Long Non-Coding RNA AWPPH Promotes Postoperative Distant Recurrence in Resected Non-Small Cell Lung Cancer by Upregulating Transforming Growth Factor beta 1 (TGF-β1)

Abstract

Background Postoperative recurrence of cancers is responsible for a large portion of deaths in cancer patients. Our study investigated the involvement of lncRNA AWPPH in recurrence of resected non-small cell lung cancer (NSCLC). Material/Methods A total of 128 patients were followed up for 3 years. Blood was extracted from each patient on the day of discharge, the day of the diagnosis of recurrence, or at the end of follow-up. Blood from 30 healthy controls was used as a control group. Patient were divided into 3 groups – a non-recurrence group (NR, n=54), a local recurrence group (LR, n=42), and a distant recurrence (DR, n=32) group – according to the follow-up results. Blood AWPPP was detected by qRT-PCR. AWPPH expression vectors were transfected into cells of human NSCLC cell lines. Cell migration and invasion were detected by Transwell migration and invasion assay, respectively. TGF-β1 expression was detected by Western blot analysis. Results Blood AWPPH levels were the highest in the DR group, followed by the LR and NR groups. The lowest blood AWPPH levels were observed in the control group. Blood AWPPH levels increased significantly in the DR group but not in the NR and LR groups during follow-up. Blood AWPPH levels were positively correlated with TGF-β1 mRNA levels in the DR group but not in the NR and LR groups during follow-up. AWPPH overexpression promoted cell migration and invasion and upregulated TGF-β1 expression. Conclusions lncRNA AWPPH can promote postoperative distant recurrence in resected NSCLC by upregulating TGF-β1.

Novel long non‐coding RNA LINC02323 promotes epithelial‐mesenchymal transition and metastasis via sponging miR‐1343‐3p in lung adenocarcinoma

“…Many of these lncRNAs are regulated by TGF-β. [11][12][13][14][15] LncRNAs play essential roles in the migration, invasion and EMT and are discovered to act as miRNA sponges to participate in cancer progression. [16][17][18] Our previous study has shown that six lncRNAs, including LINC02323, are associated with metastasis and prognosis of LUAD.…”

MiRNAs and LncRNAs: Dual Roles in TGF-β Signaling-Regulated Metastasis in Lung Cancer

“…The positive roles of miRNAs and lncRNAs can be concluded as follows: miR-93 [59], miR-128-3p [61], miR-9 [62], miR-134, miR-487b [65], miR-330-3p [67], miR-1246 [68], miR-23a [74], HCP5 [107], NORAD [18], XIST [19,20], linc00673 [109], MEG3 [110], MEG8 [111], and ATB [113] can enhance TGF-β signaling-induced EMT. MiR-9 [63], miR-9-5p [71], ATB [112], TBILA [115] lnc-MMP2-2 [116], and AWPPH [117] can accelerate TGF-β signaling-mediated lung cancer cell migration and invasion. Lnc-MMP2-2 can also increase vascular permeability [116].…”

“…lnc-MMP2-2→E-cadherin↓, N-cadherin↑, vimentin↑→invasion↑, migration↑ [116] lnc-MMP2-2→occludin↓, Zo-1↓→vascular permeability↑ lnc-MMP2-2→MMP2↑→metastasis↑ lncRNA AWPPH NCI-H1993, NCI-H2170 AWPPH→TGF-β1↑→invasion↑, migration↑ [117] lncRNA CASC11 SHP-77, DMS79 CASC11→TGF-β1↑→stemness↑ [118] Abbreviations: nc-RNA, non-coding RNA; miR, microRNA; NEDD4L, Neural precursor cell expressed developmentally downregulated gene 4-like; TGF-β, transforming growth factor-β; EMT, epithelial-mesenchymal transition; SMURF2, Smad ubiquitin regulatory factor 2; cPP1, catalytic subunit of protein phosphatase 1; MAGI2, membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2; SOX7, SRY-Box 7; TGFBR2, TGF-β receptor 2; lncRNA, long non-coding RNA; HCP5, histocompatibility leukocyte antigen complex P5; XIST, X inactivate-specific transcript; ZEB2, Zinc finger E-box-binding homeobox 2; lncRNA-ATB, lncRNA activated by TGF-β; AKT, protein kinase B; JAK, Janus-activated kinase; STAT3, signal transducer and activator of transcription-3; TBILA, TGF-β-induced lncRNA; HGAL, human germinal center-associated lymphoma; JAB1, c-Jun activation domain-binding protein 1; Zo-1, zonula occludens-1; MMP2, matrix metalloprotease 2. [106] lncRNA HAND2-AS1 H1581, H1993 HAND2-AS1→TGF-β1/Smad2/3 signal↓→invasion↓, migration↓, stemness↓ [119] lncRNA linc01186 A549 linc01186→EMT↓→invasion↓, migration↓ [120] lncRNA LINP1 A549 LINP1→E-cadherin↑, vimentin↓, Snail↓→EMT↓ [121] lncRNA ANCR NCI-H23, NCI-H522 ANCR→TGF-β1↓→invasion↓, migration↓ [122] lncRNA NKILA A549, H226 NKILA→NF-κB↓→Snail↓→EMT↓→invasion↓, migration↓ [123] Abbreviations: nc-RNA, non-coding RNA; miR, microRNA; EMT, epithelial-mesenchymal transition; TGF-β, transforming growth factor-β; SULF2, Sulfatase 2; ZEB1, Zinc finger E-box-binding homeobox 1; MTDH, metadherin; FOXM1, forkhead Box M1; FOXQ1, forkhead box Q1; Sp1, specificity protein 1; SOX4, sex-determining region Y-box 4; TGFBR1, TGF-β receptor 1; CCNE2, cyclin E2; AKT, protein kinase B; CSCs, cancer stem cells; lncRNA, long non-coding RNA; LINP1, lncRNA in nonhomologous end joining (NHEJ) pathway 1; NF-κB, nuclear factor-kappa B; NKILA, NF-κB Interacting LncRNA.…”

“…AWPPH can stimulate TGF-β1 protein expression to promote NSCLC migration and invasion. Moreover, high AWPPH can indicate the postoperative distant recurrence of NSCLC patients [117].…”

Long noncoding RNA OSER1‑AS1 promotes the malignant properties of non‑small cell lung cancer by sponging microRNA‑433‑3p and thereby increasing Smad2 expression

“…Many recent studies have demonstrated the abnormal expression of various long noncoding RNAs (lncRNAs) in non-small cell lung cancer (NSCLC) (31)(32)(33). These dysregulated lncRNAs act as important regulators of the pathogenesis of NSCLC and have crucial effects on NSCLC tumorigenesis, progression, and metastasis (34)(35)(36).…”