Novel Siglec-15-Sia axis inhibitor leads to colorectal cancer cell death by targeting miR-6715b-3p and oncogenes

Mohammed Saqif Ahmad, Maria Braoudaki, Hershna Patel, Irshad Ahmad, Shagufta Waseem, Shoib Siddiqui

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Abstract

Siglecs are well known immunotherapeutic targets in cancer. Current checkpoint inhibitors have exhibited limited efficacy, prompting a need for novel therapeutics for targets such as Siglec-15. Presently, small molecule inhibitors targeting Siglec-15 are not explored alongside characterised regulatory mechanisms involving microRNAs in CRC progression. Therefore, a small molecule inhibitor to target Siglec-15 was elucidated in vitro and microRNA mediated inhibitor effects were investigated. Our research findings demonstrated that the SHG-8 molecule exerted significant cytotoxicity on cell viability, migration, and colony formation, with an IC 50 value of approximately 20µM. SHG-8 exposure induced late apoptosis in vitro in SW480 CRC cells. Notably, miR-6715b-3p was the most upregulated miRNA in high-throughput sequencing, which was also validated via RT-qPCR. MiR-6715b-3p may regulate PTTG1IP, a potential oncogene which was validated via RT-qPCR and in silico analysis. Additionally, molecular docking studies revealed SHG-8 interactions with the Siglec-15 binding pocket with the binding affinity of -5.4 kcal/mol, highlighting its role as a small molecule inhibitor. Importantly, Siglec-15 and PD-L1 are expressed on mutually exclusive cancer cell populations, suggesting the potential for combination therapies with PD-L1 antagonists.

Original languageEnglish
Article number1254911
Pages (from-to)1-17
Number of pages17
JournalFrontiers in Immunology
Volume14
DOIs
Publication statusPublished - 6 Oct 2023

Keywords

  • Siglec-15
  • colorectal cancer
  • gene expression
  • inhibitor
  • miRNA
  • sialic acid
  • MicroRNAs/genetics
  • Humans
  • Sialic Acid Binding Immunoglobulin-like Lectins/antagonists & inhibitors
  • Apoptosis/genetics
  • Colorectal Neoplasms/drug therapy
  • Cell Proliferation/genetics
  • Molecular Docking Simulation
  • B7-H1 Antigen/genetics
  • Oncogenes

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