2. Academic Validation
  3. Targeting the lncRNA DUXAP8/miR-29a/ PIK3CA Network Restores Doxorubicin Chemosensitivity via PI3K-AKT-mTOR Signaling and Synergizes With Inotuzumab Ozogamicin in Chemotherapy-Resistant B-Cell Acute Lymphoblastic Leukemia

Targeting the lncRNA DUXAP8/miR-29a/ PIK3CA Network Restores Doxorubicin Chemosensitivity via PI3K-AKT-mTOR Signaling and Synergizes With Inotuzumab Ozogamicin in Chemotherapy-Resistant B-Cell Acute Lymphoblastic Leukemia

  • Front Oncol. 2022 Mar 2;12:773601. doi: 10.3389/fonc.2022.773601.
Li Zhang 1 2 3,  Shixia Zhou 4 5,  Tiejun Zhou 6,  Xiaoming Li 4 5,  Junling Tang 4 5
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, China.
  • 2 Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, China.
  • 3 Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
  • 4 Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
  • 5 Stem Cell Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
  • 6 Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
PMID: 35311115 DOI: 10.3389/fonc.2022.773601
Abstract

Purpose: This study aimed to determine the expression profiles of long non-coding RNA (lncRNA), MicroRNA (miRNA), and mRNA in chemotherapy-resistant B-cell acute lymphoblastic leukemia (B-ALL).

Methods: LncRNA, miRNA, and mRNA profiles were assessed by RNA-seq in diagnostic bone marrow samples from 6 chemotherapy-resistant and 6 chemotherapy-sensitive B-ALL patients. The lncRNA DUXAP8/miR-29a/PIK3CA signaling network was identified as the most dysregulated in chemoresistant patient samples, and its effect on cellular phenotypes, PI3K-AKT-mTOR signaling, and chemosensitivity of doxorubicin (Dox)-resistant Nalm-6 (N6/ADR), and Dox-resistant 697 (697/ADR) cells were assessed. Furthermore, its synergy with inotuzumab ozogamicin treatment was investigated.

Results: 1,338 lncRNAs, 75 miRNAs, and 1620 mRNAs were found to be dysregulated in chemotherapy-resistant B-ALL in comparison to chemotherapy-sensitive B-ALL patient samples. Through bioinformatics analyses and RT-qPCR validation, the lncRNA DUXAP8/miR-29a/PIK3CA network and PI3K-AKT-mTOR signaling were identified as significantly associated with B-ALL chemotherapy resistance. In N6/ADR and 697/ADR cells, LncRNA DUXAP8 overexpression and PIK3CA overexpression induced proliferation and inhibited Apoptosis, and their respective knockdowns inhibited proliferation, facilitated Apoptosis, and restored Dox chemosensitivity. MiR-29a was shown to affect the lncRNA DUXAP8/PIK3CA network, and luciferase reporter gene assay showed direct binding between lncRNA DUXAP8 and miR-29a, as well as between miR-29a and PIK3CA. Targeting lncRNA DUXAP8/miR-29a/PIK3CA network synergized with inotuzumab ozogamicin's effect on N6/ADR and 697/ADR cells.

Conclusion: Targeting the lncRNA DUXAP8/miR-29a/PIK3CA network not only induced an apoptotic effect on Dox-resistant B-ALL and restored Dox chemosensitivity via PI3K-AKT-mTOR signaling but also showed synergism with inotuzumab ozogamicin treatment.

Keywords

B-cell acute lymphoblastic leukemia; PI3K-AKT-mTOR signaling; chemotherapy resistance; lncRNA DUXAP8/miR-29a/PIK3CA network; lncRNA expression profile.

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