title: TPL2 Is an Oncogenic Driver in Keratocanthoma and Squamous Cell Carcinoma.
abstract: Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development, as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here, we show that TPL2 overexpression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically, activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK, mTOR, NF-κB, and p38 MAPK leads to TPL2-mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly, TPL2 overexpression is required for iTPL2 TG-driven SCC and KA-like cSCC tumor maintenance, validating TPL2 as a possible drug target for the treatment of SCC/KA. Finally, we verified that TPL2 is overexpressed in human cutaneous metastatic SCC and KA clinical specimens compared with normal skin. Taken together, our results establish TPL2 as an oncogenic driver in SCC/KA development. Cancer Res; 76(22); 6712-22. ©2016 AACR.
authors: Department of Urology, Dermatology, and Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Jun-Han
authors: JH
authors: Lee
authors: Department of Urology, Dermatology, and Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Joo-Hyung
authors: JH
authors: Lee
authors: Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Sang Hyuk
authors: SH
authors: Lee
authors: Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Sung-Im
authors: SI
authors: Do
authors: Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju, Korea.
authors: Sung-Dae
authors: SD
authors: Cho
authors: Department of Medical Microbiology, Lund University, Malmö, Sweden.
authors: Ola
authors: O
authors: Forslund
authors: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors: Kyung-Soo
authors: KS
authors: Inn
authors: Food Industry Research Institute, Department of Bio and Functional Food, College of Medical Science, Jeonju University, Jeonju, Korea.
authors: Jeong-Sang
authors: JS
authors: Lee
authors: Department of Pathology, New York University Langone Medical Center, New York, New York.
authors: Fang-Ming
authors: FM
authors: Deng
authors: Department of Pathology, New York University Langone Medical Center, New York, New York.
authors: Jonathan
authors: J
authors: Melamed
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors: Jae U
authors: JU
authors: Jung
authors: Department of Urology, Dermatology, and Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin. jeongjoseph@snu.ac.kr.
authors: Joseph H
authors: JH
authors: Jeong
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D009857:Oncogenes; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology