A central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53.
In a new paper, Benjamin ORY and colleagues from the Leif Ellisen lab at the MGH and Harvard Med School Cancer center identified a new and physiologically important microRNA-related mechanism of p63/p73 cross-talk which governs the balance between pro-survival and pro-apoptotic programs in a common type of skin cancer called squamous cell carcinoma (SCC).
This type of cancer remains one of the most resistant to available chemotherapies. Many cancer therapeutic strategies are directed at restoring the function of the tumor suppressor gene p53, because when active, cells are more sensitive to the DNA damage induced by
chemotherapy. Other proteins related to p53, including p63 and p73 have also been implicated in cancer and cell sensitivity to
chemotherapy. Both p63 and p73 are overexpressed in SCC, and are thought to play a role in chemoresistance.
The researchers identified a subset of microRNA which target p73 for inhibition, including miR-193a-5p, a direct endogenous transcriptional target repressed by p63 and activated by pro-apoptotic p73 isoforms in both normal and tumor cells. Consequently, chemotherapy
treatment causes p63/p73-dependent induction of this miR, thereby limiting chemosensitivity due to miR-mediated feedback control of p73. The Boston researchers demonstrate that interrupting this feedback by inhibiting miR-193a suppresses tumor cell viability and induces dramatic chemosensitivity both in vitro and in vivo. Thus, they have identified a direct, miR-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition provides a new therapeutic opportunity in p53-deficient tumors.
The researchers believe that these findings identify a pro-survival mechanism in SCC, and may highlight new therapeutic targets in the fight against cancer.
Benjamin Ory, Matthew R. Ramsey, Catherine Wilson, Douangsone D. Vadysirisack, Nicole Forster, James W. Rocco, S. Michael Rothenberg and Leif W. Ellisen. A