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The long non-coding RNA PIK3CD-AS2 promotes lung adenocarcinoma progression via YBX1-mediated suppression of p53 pathway.

ABSTRACT: The underlying mechanisms of long non-coding RNAs (lncRNA) participating in the progression of lung cancers are largely unknown. We found a novel lncRNA, PIK3CD antisense RNA 2 (PIK3CD-AS2), that contributes to lung adenocarcinoma (LUAD) progression. The expression characteristics of PIK3CD-AS2 in LUAD were analyzed using microarray expression profile, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and validated in 92 paired LUAD tissues by chromogenic in situ hybridization. Our data confirmed that PIK3CD-AS2 expression is a crucial regulator of LUAD progression and associated with shorter patient survival. In vitro studies showed that PIK3CD-AS2 increased cell growth and slowed apoptosis in p53wt cells but not in p53null cells. Mechanically, it is demonstrated that PIK3CD-AS2 bound to and maintained the stability of Y-box binding protein 1 (YBX1), a potent destabilizer of p53, by impeding its ubiquitination and degradation. Downexpression of YBX1 reversed PIK3CD-AS2-mediated inhibition of p53 signaling. Additionally, the therapeutic effect evaluation of a locked nuclear acid (LNA) specifically targeting PIK3CD-AS2 showed an anti-tumor activity in mice with A549 cells xenograft and p53 wild-type LUAD patient-derived tumor xenograft (PDTX) model. Clinically, the high expression of PIK3CD-AS2 showed a poor disease-free survival in p53 wild-type patients in TCGA database. Our findings suggest that PIK3CD-AS2 regulates LUAD progression and elucidate a new PIK3CD-AS2/YBX1/p53 signaling axis, providing a potential lncRNA-directed therapeutic strategy especially in p53 wild-type LUAD patients.

SUBMITTER: Zheng X

PROVIDER: S-EPMC7067885 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The long non-coding RNA PIK3CD-AS2 promotes lung adenocarcinoma progression via YBX1-mediated suppression of p53 pathway.

Zheng Xiufen X Zhang Junying J Fang Tian T Wang Xiaoxiao X Wang Siwei S Ma Zhifei Z Xu Youtao Y Han Chencheng C Sun Mengting M Xu Lin L Wang Jie J Yin Rong R

Oncogenesis 20200312 3

The underlying mechanisms of long non-coding RNAs (lncRNA) participating in the progression of lung cancers are largely unknown. We found a novel lncRNA, PIK3CD antisense RNA 2 (PIK3CD-AS2), that contributes to lung adenocarcinoma (LUAD) progression. The expression characteristics of PIK3CD-AS2 in LUAD were analyzed using microarray expression profile, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and validated in 92 paired LUAD tissues by chromogenic in situ hybridi ...[more]

PMID: 32165621

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Project description:Prostate cancer (PCa) is one of the principal causes of cancer‑related death worldwide. The roles and mechanisms of long non‑coding RNA (lncRNA) involved in the development of PCa remain incompletely understood. The present study aimed to investigate the role and mechanism of lncRNA in PCa tumorigenesis. In the present study, lncRNA cancer susceptibility candidate 11 (CASC11) was revealed to be a crucial regulator of PCa progression. The expression profiles of CASC11 in PCa were identified through analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets, and validated in human PCa specimens and cell lines. Gain‑ and loss‑of‑function assays were utilized to explore the biological role of CASC11 in PCa initiation and progression. RNA‑sequencing, RNA pull‑down and RNA immunoprecipitation analyses were used to explore potential mechanisms with which CASC11 may be associated. Rescue experiments were further conducted to confirm this association. The present results revealed that CASC11 was dominantly distributed in the nuclei of PCa cells, and was highly expressed in PCa tissues and cells. Overexpression of CASC11 was markedly associated with increased tumor proliferation and migratory ability. Functionally, decreased proliferation and migration, as well as inhibited xenograft tumor growth, were observed in CASC11‑silenced PCa cells, whereas the opposite effects were detected in CASC11‑overexpressing cells. Mechanistically, CASC11 promoted progression of the cell cycle and competitively interacted with Y‑box binding protein 1 (YBX1) to block the p53 pathway. Given this, poly (β‑amino ester) (PBAE)/small interfering RNA‑CASC11 (si‑CASC11) nanoparticles were applied to inhibit CASC11 expression and enhance the antitumor effect in vivo. The results revealed that PBAE/si‑CASC11 nanoparticles augmented the antitumor efficacy of CASC11 knockdown in vivo. In conclusion, the present study suggested that CASC11 may regulate PCa progression and elucidated a novel CASC11/YBX1/p53 signaling axis, providing a potential lncRNA‑directed therapeutic strategy particularly for the treatment of patients with PCa.

Dataset Information

The long non-coding RNA PIK3CD-AS2 promotes lung adenocarcinoma progression via YBX1-mediated suppression of p53 pathway.

Publications

The long non-coding RNA PIK3CD-AS2 promotes lung adenocarcinoma progression via YBX1-mediated suppression of p53 pathway.

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