lnc-REG3G-3-1/miR-215-3p Promotes Brain Metastasis of Lung Adenocarcinoma by Regulating Leptin and SLC2A5

Abstract

This study aims to explore the role and mechanism of specific lncRNA in brain metastasis (BM) from lung adenocarcinoma (LADC), providing an effective biomarker for early diagnosis and targeted therapy of BM from LADC. Based on the gene expression profiles of lncRNA and mRNA in LADC and BM tissues detected by Gene Chip, lnc-REG3G-3-1 was selected, and the related genes, including miR-215-3p, leptin, and SLC2A5, were identified by data analysis. Human LADC cell lines A549 and H1299 were cultured. Dual-luciferase and endogenous validation experiments were used to confirm the regulation between these genes. Real-time quantitative reverse transcription-polymerase chain reaction and Western blotting were used to detect gene expression. The tumor metastasis-related gene function of lnc-REG3G-3-1 and miR-215-3p in H1299 cells was verified by Transwell invasion, migration assays, and scratch testing. Nude mice xenograft tumors constructed with decreased lnc-REG3G-3-1 confirmed the influences on gene expression in vivo. lnc-REG3G-3-1 was highly expressed in BM tissues that originated from LADC compared with that in primary cancer tissues. lnc-REG3G-3-1 reduced miR-215-3p expression, thereby regulating the target genes leptin and SLC2A5 and the signaling pathways, taking part in the lnc-REG3G-3-1/miR-215-3p axis in the process of BM from LADC. lnc-REG3G-3-1, leptin, and SLC2A5 through regulating signaling pathways may be jointly involved in the regulation of the biological process of BM in patients with LADC.

Long non-coding RNA AC122108.1 promotes lung adenocarcinoma brain metastasis and progression through the Wnt/β-catenin pathway by directly binding to aldolase A

“…In summary, the expression of specific lncRNAs has been reported to be correlated with clinical features in LAD, and the utility of lncRNAs in the diagnosis and prognosis of LAD has significant clinical value (33,34,55). In this study, we demonstrated that AC122108.1 was significantly upregulated in LAD BM cells and tissues, and that the expression of AC122108 was correlated with the malignancy of tumors, including tumor proliferation, apoptosis, invasion, migration, and metastasis.…”

“…Previous studies have shown that lncRNAs participate in the progression of human cancers, and can serve as biomarkers and therapeutic targets for tumors (30). As hallmarks of LAD, migration, invasion, and metastasis are regulated by lncRNAs (31,32), and many lncRNAs also play a critical role in LAD BM (33,34). Initially, lncRNA was considered to be RNA without biological functions.…”

The Significance of MicroRNAs in the Molecular Pathology of Brain Metastases

“…Downregulation of miR-215-3p leads to higher cell viability, migration, invasiveness, and expression of leptin and solute carrier family 2 member 5 (SLC2A5), followed by significant upregulation of VEGF, serine/threonine/tyrosine interacting like 1 (STYXL1), and flavin adenine dinucleotide synthetase 1 (FLAD1) mRNA levels and downregulation of Akt, phosphoinositide 3-kinase (PI3K), and sex-determining region-box transcription factor 4 (SOX4) mRNA levels. Higher leptin expression plays a crucial role in the promotion of metastases, especially due to the activation of the mammalian target of rapamycin (mTOR) pathway [ 123 ].…”

Leptin and Cancer: Updated Functional Roles in Carcinogenesis, Therapeutic Niches, and Developments

“…The study also provided evidence that leptin-induced malignancies were driven through the activation of the ERK signaling axis [ 76 ]. In a study of brain metastasis of lung adenocarcinoma, activation of leptin signaling was highlighted in the context of the lnc-REG3G-3-1 high /miR-215-3p low axis [ 77 ]. The assessment of leptin drug resistance showed that bone marrow-derived mesenchymal stem cells could release leptin to induce erlotinib resistance in lung adenocarcinoma cells by activating IGF-1R signaling in a hypoxic environment, suggesting a predictive role of leptin expression for therapeutic response [ 78 ].…”

“…↑: [67,70] ↑: [67] ↓: [66] Lung Cancer ↑: [79,80] ↑: [76,77,80] ↑: (erlotinib) [78], (cisplatin) [79] Pancreatic Cancer ↑: [82,87,88] ↑: [83] ↑: (gemcitabine) [86], (5-FU) [87] Prostate Cancer ↑: [89] ↑: [89,90] ↓: [89] Gallbladder cancer ↑: [91] Myeloma ↑: (bortezomib) [92] Chondrosarcoma ↑: [93,94] ↑: increase.↓: decrease.…”