1. The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China.
2. Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China.
3. Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
4. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
# Yixin Chen and Xin Gao contributed equally to this work.
Background: Advanced stomach adenocarcinoma (ASTAD) is a highly malignant and prognostically poor stage of gastric cancer. Recently, long noncoding RNA (lncRNA) was found to play a crucial role, including as competing endogenous RNA (ceRNA) in cancer. However, studies on large-scale sample in ASTAD are still lacking, thus we constructed the ceRNA network of ASTAD to explore its molecular mechanism.
Methods: We compared the expression of mRNAs, lncRNAs and miRNAs between ASTAD and normal tissues utilizing RNA-Seq and miRNA-seq Data from The Cancer Genome Atlas (TCGA). GO and KEGG enrichment analysis were executed for annotating the functions of differentially expressed mRNAs. Subsequently, we investigated the expression correlations between the differentially expressed lncRNAs and their respective mRNAs by constructing a ceRNA network. Kaplan-Meier survival analysis was used to assess the relationship between high/low risk scores based on this network with patient prognosis in TCGA training cohort and GSE15459 validation cohort. In vitro functional assays were employed to verify the cancer-promoting effects of key lncRNAs in the ceRNA network and their possible mechanisms.
Results: In ASTAD tissues, a total of 176 lncRNAs, 124 miRNAs, and 2205 mRNAs were identified as differentially expressed. Our constructed ceRNA network consisted 6 differentially expressed lncRNAs (PVT1, MAGI2-AS3, KCNQ1OT1, LINC02086, AC125807.2 and LINC02535), 25 miRNAs and 130 mRNAs, and the risk score derived from these lincRNAs could predict ASTAD patient outcomes. Key lncRNA LINC02086 was experimentally verified to enhance proliferation and migration of gastric cancer cells by competitively binding to miR-93a-5p with MMP3.
Conclusion: Our comprehensive ceRNA network for ASTAD provides valuable insights into its molecular mechanisms, and LINC02086 may be used as an innovative target for clinical treatment.
Keywords: ASTAD, ceRNA network, TCGA, molecular mechanisms