Abstract
Gastric cancer (GC) is a highly prevalent type of metastatic tumor. The mechanisms underlying GC metastasis are poorly understood. Some long noncoding RNAs (lncRNAs) reportedly play key roles in regulating metastasis of GC. However, the biological roles of five natural antisense lncRNAs (AC093818.1, CTD-2541M15.1, BC047644, RP11-597M12.1, and RP11-40A13.1) in GC metastasis remain unclear. In this study, the expression of these lncRNAs was measured by quantitative reverse transcription-polymerase chain reaction. Migration and invasion were evaluated by wound-healing and the Transwell assay, respectively. Stable cells were injected into the tail veins of nude mice. Sections of collected lung and liver tissues were stained using hematoxylin and eosin. Protein expression was analyzed by western blot. RNA immunoprecipitation (RIP) assay was used to verify whether the STAT3 and SP1 transcription factors bound to AC093818.1 in GC cells. Expression levels of the five lncRNAs, especially AC093818.1, were significantly upregulated in metastatic GC tissues relative to those in nonmetastatic GC tissues. AC093818.1 expression was correlated with invasion, lymphatic metastasis, distal metastasis, and tumor-node-metastasis stage. AC093818.1 expression was highly sensitive and specific in the diagnosis of metastatic or nonmetastatic GC. AC093818.1 overexpression promoted GC migration and invasion in vitro and in vivo. AC093818.1 overexpression increased PDK1, p-AKT1, and p-mTOR expression levels. AC093818.1 silencing decreased these expressions. AC093818.1 bound to transcription factors STAT3 and SP1, and SP1 or STAT3 silencing could alleviated the effect of AC093818.1 overexpression. The data demonstrate that lncRNA AC093818.1 accelerates gastric cancer metastasis by epigenetically promoting PDK1 expression. LncRNA AC093818.1 may be a potential therapeutic target for metastatic GC.
Highlights
Gastric cancer (GC) is one of the most common cancers worldwide[1]
We investigated the expression of five upregulated natural antisense long noncoding RNAs (lncRNAs) (AC093818.1, CTD-2541M15.1, BC047644, RP11-597M12.1, and RP1140A13.1), that were previously identified[17], and evaluated their role in GC metastasis
597M12.1, and RP11-40A13.1 levels were significantly upregulated in metastatic GC tissues relative to those in nonmetastatic GC tissues (Supplementary Fig. 1)
Summary
Gastric cancer (GC) is one of the most common cancers worldwide[1]. Compared to most countries, GC-associated morbidity and mortality are generally higher in East Asia, in Korea, Mongolia, Japan, and China[2,3]. LncRNAs are involved in a wide range of biological processes including cell proliferation, metastasis, differentiation, inflammation, and angiogenesis[8,9,10]. Official journal of the Cell Death Differentiation Association. Ba et al Cell Death and Disease (2020)11:64 have revealed that lncRNAs participate in the progression of GC by regulating metastasis and angiogenesis[11]. The ncRNAs Z3812, LINC0160613, and SNHG16 regulate cell metastasis in GC. LINC0141014, PVT115, and MALAT116 contribute to the regulation of vasculogenic mimicry and angiogenesis, which can in turn aggravate GC progression. Song et al identified 2710 differentially regulated lncRNAs in lymph node-metastasized samples (1381 upregulated and 1329 downregulated) relative to primary GC samples[17]. The effects of these lncRNAs on GC metastasis remain unclear
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