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A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma
Benjamin Ory, … , S. Michael Rothenberg, Leif W. Ellisen
Benjamin Ory, … , S. Michael Rothenberg, Leif W. Ellisen
Published January 10, 2011
Citation Information: J Clin Invest. 2011;121(2):809-820. https://doi.org/10.1172/JCI43897.
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Research Article Genetics Article has an altmetric score of 1

A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma

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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

Benjamin Ory, Matthew R. Ramsey, Catherine Wilson, Douangsone D. Vadysirisack, Nicole Forster, James W. Rocco, S. Michael Rothenberg, Leif W. Ellisen

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Figure 4

Direct inhibition of p73 by miR-193a is opposed by p63.

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Direct inhibition of p73 by miR-193a is opposed by p63.
(A) Endogenous p...
(A) Endogenous p73 mRNA is inhibited 48 hours following transfection of JHU-029 cells with a miR-193a mimic compared with a scrambled control miR. (B) Endogenous p73 mRNA is derepressed 48 hours following transfection of JHU-029 cells with a miR-193a antagomir (anti-miR) compared with scrambled control (anti-Ct) antagomir. (C) Schematic of the p73 3′ UTR reporter construct showing putative miR-193a seed-binding sequences (WT seed BS) and nucleotide changes introduced in the mutant reporter (mutant seed BS). (D) UTR-dependent regulation of p73 protein requires miR-193a seed-binding sequences. Immunoblots of lysates following cotransfection of a TAp73β cDNA linked to the WT (left 2 panels) or mutant (mut, right panels) 3′ UTR, together with either a miR-193a mimic, a specific antagomir (anti-miR), or respective controls. Bar graphs below show densitometry. Blots are representative of triplicate experiments. (E) Endogenous p73 mRNA is regulated by p63. Retroviral ΔNp63α or vector control were expressed in JHU-029 cells followed by QRT-PCR for ΔNp63 or TAp73. (F) Endogenous p63-mediated regulation of p73 mRNA. Infection of JHU-029 cells with lentiviral p63 shRNA or scrambled control, followed by QRT-PCR for ΔNp63 or TAp73. (G) Regulation of p73 protein by p63. Retroviral ΔNp63α expression as in E was followed by IP/immunoblot (p73) or immunoblot (p63). Right, densitometry analysis for p73. Heavy chain (HC) loading control. (H) Endogenous p63-mediated regulation of p73 protein. Lentiviral p63 knockdown as in F, followed by analysis as in G. Error bars show SEM for triplicate measurements.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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