2. Academic Validation
  3. The roles and molecular mechanisms of long non-coding RNA WT1-AS in the maintenance and development of gastric cancer stem cells

The roles and molecular mechanisms of long non-coding RNA WT1-AS in the maintenance and development of gastric cancer stem cells

  • Heliyon. 2023 Mar 21;9(4):e14655. doi: 10.1016/j.heliyon.2023.e14655.
Xiaobei Zhang 1,  Meng Jin 1,  Shiqi Liu 1,  Mingde Zang 2,  Lei Hu 3,  Tao Du 4,  Baogui Zhang 1
Affiliations

Affiliations

  • 1 The Affiliated Hospital of Jining Medical University, Jining, 272000, China.
  • 2 Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3 Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, People's Republic of China.
  • 4 Department of Gastrointestinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
PMID: 37025896 DOI: 10.1016/j.heliyon.2023.e14655
Abstract

It has been proposed that Cancer Stem Cells (CSCs) are responsible for almost all malignant phenotypes of tumors. Long non-coding RNA WT1 antisense RNA (WT1-AS) has been found to be implicated in lung Cancer cell stemness. However, the roles and molecular mechanisms of WT1-AS in the development of gastric Cancer Stem Cells (GCSCs) remain unknown. Our present study showed that WT1-AS negatively regulated WT1 expression in GCSCs. WT1-AS knockdown or Wilms' tumor 1 (WT1) overexpression improved GCSC proliferative and migratory capacities, inhibited GCSC Apoptosis, potentiated the resistance of GCSCs to 5-FU, promoted GCSC EMT, induced HUVEC angiogenesis, enhanced GCSC stemness, and facilitated in-vitro 3D GCSC aggregate formation. WT1-AS overexpression exerted reverse effects. WT1-AS ameliorated the malignant phenotypes of GCSCs by down-regulating WT1 in vitro. WT1-AS inhibited tumor growth and metastasis, and reduced tumor stemness in GCSCs-derived (s.c., i.p., and i.v.) xenografts in vivo. Moreover, XBP1 was identified as an upstream regulator of WT1-AS in GCSCs. Also, 4 potential WT1-AS downstream targets (i.e. PSPH, GSTO2, Fyn, and PHGDH) in GCSCs were identified. Additionally, CACNA2D1 was demonstrated to be a downstream target of the WT1-AS/WT axis. XBP1 or CACNA2D1 knockdown exerted an adverse effect on the maintenance of stem cell-like behaviors and characteristics of GCSCs. In conclusion, WT1-AS weakened the stem cell-like behaviors and characteristics of GCSCs in vitro and in vivo by down-regulating WT1. Investigations into the molecular mechanisms underlying the complex phenotypes of GCSCs might contribute to the better management of gastric Cancer.

Keywords

Gastric cancer stem cells; Growth; Metastasis; RNA sequencing; WT1-AS.

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