Scientists identify new targets to restore damage caused by cancer development
Important discovery has potential for new cancer therapy
The Hormel Institute's Drs. Adrian Mansini, Estanislao Peixoto, Suji Jin, Kristen Thelen, and SURE intern researcher Maetzin Cruz-Reyes, along with lab section leader and professor Dr. Sergio Gradilone, published groundbreaking research in the high impact journal Hepatology.
The article, "MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma," was published this week in what is considered the premier publication in the field of liver disease. Hepatology publishes research concerning all aspects of liver structure, function and disease and each month, the distinguished Editorial Board selects only the best articles on subjects such as liver cancer, immunology, chronic hepatitis and related liver diseases.
"This research is critically important because we discovered the mechanisms underlying the ability of tumor cells to eliminate primary cilia," said Dr. Gradilone.
Primary cilia, performing as a cell's antenna, are in almost every cell of the human body. Like an antenna, cilia signal the environment connecting the cell's interior with its surroundings, and work as tumor suppressors. The research team found that tumor cells have a mechanism that destroys the cellular antenna (the cilium). This mechanism includes the regulatory molecules microRNAs, miR-433 and miR-22, resulting in the abnormal over production of a protein that destroys the antenna.
"We are constantly seeking new treatments for cancer and this particular study focused on bile duct cancer," said Dr. Gradilone.
"This cancer has very limited treatment options but by identifying the key mechanisms that tumor cells use to eliminate cilia, we found new targets to induce the restoration of the cellular antenna as a therapeutic approach."
Going forward, The Hormel Institute, University of Minnesota scientific team will expand on this novel approach, referred to as “ciliotherapy," as it may be applicable to other tumors. The loss of primary cilia has now been described in more frequent cancers like breast, pancreatic, kidney, ovarian, and colon, among others.
In collaboration with Mayo Clinic physicians and pharmaceutical companies, The Hormel Institute team is aiming to establish the first clinical trial to test this novel approach.
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The loss of primary cilia by the overexpression of HDAC6 in cholangiocarcinoma (CCA) induces the disengagement between the environment and the cell interior and induces the derepression of tumorigenic pathways like MAPK and Hh. Therefore, we propose that the restoration of primary cilia by targeting HDAC6, miR-22, miR-433, and/or Exportin-5 would be a potential approach to reduce CCA growth.
The downregulation of Exportin-5 in CCA induces the accumulation of the precursor forms of miR-22 and miR-433 in the nucleus. Therefore, the levels of mature miR-22 and miR-433 in the cytoplasm are significantly decreased and the translational repression of target messenger RNAs like Hdac6 is lost, inducing an increase in HDAC6 protein levels.