2. Academic Validation
  3. Engineering redirected NF-κB/OIP5 expression programs to enhance tumor responses to chemotherapy in bladder cancer

Engineering redirected NF-κB/OIP5 expression programs to enhance tumor responses to chemotherapy in bladder cancer

  • Sci Bull (Beijing). 2023 Dec 30;68(24):3207-3224. doi: 10.1016/j.scib.2023.11.027.
Binbin Zheng 1,  Liman Niu 1,  Haibo Xu 1,  Yubin Yang 2,  Yanping Chen 2,  Chenguang Wang 3,  Wei Chen 4,  Weiren Huang 5
Affiliations

Affiliations

  • 1 Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, International Cancer Center of Shenzhen University, Shenzhen 518039, China; Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 2 Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, International Cancer Center of Shenzhen University, Shenzhen 518039, China.
  • 3 Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 4 Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, International Cancer Center of Shenzhen University, Shenzhen 518039, China; Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen 518035, China.
  • 5 Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, International Cancer Center of Shenzhen University, Shenzhen 518039, China; Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen 518035, China. Electronic address: [email protected].
PMID: 37993335 DOI: 10.1016/j.scib.2023.11.027
Abstract

Nuclear factor kappa-B (NF-κB), a pivotal transcriptional regulator, plays a crucial role in modulating downstream genes implicated in tumor drug resistance. We establish a programmable system within bladder Cancer cells to tailor drug responses by employing a synthetic clustered regularly interspaced short palindromic repeats (CRISPR)-based expression strategy that emulates natural transcriptional regulators. Our investigation uncovers the functional significance of Opa-interacting protein 5 (OIP5), upregulated upon NF-κB activation, as a key regulator governing drug-resistance to vincristine (VCR) treatment in bladder Cancer. Through engineered guide RNAs (sgRNAs) targeting OIP5 to integrate NF-κB Aptamers, we construct a modular scaffold RNA that encodes both the target locus and regulatory functionality. This engineered CRISPR scaffold RNA effectively responds to VCR stimulus by binding with activated NF-κB. Intriguingly, it redirects NF-κB to attenuate OIP5 expression-a reversal of its original role-while concurrently obstructing multiple NF-κB-mediated drug resistance pathways. This dual action thwarts drug resistance development. Further enhancing therapeutic potential, we develop a versatile nanoparticle system capable of co-delivering CRISPR scaffold RNAs and VCR. This synergistic approach demonstrates potent anti-tumor effects in both in vitro and in vivo settings. Our nanoparticle-mediated combination presents a compelling proof-of-concept, showcasing the utility of engineered CRISPR-based synthetic expression programs to reconfigure cellular drug responses and heighten tumor cell susceptibility to chemotherapy.

Keywords

Drug resistance; Gene circuit; NF-κB; OIP5; RNA engineering; Vincristine.

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