title: A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma.
abstract: The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated in many human cancers. Therefore, 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. The p53-related transcription factors p63 and p73 exhibit distinct functions—p73 mediates chemosensitivity while p63 promotes proliferation and cell survival—and are both overexpressed in squamous cell carcinomas (SCCs). However, how p63 and p73 interact functionally and govern the balance between prosurvival and proapoptotic programs in SCC remains elusive. Here, we identify a microRNA-dependent mechanism of p63/p73 crosstalk that regulates p53-independent survival of both human and murine SCC. We first discovered that a subset of p63-regulated microRNAs target p73 for inhibition. One of these, miR-193a-5p, expression of which was repressed by p63, was activated by proapoptotic p73 isoforms in both normal cells and tumor cells in vivo. Chemotherapy caused p63/p73-dependent induction of this microRNA, thereby limiting chemosensitivity due to microRNA-mediated feedback inhibition of p73. Importantly, inhibiting miR-193a interrupted this feedback and thereby suppressed tumor cell viability and induced dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, microRNA-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition may provide a new therapeutic opportunity in p53-deficient tumors.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ory
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ramsey
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.forename: Douangsone D
authors.initials: DD
authors.lastname: Vadysirisack
authors.forename: Nicole
authors.initials: N
authors.lastname: Forster
authors.forename: James W
authors.initials: JW
authors.lastname: Rocco
authors.forename: S Michael
authors.initials: SM
authors.lastname: Rothenberg
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins