Dataset Information

TAp63-regulated microRNAs suppress cutaneous squamous cell carcinoma

ABSTRACT: TAp63 is a transcription factor belonging to the p53 family with important tumor suppressive functions. We show that TAp63-/- mice exhibit an increased susceptibility to UVR-induced cutaneous squamous cell carcinoma (cuSCC). These tumors showed global disruption of miRNA and mRNA expression when compared to tumors arising in wild-type mice. A comparison to similarly sequenced human cuSCC tumors identified miR-30c-2* and miR-497 as being significantly underexpressed in cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and xenografts. Proteomic profiling of cells transfected with either miRNA showed significant downregulation of proteins related to cell cycle progression and mitosis. A cross-platform comparison of the RNAseq and proteomics signatures identified 7 downregulated proteins, which are also frequently overexpressed in both mouse and human cuSCC. Knockdown of AURKA, KIF18B, PKMYT1, and ORC1 in cuSCC cell lines suppressed tumor cell proliferation and induced cell death. Additionally, we found that an investigational, oral, selective inhibitor of AURKA suppressed cuSCC cell growth and induced cell death, and showed anti-tumor effects in vivo. Our data establishes TAp63 as an essential regulator of miRNA expression during skin carcinogenesis and reveals a novel network of miRNAs and mRNAs, which include potential targets for therapeutic intervention.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Squamous Cell Of Epidermis, Skin

DISEASE(S): Squamous Cell Carcinoma

SUBMITTER: John Koomen

LAB HEAD: Elsa Flores, PhD

PROVIDER: PXD014261 | Pride | 2020-07-07

REPOSITORIES: Pride

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			Action	DRS
	20170711_Flores-Andrew_TMT6_01.raw	Raw
	20170711_Flores-Andrew_TMT6_01.raw (F007312).mzid_20170711_Flores-Andrew_TMT6_01.raw_(F007312).pride.mgf.gz	Mzid
	20170711_Flores-Andrew_TMT6_01.raw (F007312).pride.mztab.gz	Mztab
	20170711_Flores-Andrew_TMT6_01.rawF007312.mzid.gz	Mzid
	20170711_Flores-Andrew_TMT6_01.rawF007312.mzid_20170711_Flores-Andrew_TMT6_01.raw_F007312.MGF	Mzid

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Publications

TAp63-Regulated miRNAs Suppress Cutaneous Squamous Cell Carcinoma through Inhibition of a Network of Cell-Cycle Genes.

Davis Andrew John AJ Tsinkevich Maksym M Rodencal Jason J Abbas Hussein A HA Su Xiao-Hua XH Gi Young-Jin YJ Fang Bin B Rajapakshe Kimal K Coarfa Cristian C Gunaratne Preethi H PH Koomen John M JM Tsai Kenneth Y KY Flores Elsa R ER

Cancer research 20200310 12

TAp63 is a p53 family member and potent tumor and metastasis suppressor. Here, we show that <i>TAp63<sup>-/-</sup></i> mice exhibit an increased susceptibility to ultraviolet radiation-induced cutaneous squamous cell carcinoma (cuSCC). A human-to-mouse comparison of cuSCC tumors identified miR-30c-2* and miR-497 as underexpressed in TAp63-deficient cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and tumors. Proteomic profiling of cells expressing eith ...[more]

PMID: 32156775

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