A Potential Therapeutic Target in Urological Cancers

“…However, the intermediate regulator between miR-145 and GAS5 was not identified (23). Interestingly, some studies revealed that a genetic polymorphism in GAS5 known as rs145204276, a 5-bp indel polymorphism (-/AGGCA) in the GAS5 promoter, is involved in PCa (24)(25)(26). One demonstrated that the presence of rs145204276 markedly reduced the lymph node and seminal vesicle infiltration of PCa cells, especially among patients older than 65 years old.…”

“…The mechanism of rs145204276 activity was revealed by another, which showed that rs145204276 greatly upregulated GAS5 and stimulated its transcription. By downregulating miR-1284, activated GAS5 could inhibit high mobility group box 1 (HMGB1), which has been identified as playing a promotive role in carcinogenesis (24). Furthermore, researchers also discovered that miR-21 might be correlated with GAS5.…”

The essential role of long non-coding RNA GAS5 in glioma: interaction with microRNAs, chemosensitivity and potential as a biomarker

“…Studies had also shown that GAS5 rs145204276 and HOTAIR rs4759314 polymorphisms affected the expression of GAS5 and HOTAIR, affecting the survival rates of prostate cancer. GAS5targeted miR-1284, and HOTAIR-targeted miR-22 acted on high mobility group box 1 (HMGB1) [55].…”

<p>Long Non-Coding Small Nucleolar RNA Host Genes (SNHGs) in Endocrine-Related Cancers</p>

“…[130][131][132] In terms of its mechanism of action, GAS5 may act as a sponge for miR-103, which in turn, inactivates the AKT/mTOR signaling pathway, thus inhibiting prostate cancer cell proliferation. 131 In addition, two single nucleotide polymorphisms (SNPs) located in the chromosomal segment of GAS5 (rs55829688 and rs145204276) can increase GAS5 expression, [133][134][135] and are associated with improved survival in prostate cancer. 133 Patients with prostate cancer and the GAS5 rs145204276 polymorphism are associated with a low risk of pathologic N stage and seminal vesicle invasion.…”

“…135 Furthermore, patients with prostate cancer aged >65 years who carry the GAS5 rs145204276 polymorphism show decreased risk of clinical T stage, pathologic N stage, and lymphovascular invasion. 135 Differential expression of GAS5 due to these SNPs likely affects the miR-21/programmed cell death 4 (PDCD4)/PTEN axis, 133 as well as the miR-1284/AKT 133 and miR-1284/high mobility group box 1 (HMGB1) 134 pathways. In addition, overexpression of miR-145 can upregulate GAS5 expression, although GAS5 overexpression (or silencing) has no effect on miR-145 levels.…”