Long noncoding RNA BC005927 upregulates EPHB4 and promotes gastric cancer metastasis under hypoxia

Abstract

Hypoxia plays a critical role in the metastasis of gastric cancer (GC), yet the underlying mechanism remains largely unclear. It is also not known whether long, noncoding RNAs (lncRNAs) are involved in the contribution of hypoxia to GC metastasis. In the present study, we found that lncRNA BC005927 can be induced by hypoxia in GC cells and mediates hypoxia‐induced GC cell metastasis. Furthermore, BC005927 is frequently upregulated in GC samples and increased BC005927 expression was correlated with a higher tumor‐node‐metastasis stage. GC patients with higher BC005927 expression had poorer prognoses than those with lower expression. Additional experiments showed that BC005927 expression is induced by hypoxia inducible factor‐1 alpha (HIF‐1α); ChIP assay and luciferase reporter assays confirmed that this lncRNA is a direct transcriptional target of HIF‐1α. Next, we found that EPHB4, a metastasis‐related gene, is regulated by BC005927 and that the expression of EPHB4 was positively correlated with that of BC005927 in the clinical GC samples assessed. Intriguingly, EPHB4 expression was also increased under hypoxia, and its upregulation by BC005927 resulted in hypoxia‐induced GC cell metastasis. These results advance the current understanding of the role of BC005927 in the regulation of hypoxia signaling and offer new avenues for the development of therapeutic interventions against cancer progression.

Long non‐coding RNA MIF‐AS1 promotes gastric cancer cell proliferation and reduces apoptosis to upregulate NDUFA4

“…ZFAS1 was upregulated in gastric cancer and its overexpression contributed to poor prognosis and shorter survival of patients through repression of KLF2 and NKD2 . Moreover, LINC00668, BC005927, and GAS5 have also been implicated in the progression of gastric cancer by regulating the protein expression of target genes at the epigenetic level. In addition to direct epigenetic regulation, lncRNA‐induced dysregulation of mRNA in gastric cancer may be dependent on miRNA‐mediated indirect regulation .…”

The interplay between HIF-1α and noncoding RNAs in cancer

“…Similar to the classical interactive mode between HIF-1α and miRNAs, HIF-1α can also directly interact with the HREs in the lncRNA BC005927 promoter region, inducing lncRNA BC005927 to play its oncogenic role in gastric cancer by upregulating EPH receptor B4 (EPHB4) [81]. In addition, HIF-1α-mediated direct interactions regulate the expression of numerous lncRNAs, including lncRNA BX111 [82], lncRNA UCA1 [83,84], lncRNA FALEC [85], lncRNA MALAT1 [86], lncRNA ANRIL [87], and lncRNA NUTF2P3-001 [88], all of which play key roles in the development of tumors.…”

“…Although belonging to the lncRNA family, circRNAs are always discussed separately due to their unique structure gastric cancer upregulation transcriptional activation promotes invasion and metastasis [81] lncRNA BX111 pancreatic cancer upregulation transcriptional activation promotes EMT, proliferation, migration and invasion [82] lncRNA UCA1 osteosarcoma upregulation transcriptional activation promotes growth [83] lncRNA UCA1 bladder cancer upregulation transcriptional activation promotes proliferation, migration and invasion, inhibits apoptosis [84] lncRNA FALEC prostate cancer upregulation transcriptional activation promotes proliferation, migration and invasion [85] lncRNA MALAT1 HeLa and HEK-293T cells upregulation transcriptional activation N.A. [86] lncRNA ANRIL osteosarcoma upregulation transcriptional activation promotes invasion, inhibits apoptosis [87] lncRNA NUTF2P3-001 pancreatic cancer upregulation transcriptional activation promotes viability, proliferation and invasion [88] lncRNA HOTAIR lung cancer upregulation transcriptional activation promotes proliferation, migration and invasion [89] lncRNA HOTAIR pan-cancer upregulation transcriptional activation N.A.…”

“…Both Low expression of miR-592 [144] and high expression of miR-130b [184] can bring about poorer OS in hepatocellular carcinoma patients. For gastric cancer, it has been demonstrated that miR-421 regulated by HIF-1α not only causes longer OS, but also can shorten the time to relapse of patients [185], and lncRNA BC005927 induced by hypoxia is also frequently upregulated in gastric cancer samples, showing adverse effects on a series of prognostic parameters, such as TNM stage, lymph node metastasis, and survival time [81]. Not surprisingly, scholars have revealed that aberrant expression of lncRNA H19 [92] and miR-215 [186] in glioblastoma confers a poor prognosis for patients.…”

The Roles of Hypoxia-Inducible Factors and Non-Coding RNAs in Gastrointestinal Cancer

“…Therefore, hypoxia-induced UCA1 promotes cell migration by increasing EGFR expression in GC. Hypoxia can also induce the lncRNA BC005927 in GC cells, which is involved in hypoxia-induced metastasis [40], frequently upregulated in GC samples, and associated with poor prognosis, with high BC005927 expression decreasing the overall survival of patients with GC. ChIP and luciferase reporter assays have shown that BC005927 is directly regulated by HIF-1α and upregulated by the metastasis-related gene, EPHB4.…”