2. Academic Validation
  3. High throughput screening of nuclear receptors identifies NR4A1 as a novel tumor suppressor in gallbladder cancer

High throughput screening of nuclear receptors identifies NR4A1 as a novel tumor suppressor in gallbladder cancer

  • Int J Biol Macromol. 2026 Jun 11:373:152939. doi: 10.1016/j.ijbiomac.2026.152939.
Sajib Kumar Sarkar 1,  Arnab Nayek 1,  Nihar Ranjan Dash 2,  Prasenjit Das 3,  Deepak Kumar 1,  Om Saswat Sahoo 1,  Anand Nagar 4,  Vinay Kumar Kapoor 5,  Ratnakar Shukla 6,  Ruby Dhar 7,  Subhradip Karmakar 8
Affiliations

Affiliations

  • 1 Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India.
  • 2 Department of GI Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India.
  • 3 Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India.
  • 4 Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Rishikesh, 249203, India.
  • 5 Department of HPB Surgery and Liver transplant, Mahatma Gandhi Medical College and Hospital, Jaipur, 302022, India.
  • 6 Department of Clinical Research, Sharda University, Greater Noida, 201310, India.
  • 7 Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India; Department of Biochemistry, Kasturba Medical College, Manipal, 576104, India. Electronic address: [email protected].
  • 8 Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India. Electronic address: [email protected].
PMID: 42276489 DOI: 10.1016/j.ijbiomac.2026.152939
Abstract

Gallbladder Cancer (GBC) is a major malignancy of the hepato-biliary tract, often detected at advanced, inoperable stages with limited therapeutic options. Nuclear receptors (NRs), a family of ligand-dependent transcription factors, play key roles in Cancer biology and represent promising drug targets. mRNA expression of 48 NRs was profiled in GBC (n = 13) and chronic cholecystitis tissues using the Nanostring nCounter platform, identifying NR4A1 as significantly downregulated. NR4A1 activity was modulated in GBC cell lines using the agonist Cytosporone B (CSNB) or siRNA knockdown, and effects on proliferation, invasion, and cell cycle were assessed by qPCR, flow cytometry, and functional assays. NR4A1 was markedly downregulated in GBC tissues and NOZ cells. CSNB treatment increased NR4A1 expression, reduced migration and invasion, and induced G0/G1 arrest. RNA-seq following CSNB treatment highlighted downregulation of pathways related to cell proliferation. NR4A1 knockdown lead to reduction in epithelial markers and increase in proliferation markers like mki67. NR4A1 loss was also associated with adverse survival outcomes. Our findings highlight NR4A1 as a key tumor suppressor in GBC, whose loss confers proliferative and invasive advantages. Pharmacological activation of NR4A1 effectively counteracts these oncogenic traits, highlighting its potential as a therapeutic target, especially for advanced GBC.

Keywords

Biomarker; Gallbladder cancer; NR4A1; Nanostring nCounter; Nuclear receptor; Tumor suppressor.

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