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

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

  • Oncogenesis. 2020 Mar 12;9(3):34. doi: 10.1038/s41389-020-0217-0.
Xiufen Zheng  # 1 2,  Junying Zhang  # 3,  Tian Fang  # 4,  Xiaoxiao Wang  # 5,  Siwei Wang 1,  Zhifei Ma 1,  Youtao Xu 1,  Chencheng Han 1,  Mengting Sun 6,  Lin Xu 1,  Jie Wang 7 8 9,  Rong Yin 10 11 12
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
  • 2 Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Hainan, 570102, China.
  • 3 Clinical Cancer Research Center, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
  • 4 Department of Comparative Medicine, Jinling Hospital, Clinical School of Medical College of Nanjing University, Nanjing, 210093, China.
  • 5 GCP Research Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of TCM, Nanjing, 210029, China.
  • 6 Department of Tumor Biobank, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
  • 7 Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China. wangjie5204007@hotmail.com.
  • 8 Department of Tumor Biobank, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China. wangjie5204007@hotmail.com.
  • 9 Department of Science & Technology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China. wangjie5204007@hotmail.com.
  • 10 Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China. rong_yin@njmu.edu.cn.
  • 11 Department of Tumor Biobank, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China. rong_yin@njmu.edu.cn.
  • 12 Department of Science & Technology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China. rong_yin@njmu.edu.cn.
  • # Contributed equally.
PMID: 32165621 DOI: 10.1038/s41389-020-0217-0
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.

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