p73 loss triggers conversion to squamous cell carcinoma reversible upon reconstitution with TAp73alpha.
The expression level of the p53 family member, p73, is frequently deregulated in human epithelial cancers, correlating with tumor invasiveness, therapeutic resistance, and poor patient prognosis. However, the question remains whether p73 contributes directly to the process of malignant conversion or whether aberrant p73 expression represents a later selective event to maintain tumor viability. We explored the role of p73 in malignant conversion in a clonal model of epidermal carcinogenesis. Whether sporadic or small interfering RNA (siRNA) induced, loss of p73 in initiated p53+/+ keratinocytes leads to loss of cellular responsiveness to DNA damage by ionizing radiation (IR) and conversion to squamous cell carcinoma (SCC). Reconstitution of TAp73alpha but not DeltaNp73alpha reduced tumorigenicity in vivo, but did not restore cellular sensitivity to IR, uncoupling p73-mediated DNA damage response from its tumor-suppressive role. These studies provide direct evidence that loss of p73 can contribute to malignant conversion and support a role for TAp73alpha in tumor suppression of SCC. The results support the activation of TAp73alpha as a rational mechanism for cancer therapy in solid tumors of the epithelium.
Johnson
Jodi
J
Department of Dermatology, OHSU Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
Lagowski
James
J
Sundberg
Alexandra
A
Lawson
Sarah
S
Liu
Yuangang
Y
Kulesz-Martin
Molly
M
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D015603:Keratinocytes / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D020033:Protein Isoforms; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins