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LncRNA PAXIP1-AS1 fosters the pathogenesis of pulmonary arterial hypertension via ETS1/WIPF1/RhoA axis.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a life-threatening disease featured with elevated pulmonary vascular resistance and progressive pulmonary vascular remodelling. It has been demonstrated that lncRNA PAXIP1-AS1 could influence the transcriptome in PAH. However, the exact molecular mechanism of PAXIP1-AS1 in PAH pathogenesis remains largely unknown. In this study, in vivo rat PAH model was established by monocrotaline (MCT) induction and hypoxia was used to induce in vitro PAH model using human pulmonary artery smooth muscle cells (hPASMCs). Histological examinations including H&E, Masson's trichrome staining and immunohistochemistry were subjected to evaluate the pathological changes of lung tissues. Expression patterns of PAXIP1-AS1 and RhoA were assessed using qRT-PCR and Western blotting, respectively. CCK-8, BrdU assay and immunofluorescence of Ki67 were performed to measure the cell proliferation. Wound healing and transwell assays were employed to evaluate the capacity of cell migration. Dual-luciferase reporter assay, co-immunoprecipitation, RIP and CHIP assays were employed to verify the PAXIP1-AS1/ETS1/WIPF1/RhoA regulatory network. It was found that the expression of PAXIP1-AS1 and RhoA was remarkably higher in both lung tissues and serum of MCT-induced PAH rats, as well as in hypoxia-induced hPASMCs. PAXIP1-AS1 knockdown remarkably suppressed hypoxia-induced cell viability and migration of hPASMCs. PAXIP1-AS1 positively regulated WIPF1 via recruiting transcriptional factor ETS1, of which knockdown reversed PAXIP1-AS1-mediated biological functions. Co-immunoprecipitation validated the WIPF1/RhoA interaction. In vivo experiments further revealed the role of PAXIP1-AS1 in PAH pathogenesis. In summary, lncRNA PAXIP1-AS1 promoted cell viability and migration of hPASMCs via ETS1/WIPF1/RhoA, which might provide a potential therapeutic target for PAH treatment.

SUBMITTER: Song R

PROVIDER: S-EPMC8335679 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A growing number of dysregulated long non‑coding (lnc)RNAs have been verified to serve an essential role in human prostate cancer. However, the underlying mechanisms of lncRNA MNX1 Antisense RNA 1 (MNX1‑AS1) in prostate cancer has not been explored. Therefore, the present study aimed to explore the function of MNX1‑AS1 in prostate cancer tumorigenesis and investigate the in‑depth mechanism. The expression of MNX1‑AS1, microRNA (miR)‑2113 and murine double min 2 (MDM2) in prostate cancer tissues and corresponding normal tissues were assessed by reverse transcription‑quantitative PCR. The protein expression levels of MDM2 were detected by western blotting. LNCaP and PC‑3 cells were transfected with short hairpin (sh)‑MNX1‑AS1, miR‑2113 mimics, miR‑2113 inhibitor and pCDH‑MDM2 vector using Lipofectamine® 3000. Cell proliferation, migration and invasion abilities were assessed by CCK‑8 assay, colony formation and Transwell assay, respectively. Dual luciferase reporter assay was carried out to confirm the putative targets of MNX1‑AS1 and miR‑2113. Tumor formation experiment in nude mice was applied to evaluate the tumor growth effect of MNX1‑AS1 in vivo. The expression of MNX1‑AS1 was significantly upregulated in the prostate cancer tissues and cell lines. MNX1‑AS1 knockdown suppressed the abilities of cell viability and migration and invasion in vitro and inhibited tumor growth in vivo. Additionally, luciferase reporter assay revealed that MNX1‑AS1 could target miR‑2113 and negatively interacted with miR‑2113 in prostate cancer cells. miR‑2113 directly targeted to MDM2 and negatively modulated the expression of MDM2. Rescue assays suggested that the viability, migration and invasion of impaired cells triggered by transfection with sh‑MNX1‑AS1 alone could be recovered by co‑transfection with sh‑MNX1‑AS1 + miR‑2113 inhibitor or sh‑MNX1‑AS1 + pCDH‑ MDM2 vector. The present study demonstrated that MNX1‑AS1 promoted prostate cancer progression through regulating miR‑2113/ MDM2 axis.

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LncRNA PAXIP1-AS1 fosters the pathogenesis of pulmonary arterial hypertension via ETS1/WIPF1/RhoA axis.

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